Clinical trial NCT03478982
Conditions: Epilepsy
Sponsor: Engage Therapeutics, Inc.
Start date: 2018-03-16; Completion date: 2020-01-04
Enrollment: 156 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, double-blind, randomized, parallel group, dose-ranging study to investigate the efficacy and clinical usability of STAP-001 in adult (18 years of age and older) subjects with epilepsy with a predictable seizure pattern. These subjects have an established diagnosis of focal or generalized epilepsy with a documented history of predictable seizure episodes. This is an in-patient study. The subjects will be admitted to a Clinical Research Unit (CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the in-patient unit will be 2-8 days. One seizure event per subject will be treated with study medication. The duration and timing of the seizure event and occurrence of subsequent seizures will be assessed by the Staff Caregiver(s)1 through clinical observation and confirmed with video electroencephalogram (EEG).

Detailed description:

Arms: arm 1: single dose for inhalation arm 2: single dose for inhalation arm 3: single dose for inhalation
Interventions: intervention 1: Staccato Alprazolam intervention 2: Placebos
Intervention descriptions: intervention 1: single dose for inhalation intervention 2: single dose for inhalation

Protocol documents:
Prot_000.pdf: 
20172999 
Staccato Alprazolam (STAP-001) 
Protocol ENGAGE-E-001 
01 FIRebBruAaprypr2o0v1e9d at the 
Engage TherapPeruottioccs,oIlnLce. vel 
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CONFIDENTIAL 
This document is a confidential communication of Engage Therapeutics, Inc. (Engage). The recipient 
agrees that no information contained herein will be published or disclosed without prior written 
approval of Engage, except that this document may be disclosed to appropriate institutional review 
boards or duly authorized representatives of the US Food and Drug Administration (FDA) under the 
condition that they are asked to maintain confidentiality. 
Oct 08, 2018 
A Double-Blind, Placebo-Controlled, Inpatient, Dose-Ranging Efficacy Study of 
Staccato Alprazolam (STAP-001) in Subjects with Epilepsy with a Predictable 
Seizure Pattern 
 
 
INVESTIGATIONAL PRODUCT: 
Staccato Alprazolam (STAP-001) 
PROTOCOL NUMBER: 
ENGAGE-E-001 
PROTOCOL VERSION: 
7.0 
PROTOCOL DATE: 
01 February 2019 
EudraCT NUMBER: 
Not Applicable 
IND NUMBER: 
132,755 
 
 
SPONSOR NAME / ADDRESS: 
Engage Therapeutics, Inc. 
31 Lenox Road 
Summit, NJ 07901 
 
 
 
 


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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
 
 
Medical Monitor Contact Information 
Name 
 
Title 
Medical Monitor 
Address 
 
Phone 
 
Email 
 
 
 
Emergency Contact Information 
site specific phone tree to be provided 


 
 


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Protocol Number: ENGAGE-E-001 
Version: 7.0 
 
 
Signature of Site Principal Investigator 
dd mmm yyyy 
Printed Name of Site Principal Investigator 
Institution Name: 
 
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Investigational Review Board procedures, instructions from Engage representatives, the 
Declaration of Helsinki, International Conference on Harmonization Good Clinical 
Practices Guidelines, and local regulations governing the conduct of clinical studies. 


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1. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Engage Therapeutics, Inc. 
Name of Investigational Product: 
Staccato Alprazolam (STAP-001) 
Name of Active Ingredient: 
alprazolam (8-Chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine) 
Title of Study: 
A Double-Blind, Placebo-Controlled, Inpatient, Dose-Ranging Efficacy Study of Staccato 
Alprazolam (STAP-001) in Subjects with Epilepsy with a Predictable Seizure Pattern 
Study center(s): Approximately 50 Study Sites with access to Clinical Research Unit (CRU) or 
Epilepsy Monitoring Unit (EMU) in the US, Canada, Australia and Jamaica 
Studied period (years): 
Estimated date first subject screened: March 2018 
Estimated date last subject completed: August 2019 
Phase of development: 2b 
Objectives: 
The primary objectives are: 
• 
To assess the efficacy of STAP-001 in treating a seizure episode 
• 
To assess the clinical feasibility and safety of the inhalation of STAP-001 in subjects during a 
seizure episode 
• 
To assess the sedation associated with administration of STAP-001 
Methodology: 
This is a multi-center, double-blind, randomized, parallel group, dose-ranging study to investigate the 
efficacy and clinical usability of STAP-001 in adult (18 years of age and older) subjects with epilepsy 
with a predictable seizure pattern. These subjects have an established diagnosis of focal or 
generalized epilepsy with a documented history of predictable seizure episodes as outlined in 
inclusion criterion #3. This is an in-patient study. The subjects will be admitted to a Clinical Research 
Unit (CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in 
the in-patient unit will be 2-8 days. One seizure event per subject will be treated with study 
medication. A treatable seizure event includes a predictable seizure episode, such that a change in the 
persistence of the seizure episode can be detected. The duration and timing of the seizure event and 
occurrence of subsequent seizures will be assessed by the Staff Caregiver(s)1 through clinical 
observation and confirmed with video electroencephalogram (EEG). 
 
 
1 Staff member(s) assigned and trained to observe the subject throughout the entire Treatment Phase and facilitate 
the study drug administration as appropriate. Staff Caregivers will be accountable for the study medication and each 
handoff will be recorded. 


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The study consists of two parts: Part 1 Open-Label Feasibility; Part 2 - Double-Blind. Each part is 
divided into four phases: Screening; Qualification prior to entering the in-patient unit; Treatment in 
the in-patient unit; and Post-Treatment Safety Follow-Up. Subjects will provide appropriately- 
obtained informed consent or will have a legally authorized representative (LAR) sign the informed 
consent on his or her behalf prior to completing any study-related procedures. 
The Screening Visit will involve the items identified in the Schedule of Events, including Informed 
Consent and distribution of the seizure diary. As part of the screening process the seizure events of 
the subjects must be confirmed as acceptable for continuation in the study by the Epilepsy Study 
Consortium Review Board.  Eligible subjects will enter a Qualification phase during which the 
subject must have at least 4 or more predictable seizure episodes in a 28-day Qualification Period 
with no more than one week without a predictable episode. The Qualification Period may be extended 
beyond 28 days up to 56 total days to provide flexibility for scheduling of the Qualification Visit and 
Treatment Visit. The 28 days of the seizure diary activity immediately prior to the Qualification Visit 
will be assessed for qualification. At the end of the Qualification Period the Medical Monitor will 
review the seizure diary to confirm acceptable seizure frequency and subject’s advancement into the 
Treatment Phase. Subjects meeting the qualification criteria will enter the CRU/EMU within 7 days 
from the end of the Qualification Period. 
Part 1 Open-Label Feasibility 
The first subjects enrolled in the study will participate in an open-label feasibility evaluation. 
Enrollment in this phase will end when there are data from at least eight individual subjects with a 
treated single seizure episode in a CRU/EMU. The subjects will be enrolled in 3-8 sites, up to three 
subjects per site. Eligible and qualified subjects will receive a single dose of 1 mg STAP-001 at the 
onset of their predictable seizure episode. The subjects will undergo all study procedures and 
evaluations as outlined in this protocol. The feasibility data (with special emphasis on the drug 
administration and clinical assessment procedures) from these eight subjects will be analyzed and 
reviewed by the Sponsor and study team before starting the double-blind part of the study. If deemed 
necessary based on the feasibility data, the study protocol will be amended (for example, to change the 
drug administration procedure or to redefine the time frame for primary endpoint assessment), before 
starting the double-blind part of the study. 
Part 2: Double-Blind 
After admission to the in-patient unit, eligible and qualified subjects will be randomly assigned (1:1:1) 
to one of two doses of STAP-001 (1 mg or 2 mg) or Staccato placebo. Randomization will be stratified 
by the use of inducing vs non-inducing AEDs and for use of chronic daily benzodiazepines (yes or no). 
For each subject, a single seizure episode will be treated and assessed. Study medication will be self- 
administered (when feasible) or administered by a Staff Caregiver when a predictable seizure episode 
starts. Assessment of the seizure activity is based on clinical observation by the Staff Caregiver using 
a stopwatch. In addition, a video EEG will record the occurrence, start time, and duration of the seizure 
event. Pharmacokinetic (PK) samples will be collected 10, 30 and 60 minutes, and 2 and 6 hours after 
the administration of the study drug. If possible, subjects will signal when they experience a seizure 
event.  Subject  will  be  under  video  EEG surveillance  throughout  the Treatment  Phase. The  Staff 
Caregiver will signal the event for the video EEG recording, start the stop watch at the time of drug 


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administration, and mark the occurrence of the seizure event on a seizure diary. If the seizure episode 
does not stop within 5 minutes of the study drug administration, rescue medication other than 
alprazolam may be administered at the discretion of the principal investigator per the protocol of the 
research unit. The study exit procedures will be conducted 24 to 32 hours after the administration of 
study medication or when the subject discontinues from the study. 
After discharge from the in-patient unit there will be a safety-follow-up phone contact 14 days (±2 
days) after the subject received the study medication. 
Number of subjects (planned): 
Assuming a 10% drop-out/protocol violation rate, approximately 115 subjects will be randomized in 
the double-blind part of the study to provide approximately 35 evaluable subjects per treatment arm. 
Approximately 30% of the overall study population randomized in the study may be subjects being 
treated with chronic daily benzodiazepines as part of their epilepsy management. Approximately 9 
subjects will be enrolled in the open-label feasibility part to provide 8 evaluable subjects. 
Approximately 50 trial sites will be recruited to conduct the study. The data base will be locked after 
the last subject included in the double-blind treatment period completes the study. 
Diagnosis and main criteria for inclusion: 
Subjects eligible for enrollment in the study must meet all of the following inclusion criteria and none 
of the exclusion criteria: 
Inclusion Criteria: 
1. Subject is able to provide, personally signed, and dated informed consent to participate in the 
study or will have a legally authorized representative (LAR) sign the informed consent on his or 
her behalf before completing any study related procedures. 
2. Male or female ≥ 18 years of age. 
3. Has an established diagnosis of focal or generalized epilepsy or focal and generalized epilepsy 
with a documented history of predictable seizure episodes that includes at least one of the 
following: 
• 
Generalized seizure episodes starting with a flurry of absence seizures or myoclonic seizures 
with a minimum duration of 5 minutes 
• 
Episodes of a prolonged focal seizure with a minimum duration of 3 minutes 
• 
Episodes of multiple (≥2) seizures within a 2-hour time period 
4. Prior to randomization, has experienced ≥4 seizure episodes with predictable pattern during the 
last 4 weeks (qualification period) and no more than one week without a predictable seizure 
episode before entry into the in-patient unit. 
5. Female participants (if of child-bearing potential and sexually active) and male participants (if 
sexually active with a partner of child-bearing potential) who agree to use a medically acceptable 
and effective birth control method throughout the study and for 1 week following the end of the 
study. Medically acceptable methods of contraception that may be used by the participant and/or 
his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide, 


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intrauterine device (IUD), surgical sterilization, and progestin implant or injection. Prohibited 
methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone. 
6. Subject is able to comply by the requirements of the protocol, particularly the requirements and 
specific Institution policies during the in-patient stay. 
Exclusion Criteria: 
1. History or diagnosis of non-epileptic seizures (e.g. metabolic or pseudo-seizures). 
2. History of status epilepticus in the 6 months prior to Screening 
3. Has a progressive neurological disorder such as brain tumor, demyelinating disease, or 
degenerative central nervous system (CNS) disease that is likely to progress in the next 3 months 
4. Use of strong CYP 3A4 inhibitors; including azole antifungal agents (e.g., etoconazole, 
itraconazole), nefazodone, fluvoxamine, cimetidine, HIV protease inhibitors (e.g., ritonavir) 
5. Has severe chronic cardio-respiratory disease 
6. History of HIV-positivity. 
7. Pregnant or breast-feeding. 
8. Clinically significant renal or hepatic insufficiency (hepatic transaminases >2 times the upper 
limit of normal (ULN) or creatinine ≥ 1.5 x ULN). 
9. History of acute narrow angle glaucoma, Parkinson's disease, hydrocephalus, or history of 
significant head trauma. 
10. Subjects who use medications to treat airways disease, such as asthma or COPD or have any 
acute respiratory signs/symptoms (e.g., wheezing). 
11. Use of any investigational drug within 30 days or 5 half-lives of the investigational drug prior to 
administration of study medication, whichever is longer 
12. A history within the past 1 year of drug or alcohol dependence or abuse. 
13. Positive urine screen for drugs of abuse at Screening (positive Cannabis/Cannabinol results are 
acceptable if there is a documented history of stable use for medical purposes). 
14. Known allergy or hypersensitivity to alprazolam. 
15. History of glaucoma. 
16. Subjects who currently have an active major psychiatric disorder where changes in 
pharmacotherapy are needed or anticipated during the study. 
17. Hypotension (systolic blood pressure ≤90 mm Hg, diastolic blood pressure ≤50 mm Hg), or 
hypertension (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥100 mm Hg) 
measured while seated at screening or baseline. 
18.  Significant hepatic, renal, gastroenterologic, cardiovascular (including ischemic heart disease and 
congestive heart failure), endocrine, neurologic or hematologic disease. 


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19. Subjects who, in the opinion of the Investigator, should not participate in the study for any reason, 
including if there is a question about the stability or capability of the subject to comply with the 
trial requirements. 
 
 
Investigational product, dosage and mode of administration: 
STAP-001 is a hand-held, single-dose, single-use drug-device combination product using the Staccato 
delivery system. Oral inhalation through the product initiates the controlled rapid heating of a thin 
film of excipient-free alprazolam to form a thermally generated, highly pure drug vapor. The vapor 
condenses into aerosol particles with a particle size distribution appropriate for efficient delivery to 
the deep lung. The rapid absorption of the drug provides peak plasma levels in the systemic 
circulation within minutes after administration. 
Each product is packaged inside a sealed foil pouch. Removal of a pull-tab from the product renders it 
ready for use, as indicated by illumination of a green light. Successful dosing is signaled by the 
extinguishing of the green light. 
Reference therapy, dosage and mode of administration: 
Matching Staccato Placebo (exactly same inhalation device without coated alprazolam film) 
Duration of treatment: 
Subjects will receive a single dose of study medication. 
Duration of study participation: 
Subjects will participate in the study for up to 12 weeks, including Screening and Follow-Up. The 
Screening/Qualification Phase will last no more than 63 days. After that the subjects will participate 
in the Treatment Phase in the in-patient unit for approximately 2-8 days. Finally, there’s a safety 
follow-up phone contact 14 days (±2 days) after the subject received the study treatment. 
Criteria for evaluation: 
Efficacy: 
The following will be assessed for every seizure episode and the 12-hour period following study 
medication administration: 
Primary endpoint: 
Proportion of responders in each treatment group achieving seizure activity cessation within 2 
minutes after the administration of the study drug and no recurrence of seizure activity within 2 
hours. 
Secondary endpoints: 
Seizure episode severity assessed by subject and/or Staff Caregiver 
Use of rescue medication 
Secondary generalization (evolution to a complex partial seizure and/or a generalized tonic-clonic 
seizure) 
Exploratory endpoints: 
Number of seizures during the 4, 6, and 12 hour time periods after study drug administration 
Time to next seizure event with start time >2 minutes after study drug administration 


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Pharmacokinetics: 
Blood samples will be collected for plasma alprazolam concentration measurement pre-dose and at 
10, 30, and 60 minutes, and 2 and 6 hours after the dosing of the study drug. 
Safety: 
Safety and tolerability of STAP-001 will be assessed by evaluating adverse events, vital signs, clinical 
laboratory and physical exams. 
Sedation will also be assessed using a patient VAS. 
Statistical methods: 
Sample Size: 
There are no studies in the literature to provide reliable estimates of active treatment or placebo 
response rates. A total of 115 subjects will be enrolled in the double-blind part of the study to provide 
approximately 35 evaluable subjects per treatment arm [105 patients with approximately 30% of the 
overall study population randomized in the study being subjects with chronic daily benzodiazepines 
as part of their epilepsy management]. Power calculations assume a 2-sided test and significance level 
of 0.05 with 90% power and are based on the assumption that the proportion of responders with 
STAP-001 is 57% (best active) whereas the assumed placebo responder rate is 20%. 
Efficacy Analyses: 
The efficacy population will include all subjects who have a seizure event and receive study drug 
during the double-blind Treatment Period. Data will be summarized by active treatment by dose level 
versus placebo-treated subjects (i.e., by treatment group). Continuous measures will be summarized 
descriptively (mean, standard deviation, median, minimum value, and maximum value) and 
categorical measures will be presented as number and percentage. 
All statistical tests will be 2-sided with a significance value of 0.05. There will be no adjustments for 
multiple comparisons. 
The primary efficacy analysis will be conducted following completion of the double-blind Treatment 
Period for the last subject. Additional details for statistical methods will be provided in the Statistical 
Analysis Plan. 
Pharmacokinetic Analyses: 
The PK population will include all patients who receive study drug and have at least one 
pharmacokinetic sample drawn and analyzed. Plasma concentrations will be summarized by 
descriptive statistics as appropriate and will be listed by patient. 
Safety Analyses: 
The safety population will include all subjects who receive study drug in the Treatment phase from 
both Part 1 and Part 2. Adverse events will be coded by system organ class (SOC) and preferred term 
with the Medical Dictionary for Regulatory Activities (MedDRA). Concomitant medications will be 
summarized by World Health Organization Drug Dictionary Anatomical-Therapeutic-Chemical 
(WHODrug-ATC) classification and preferred term. Adverse events (AEs), vital sign measurements, 
physical examination findings, electrocardiogram, clinical laboratory information, and concomitant 
medications will be tabulated and summarized by treatment and dose level. Separate tabulations will 
be produced for all treatment emergent AEs (TEAEs), TEAEs (by relationship to study drug), serious 
AEs (SAEs), discontinuations due to AEs or TEAEs, and AEs ≥ Grade 3 severity. By-subject listings 
will be provided for any deaths, SAEs, and AEs leading to discontinuation of treatment. 


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Schedule of Events 
 
Qualification Phase 
Treatment 
Phase 
Exit 
Proceduresa 
Follow-up 
Phone Call 
Screen 
Visit 
Qualification 
Periodb 
Qualification 
Visit 
Procedures 
Day -35 
(May extend 
to Day -63) 
Day –35 to 
Day –8 
(May extend to 
Day -63) 
Day -7 to 
Day -1 
Day 1 up to Day 8 
14 ±2 days from 
Study Drug 
Administration 
Informed consent 
X 
Review of inclusion/exclusion criteria 
X 
X 
Xc 
Medical history 
X 
Xc 
Physical examination 
X 
Xc 
X 
Neurological examination 
X 
Xc 
X 
Temperature (oral) 
X 
Xc 
Height 
X 
Weight 
X 
Xc 
Respiratory rate and heart rate 
X 
X 
X 
Blood pressure 
X 
X 
X 
O2 saturation by pulse oximetry (SpO2) 
Xde 
Seizure Episode Severity Rating Scale 
Xf 
Sedation VAS 
Xg 
Dispense and begin Seizure Diary 
X 
Xh 
Seizure Diary Completion 
X 
X 
Seizure Diary Collection and Review 
X 
X 
12-Lead ECG 
X 
Xc 
X 
Chemistry, hematology and urinalysis 
X 
Xc 
X 
 
 
 
 
a 24 to 32 hours after the treatment administration for patients who received dosing; and at the time of exit for those who didn’t seize. 
b During the Qualification Period the subject will record their seizure activity on the seizure diary. The Qualification Period may be 
extended beyond 28 days up to 56 total days to provide flexibility for scheduling of the Qualification Visit and Treatment Visit. The 
28 days of the seizure diary activity immediately prior to the Qualification Visit will be assessed for qualification. 
c At Entry to CRU/EMU 
d At timepoint 0 (+2 min), and 10 (±2 min), 30(±2 min) and 60 (±5 min) minutes, 2 (±5 min) and 6 (±5 min) hours after the dosing of 
the study drug. 
e Attached at Entry into CRU/EMU 
f At timepoint 6 (±5 min) hours after the dosing of the study drug. 
g When multiple procedures are scheduled at the same time point, the VAS assessment should be performed first, immediately 
followed by the PK draw. Collected at timepoints 10 (±2 min), 30 (±2 min) and 60 (±5 min) minutes, 2 (±5 min) and 6 (±5 min) hours 
after the dosing of the study drug. 
h Staff Caregiver completes the seizure diary during the Treatment Phase 


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Qualification Phase 
Treatment 
Phase 
Exit 
Proceduresa 
Follow-up 
Phone Call 
Screen 
Visit 
Qualification 
Periodb 
Qualification 
Visit 
Procedures 
Day -35 
(May extend 
to Day -63) 
Day –35 to 
Day –8 
(May extend to 
Day -63) 
Day -7 to 
Day -1 
Day 1 up to Day 8 
14 ±2 days from 
Study Drug 
Administration 
Urine drug screeni 
X 
Xc 
Urine Pregnancy test (if applicable) 
X 
Xc 
PK Sample collection 
Xj 
Device training 
X 
Xc 
EEG Recording 
Xek 
Study drug administrationl 
X 
Adverse event assessmentm 
X 
X 
X 
X 
X 
X 
Subject seizure events forms sent to 
Epilepsy Study Consortium Review 
Board 
Xn 
Completed seizure diary sent to 
Medical Monitor for review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
i Drug Screen needs to be negative to allow entry into the CRU/EMU and dosing of the study drug. 
j PK sample will be collected at pre-dose (at time of admission to unit) and then at 10 (±2 min), 30 (±2 min) and 60 minutes (±5 min), 
2 hours (±5 min) and 6 hours (±5 min) after the dosing of the study drug. If the PK sample is drawn outside of the timeframe, the 
sample will still be collected and evaluated. 
k Video EEG Recording will be throughout the subject’s stay at the CRU/EMU 
l At the onset of the predictable seizure 
m Adverse Events will be collected throughout the study after Informed Consent is signed and through Follow-Up 
n Forms completed and sent to review board within 48 hours after the subject or subject’s LAR signs informed consent at the 
Screening Visit. 


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Schedule of Events – Procedures in CRU/EMU 
 
Entry to 
CRU/ EMU 
Treatment Day: 
Schedule for day of Seizure Episode only 
Time 0 10 min 30 min 
1h 
2 h 
6 h 
24ha/ Exit Procedures 
Medication history 
X 
Review of eligibility criteria 
X 
Physical Examination 
X 
X 
Neurological Examination 
X 
X 
Urine pregnancy test (if applicable) 
X 
12-Lead ECG 
X 
X 
Chemistry, hematology and urinalysis 
X 
X 
Urine drug screen 
X 
Weight 
X 
Temperature (oral) 
X 
Vital Signs (BP, HR, RR) 
X 
Xe 
Xe 
Xf 
Xf 
Xf 
X 
Attach EEG electrodes 
X 
Device training 
X 
EEG Recording 
X  
 
X 
Study Med administration 
Xbcd 
Start Stopwatchd 
X ----------------------------------------------------------------------- X 
Insert Indwelling Catheter for PK samples 
X 
PK Sampling 
X 
Xe 
Xe 
Xf 
Xf 
Xf 
Sedation VASg 
Xe 
Xe 
Xf 
Xf 
Xf 
Pulse Oximetry (SpO2)h 
Xe 
Xe 
Xe 
Xf 
Xf 
Xf 
Adverse Event Assessmenti 
X ----------------------------------------------------------------------- X 
Seizure Diary 
X  
X 
Seizure Episode Severity Rating Scale 
Xf 
 
 
 
 
a Patient can be discharged after 24 to 32 hr assessments at the discretion of the study staff 
b Time 0 is defined as the start of inhalation 
c Subjects should have minimal postural changes for the first 1.5 hours after administration of study drug 
d at seizure episode onset 
e ± 2 minutes 
f ± 5 minutes 
g When multiple procedures are scheduled at the same time point, the VAS assessment should be performed first, immediately 
followed by the PK draw. 
h Attached at Entry into CRU/EMU 
i Post treatment 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
 
TABLE OF CONTENTS 
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION ............................... 2 
ENGAGE SIGNATURE PAGE ...................................................................................................3 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE ....................................................4 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................19 
4. 
INTRODUCTION AND RATIONALE .....................................................................21 
4.1. 
Background Information .............................................................................................21 
4.2. 
Study Drug Description ..............................................................................................22 
4.3. 
Preclinical Information for Staccato Alprazolam .......................................................23 
4.4. 
Clinical Information for Staccato Alprazolam ...........................................................23 
5. 
ETHICS ......................................................................................................................26 
5.1. 
Institutional Review Board (IRB) ...............................................................................26 
5.2. 
Written Informed Consent ..........................................................................................26 
6. 
STUDY OBJECTIVES ..............................................................................................28 
7. 
OVERALL STUDY DESIGN ....................................................................................29 
7.1. 
Number of Subjects and Sites .....................................................................................30 
7.2. 
Method of Treatment Assignment and Blinding (Double Blind Phase) .....................31 
7.3. 
Rationale for Study Design .........................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 33 
8.1. 
Subject Inclusion Criteria ...........................................................................................33 
8.2. 
Subject Exclusion Criteria ..........................................................................................33 
8.3. 
Subject Withdrawal Criteria .......................................................................................34 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................35 
9. 
STUDY SCHEDULE AND PROCEDURES ............................................................36 
9.1. 
Part 1: Open Label Feasibility ....................................................................................36 
9.2. 
Part 2: Double-Blind ...................................................................................................37 
10. 
DESCRIPTION OF STUDY TREATMENTS .......................................................... 40 
10.1. 
Description of Treatments ..........................................................................................40 


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10.2. 
Study Drug Materials and Management .....................................................................40 
10.3. 
Concomitant Medications and Procedures .................................................................41 
11. 
STUDY ASSESSMENTS DESCRIPTIONS .............................................................43 
11.1. 
Demographic Characteristics and Medical History ....................................................43 
11.2. 
Vital Signs, Weight, and Height .................................................................................43 
11.3. 
Physical and Neurological Examination .....................................................................43 
11.4. 
12-Lead Electrocardiogram ........................................................................................43 
11.5. 
Seizure Assessment ....................................................................................................44 
11.6. 
Pharmacokinetic Sampling .........................................................................................44 
11.7. 
Sedation Assessment - Visual Analog Scale (VAS) ...................................................44 
11.8. 
Clinical Laboratory Assessments ...............................................................................45 
12. 
ADVERSE EVENTS ..................................................................................................47 
13. 
STATISTICAL METHODS .......................................................................................53 
13.1. 
Sample Size Rationale ................................................................................................53 
13.2. 
Endpoints ....................................................................................................................53 
13.3. 
Analysis Populations ..................................................................................................54 
13.4. 
Analyses ......................................................................................................................54 
14. 
REGULATORY CONSIDERATIONS ......................................................................58 
14.1. 
Good Clinical Practice ................................................................................................58 
14.2. 
Sponsor’s Responsibilities ..........................................................................................58 
14.3. 
Investigator’s Responsibilities ....................................................................................59 
14.4. 
Protocol Amendments ................................................................................................60 
14.5. 
Audits and Inspections ................................................................................................60 
14.6. 
Quality Control and Quality Assurance ......................................................................61 
15. 
DATA HANDLING AND RECORDKEEPING .......................................................62 
15.1. 
Confidentiality ............................................................................................................62 
15.2. 
Subject Data Protection ..............................................................................................62 
15.3. 
Data Collection ...........................................................................................................62 
15.4. 
Case Report Form Completion ...................................................................................63 
15.5. 
Database Management, Data Clarification, and Quality Assurance ...........................63 
15.6. 
Inspection of Records .................................................................................................63 
15.7. 
Retention of Records ..................................................................................................64 
16. 
PUBLICATION POLICY ..........................................................................................65 
17. 
REFERENCES ...........................................................................................................66 


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Appendix 1A: Schedule of Events .................................................................................................67 
Appendix 1B: Schedule of Events – Procedures in CRU/EMU ....................................................69 
Appendix 2: Visual Analog Scale (VAS) for Sedation Assessment ..............................................70 
Appendix 3: Seizure Episode Severity Scale .................................................................................71 
Appendix 4: Alprazolam (XANAX®) Prescribing Information ...................................................72 


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LIST OF TABLES 
Table 1: 
Investigational Product ...............................................................................................40 
Table 2: 
Clinical Laboratory Assessments ...............................................................................46 


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LIST OF FIGURES 
Figure 1. Schematic Side-View of Staccato Alprazolam ...............................................................23 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
 
 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
AED 
Antiepileptic drug 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression of Improvement 
CRU 
Clinical Research Unit 
CTCAE 
Common terminology criteria for adverse events 
CYP3A4 
Cytochrome P450 3A4 
DMC 
Data monitoring committee 
DMP 
Data Management Plan 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
GABA-A 
Gamma-Aminobutyric Acid 
GCP 
Good Clinical Practice 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IPS 
Intermittent Photic Stimulation 
IRB 
Institutional Review Board 
IV 
Intravenous 
LAR 
Legally authorized representative 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
NDA 
New Drug Application 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate (Fridericia’s method) 
SAE 
Serious Adverse Event 
SPR 
Standardized Photosensitivity Range 
TEAE 
Treatment-emergent adverse events 


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ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WHODrug-ATC 
World Health Organization Drug Dictionary Anatomical- 
Therapeutic-Chemical 


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4. 
INTRODUCTION AND RATIONALE 
4.1. 
Background Information 
Staccato Alprazolam (STAP-001) is a single-use, hand-held, drug-device combination product 
that provides rapid systemic delivery by inhalation of a thermally generated aerosol of 
alprazolam. STAP-001 represents a new dosage form for alprazolam. 
 
STAP-001 is based on the proprietary Staccato delivery system developed by Alexza 
Pharmaceuticals, the product manufacturer (Section 4.2.2). STAP-001 is delivered orally to the 
deep lung for systemic delivery. The pharmacokinetics of STAP-001 is therefore similar to IV 
injections. The Staccato delivery system is user-friendly. Device actuation, aerosol formation, 
and delivery of the aerosolized drug to the deep lung are all accomplished with a single, normal 
breath by the subject. Achievement of peak plasma levels within minutes via a simple, user- 
friendly delivery system makes STAP-001 ideal for the acute treatment of seizures. 
 
Epilepsy is a brain disorder characterized by predisposition to experience recurrent seizures. It 
can occur as a result of a neurological injury, a structural brain lesion, as a part of many systemic 
medical diseases or may be genetic in origin. When seizures are not well controlled patients 
might have a need for acute treatment in addition to their maintenance anti-epileptic drug (AED) 
or might experience seizures emergencies. 
 
Alprazolam was selected as the drug to incorporate with Staccato for these acute seizures for 
several reasons. Benzodiazepines are the drug class of choice in treating seizure emergencies. 
Like the other benzodiazepines, alprazolam is an allosteric modulator at multiple GABA-A 
receptor subtypes, which is important since antiseizure properties are believed to be mediated by 
actions on different GABA-A subtypes. Second, alprazolam is potent and efficacious in various 
animal models of antiseizure activity (De Sarro et al, 1996; Herink 1997; Jenck et al, 1992; Ueki 
et al, 1981) and in one comparator study was more potent than either clonazepam or diazepam in 
reducing audiogenic seizures (De Sarro et al, 1996). Alprazolam’s well-documented anxiolytic 
action could also be of benefit in calming the individual. 
 
There are many advantages of STAP-001 for the acute treatment of seizures compared to 
existing therapy or products in development. Alprazolam is a potent, well-characterized and 
well-tolerated benzodiazepine, has rapid onset with a Tmax of 2 minutes, and the Staccato 
system delivers drugs non-invasively to the deep lung producing reliable IV-like 
pharmacokinetics. The breath-activated device delivers the drug while the subject simply takes a 
single inspiration through the mouthpiece without any other coordination needed. This drug 
delivery allows for self-administration and high reliability of delivery, producing rapid drug 
delivery and fast onset of action. 
STAP-001 was assessed in the Intermittent Photic Stimulation (IPS) model in subjects with 
photosensitive epilepsy as a proof of concept study (Protocol AMDC 002-202) for its potential as 
an AED. The positive results generated in this study provided the basis and rationale for this 
current protocol in studying STAP-001in subjects experiencing a seizure episode. The clinical 
development program for STAP-001 will focus on subtypes of subjects diagnosed with focal or 
generalized seizure disorder in which acute treatment with a benzodiazepine for a rapid anti- 
seizure activity could be beneficial. STAP-001 has been shown to produce a rapid rise in 
alprazolam plasma levels (< 2min) and effects on EEG in subjects with photosensitive epilepsy 


 
 


 
 


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indication under an open IND in the Division of Psychiatry Products and some of the studies 
conducted under that IND are not directly applicable to the STAP-001 epilepsy program and 
therefore will not be discussed below. 
Relevant to this protocol, a Phase 1 clinical study in healthy volunteers evaluating 
pharmacokinetics and safety of STAP-001 following single doses of 0.125 mg to 2 mg (Study 
002-101) and a Phase 2A trial to assess the safety, efficacy and pharmacokinetics of a single 
inhaled dose of STAP-001 on the IPS model in photosensitive epilepsy subjects (Study 002-202) 
have been conducted. 
In healthy volunteers (Study 002-101), the overall percentage of subjects who experienced at 
least one AE during treatment was 68%. The overall percent of subjects experiencing adverse 
events was higher (range 50 - 100%) in the STAP-001 groups than in the placebo group (10%). 
Within the STAP-001 group, the incidence appeared to be dose dependent with adverse events 
reported in 100% subjects after the highest dose (2 mg). The most frequently reported AEs were 
dizziness, dysgeusia, fatigue, and somnolence. In general, the adverse events observed following 
STAP-001 administration were those expected based on the pharmacological activity of the 
compound and were similar to AEs reported after oral delivery of comparable alprazolam doses. 
 
STAP-001 was assessed in the IPS model as a proof of concept study (Protocol AMDC 002-202) 
to evaluate it as a potential AED. The study was a multicenter, randomized, double-blind, 
crossover, placebo-controlled study in 5 subjects with a known stable photoparoxysmal response 
on EEG. STAP-001 0.5 mg, 1 mg, and 2 mg were compared to single doses of Staccato Placebo. 
The subjects received placebo on 2 study days, and active medication on 3 study days. During 
the study days, several procedures and IPS assessments were performed at 8 pre-determined 
times over the course of the day (1 assessment pre-dose and 7 assessments post-dose). After the 
screening visit, subjects returned 5 additional times and received Staccato Placebo (2 times) and 
STAP-001 0.5 mg, 1 mg, and 2 mg in random order. Visits were at least 7 days apart. 
 
All 5 of the subjects in the study were white female adult volunteers. The subjects ranged in age 
from 23 to 39 years (mean, 27.2 years) and had a mean weight and body mass index (BMI) of 
70.4 kg and 25.4kg/m2, respectively. 
 
A total of 4 subjects (80.0%) experienced at least 1 treatment-emergent adverse event (TEAE) 
during the study. The number of subjects experiencing AEs was similar between each of the 
treatments, with STAP-001 2 mg (n=4) and STAP-001 1 mg (n=3) having the most subjects 
reporting AEs. All of the AEs reported were mild or moderate in intensity. Nervous system 
disorders were reported by the highest number of subjects (n=4). There were no reports of 
dyspnea, wheezing or bronchospasm in any of the subjects. 
 
STAP-001 was effective in reducing the Standardized Photosensitivity Range (SPR) at the 
earliest measured time point (2 min) and the effect was sustained through the 4-hour time point 
for the 0.5 mg dose and the 6 hour time point for the 1 and 2 mg dose. A dose effect was 
apparent from 0.5 to 1 mg, however there was no apparent difference between the 1 and 2 mg 
dose on SPR. 
 
There was a rapid and marked effect of treatment with STAP-001 relative to Staccato Placebo 
treatment on the pharmacodynamics measures of sedation and sleepiness. The magnitude of 
effect was greater for the 2 mg doses and less for the 0.5 mg dose at all time points. In addition, 
the duration of the sedation/sleepiness appears to vary by dose with the 0.5 mg dose resulting in 


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the shortest duration (approximately 4 hrs) and the 2 mg dose resulting in the longest duration (6 
hrs or greater) relative to baseline. The 1 mg dose generally fell between the low and high dose 
for both magnitude and duration of sedation/sleepiness effects. 


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5. 
ETHICS 
The procedures set out in this study protocol, pertaining to the conduct, evaluation and 
documentation of this study, are designed to ensure that the Sponsor and the Investigator abide 
by Good Clinical Practice (GCP), including but not limited to Title 21 Code of Federal 
Regulations (CFR) Parts 50, 56, and 312, and the International Conference on Harmonisation 
(ICH) guidelines and directives. Compliance with these regulations also constitutes compliance 
with the ethical principles described in the current revision of the Declaration of Helsinki and 
applicable local regulatory requirements and law. 
The Investigator is responsible for protecting the rights, safety, and welfare of subjects under 
his/her care, and for the control of the medications under investigation. All ethical, regulatory, 
and legal requirements must be met before the first subject is enrolled in the study. 
 
5.1. 
Institutional Review Board (IRB) 
The Institutional Review Board (IRB)/Ethics Committee (EC) will meet all FDA requirements 
governing IRBs according to CFR, Title 21, Part 56 and applicable country and local regulatory 
requirements and law. The Investigator (or designee) must submit this study protocol and any 
amendments, the Sponsor’s approved informed consent form(s) (ICF), subject information 
sheets, subject recruitment materials, and other appropriate documents to the IRB/EC for review 
and approval. Following review of the submitted materials a copy of the written and dated 
approval/favorable opinion will be forwarded to the Sponsor (or designee). 
Any advertisements used to recruit subjects for the study will be reviewed by the Sponsor and 
the IRB/EC prior to use. 
 
5.2. 
Written Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or from the subject’s legally authorized representative (LAR). 
Whenever possible, investigators should attempt to obtain informed consent directly from the 
research participant. If this is not possible, then use of a LAR is permitted. Investigators are 
required to assess “obvious” incapacity. “Obviousness” would be based on three factors of 
capacity: 
• Ability to receive and to evaluate information effectively; 
• Ability to process the information according to the subject’s value system; and 
• Ability to make and to communicate a decision. 
The ICF, as specified by the clinical site’s IRB/EC, must follow the Protection of Human 
Subjects regulations listed in the Title 21 CRF, Part 50 and in applicable country regulatory 
requirements. The background of the proposed study, the procedures, the benefits and risks of 
the study, and that study participation is voluntary must be explained to the subject or the 
subject’s LAR. The subject or the subject’s LAR must be given sufficient time to consider 
whether to participate in the study. 
A signed and dated copy of the ICF must be given to the subject or the subject’s LAR. 
Confirmation of a subject’s informed consent must also be documented in the subject’s source 


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documentation prior to any testing under this protocol, including screening tests and assessments. 
The original signed consent form will be retained with the study records. 
All ICFs used in this study must be approved by the appropriate IRB/EC and by the Sponsor. 
The ICF must not be altered without the prior agreement of the relevant IRB/EC and the 
Sponsor. 


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6. 
STUDY OBJECTIVES 
The overall objectives of the study are to assess the efficacy and safety of a single administration 
of STAP-001 in subjects with epilepsy with a predictable seizure pattern. 
 
The primary objectives are: 
• To assess the efficacy of STAP-001 (1.0 mg and 2.0 mg) compared to placebo in treating 
a seizure episode 
• To assess the clinical feasibility and safety of the inhalation of STAP-001 (1.0 mg and 
2.0 mg) compared to placebo in subjects during a seizure episode 
• To assess the sedation associated with administration of STAP-001 (1.0 mg and 2.0 mg) 
compared to placebo 


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7. 
OVERALL STUDY DESIGN 
 
This is a multi-center, dose-ranging study to investigate the efficacy, safety, and clinical usability 
of STAP-001. Subjects (18 years of age and older) who have an established diagnosis of focal or 
generalized epilepsy with a documented history of predictable seizure episodes will be enrolled. 
This is an in-patient study.  Eligible and qualified subjects will be admitted to a CRU or EMU 
for study participation. The duration of the stay in the in-patient unit during the Treatment phase 
will be 2-8 days. One seizure event per subject will be treated with study medication. A treatable 
seizure event includes a predictable seizure episode, such that a change in the persistence of the 
seizure episode can be detected. The duration and timing of the seizure event and occurrence of 
subsequent seizures will be assessed by the study Staff Caregiver(s)1 through clinical observation 
and confirmed with video EEG. 
The study consists of two parts: Part 1- Open-Label Feasibility; Part 2 - Double-Blind. Each Part 
is divided into four phases: Screening; Qualification prior to entering the in-patient unit; 
Treatment in the in-patient unit; and Post-Treatment Safety Follow-Up. Subjects or the subject’s 
LAR will provide appropriately-obtained informed consent prior to completing any study-related 
procedures. 
The Screening visit will involve the items identified in the Schedule of Events (Appendix 1A), 
including Informed Consent and distribution of the seizure subject diary. As part of the 
screening process the seizure events of the subjects must be confirmed as acceptable for 
continuation in the study by the Epilepsy Study Consortium Review Board. Eligible subjects 
will enter a Qualification phase during which the subject must have at least 4 or more seizure 
episodes in a 28-day Qualification Period, with no more than one week without a predictable 
seizure episode. The Qualification Period may be extended beyond 28 days up to 56 total days to 
provide flexibility for scheduling of the Qualification Visit and Treatment Visit. The 28 days of 
the seizure diary activity immediately prior to the Qualification Visit will be assessed for 
qualification. At the end of the Qualification Period the Medical Monitor will review the seizure 
diary to confirm acceptable seizure frequency and subject’s advancement into the Treatment 
Phase. Subjects meeting the qualification criteria will enter the CRU/EMU within 7 days from 
the end of the Qualification Period. 
 
 
Part 1: Open-Label Feasibility 
The first subjects enrolled in the study will participate in an open-label feasibility evaluation. 
Enrollment in this phase will end when there are data from at least eight individual subjects with 
a treated single seizure episode in a CRU/EMU. The subjects will be enrolled in 3-8 sites, up to 
 
 
1 Staff member(s) assigned and trained to observe the subject throughout the Treatment Phase and facilitate the 
study drug administration as appropriate. Staff Caregivers will be accountable for the study medication and each 
handoff will be recorded. 


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three subjects per site. Eligible subjects will receive a single, dose of 1 mg STAP-001 at the 
onset of their predictable seizure episode. The subjects will undergo all study procedures and 
evaluations as outlined in this protocol. The feasibility data (with special emphasis on the drug 
administration and clinical assessment procedures) from these eight subjects will be analyzed 
and reviewed by the Sponsor before starting the double-blind part of the study. If deemed 
necessary based on the feasibility data, the study protocol will be amended (for example, to 
change the drug administration procedure or to redefine the time frame for primary endpoint 
assessment), before starting the double-blind part of the study. 
Part 2: Double-Blind 
After admission to the in-patient unit eligible and qualified subjects will be stratified by the use 
of inducing vs non-inducing AED and for the use of chronic daily benzodiazepines (yes or no) 
and randomly assigned (1:1:1) to one of two doses of STAP-001 (1 mg or 2 mg) or Staccato 
placebo. A blood sample for PK analysis (pre-dose) will be obtained. For each subject, a single 
seizure episode will be treated and assessed. Study medication will be self-administered (when 
feasible) or administered by a Staff Caregiver when a predictable seizure episode starts. 
Assessment of the seizure activity is based on clinical observation by the Staff Caregiver using a 
stop watch. In addition, a video EEG will record the occurrence, start time, and duration, of the 
seizure event. PK samples will be collected 10, 30 and 60 minutes, and 2 and 6 hours after the 
administration of the study drug. If possible, subjects will signal when they experience a seizure 
event. Subject will be under video EEG surveillance throughout the Treatment Phase. The Staff 
Caregiver will signal the event for the video EEG recording, starts the stop watch at the time of 
drug administration, and mark the occurrence of the seizure event on a seizure diary. If the 
seizure episode does not stop within 5 minutes of the study drug administration, rescue 
medication other than alprazolam may be administered at the discretion of the principal 
investigator per the protocol of the research unit. The study exit procedures will be conducted 24 
to 32 hours after the administration of study medication or when the subject discontinues from 
the study. 
After discharge from the in-patient unit there will be a safety-follow-up phone contact 14 ±2 
days after the subject received the study medication. 
 
7.1. 
Number of Subjects and Sites 
Assuming a 10% drop-out/protocol violation rate, approximately 115 subjects will be 
randomized in the double-blind part of the study to provide approximately 35 evaluable subjects 
per treatment arm. Enrollment may be stopped after 105 evaluable subjects have completed the 
double-blind phase of the study. Approximately 30% of the overall study population randomized 
in the study may be subjects being treated with chronic daily benzodiazepines as part of their 
epilepsy management. Approximately nine subjects will be enrolled in the open label feasibility 
part to provide at least eight evaluable subjects. Approximately 50 trial sites will be recruited to 
conduct the study. 


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7.2. 
Method of Treatment Assignment and Blinding (Double Blind Phase) 
After admission to the in-patient unit subjects will be randomly assigned (1:1:1) to one of 2 
doses of STAP-001 (1 mg or 2 mg) or Staccato placebo. Randomization will be stratified by the 
use of inducing vs non-inducing AEDs, and by use of daily benzodiazepines (yes or no) to 
ensure even distribution of treatment assignments in the two cohorts. 
All study participants will be blinded to study drug assignment. The device and packaging of 
STAP-001and placebo will be identical in appearance. 
 
7.3. 
Rationale for Study Design 
Part 1 is open-label and designed to assess feasibility of the study. Part 2 is double blind and 
randomized and is designed to assess treatment efficacy and safety. Double-blind, randomized, 
placebo-controlled studies are considered optimal for obtaining unbiased estimates of the 
efficacy and safety of investigational products. The single dose administration of STAP-001 
during a seizure episode is sufficient to evaluate the safety and potential of the product as an 
acute treatment of an epileptic episode. 
A large proportion of subjects with epilepsy with a predictable seizure pattern are taking chronic 
daily benzodiazepine medication. It has been speculated that the efficacy of STAP-001 may be 
reduced in these subjects because of potential cross-tolerance between benzodiazepines. 
However, it is deemed important to evaluate the efficacy of STAP-001 in this population. It is 
also important to evaluate the tolerability and safety of STAP-001 in subjects on chronic 
benzodiazepine treatment in a controlled environment. Therefore, approximately 30% of the 
overall study population randomized in the study may be subjects being treated with chronic 
daily benzodiazepines as part of their epilepsy management. The subjects will be stratified by 
concomitant chronic daily benzodiazepine use to ensure even distribution of benzodiazepine use 
across treatment arms. 
 
 
7.3.1. 
Rationale for Dose Selection 
 
To date, STAP-001 has been studied in approximately 140 subjects, including healthy 
volunteers, subjects with panic disorder, individuals with a history of sedative abuse, subjects 
with photosensitive epilepsy, and in subjects with epilepsy with predictable seizure patterns. In 
all cases, the drug was generally well tolerated with dosing up to 2 mg. Sedation is a common 
side effect of alprazolam and also provides a pharmacodynamic marker of CNS activity. In all 
studies to date, the sedation observed has been temporally associated with peak plasma levels, 
which typically occur within a few minutes of dosing, and sedation tended to be more 
pronounced with the 2 mg dose. In Study 002-202 (see summary in Section 4.4.2), the effects on 
IPS were observed for the 0.5 mg, 1 mg and 2 mg doses. The IPS effect seemed similar for the 1 
mg and 2 mg doses but there did appear to be a slightly greater extent and a longer duration of 
sedation at the 2 mg dose. Therefore, the 0.5 mg and 1 mg doses were initially chosen for this 
study. 
The analysis of the first five patients in the open label feasibility part of this study (ENGAGE-E- 
001) has shown a 60% responder rate with the 1 mg dose. In addition, the plasma alprazolam 


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concentrations of the first subjects that were dosed have been low. A further analysis of the PK 
data from previous studies has shown that the 2 mg dose consistently provides a higher exposure 
to alprazolam during the first 2 minutes after administration, whereas the 0.5 mg or 1 mg doses 
provide more flat concentrations of alprazolam. Based on these analyses it is likely that 0.5 mg 
of Staccato alprazolam will not be an efficacious dose. Staccato alprazolam has been generally 
well tolerated with dosing up to 2 mg. Therefore, the two doses of Staccato alprazolam for the 
double-blind part of the study will be amended from 0.5 mg and 1 mg to 1 mg and 2 mg. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects eligible for enrollment in the study must meet all of the following inclusion criteria and 
none of the exclusion criteria. 
8.1. 
Subject Inclusion Criteria 
1. Subject is able to provide written, personally signed, and dated informed consent to 
participate in the study or will have a legally authorized representative (LAR) sign the informed 
consent on his or her behalf before completing any study related procedures. 
2. Male or female ≥ 18 years of age. 
3. Has an established diagnosis of focal or generalized epilepsy or focal and generalized 
epilepsy with a documented history of predictable seizure episodes that includes at least 
one of the following: 
 
a. Generalized seizure episodes starting with a flurry of absence seizures or myoclonic 
seizures with a minimum duration of 5 minutes 
 
b. Episodes of a prolonged focal seizure with a minimum duration of 3 minutes 
 
c. Episodes of multiple (≥2) seizures within a 2-hour time period 
4. Prior to randomization, has experienced ≥4 seizure episodes with predictable pattern 
during the last 4 weeks (qualification period) and no more than one week without a 
predictable seizure episode before entry into the in-patient unit. 
5. Female participants (if of child-bearing potential and sexually active) and male 
participants (if sexually active with a partner of child-bearing potential) who agree to use 
a medically acceptable and effective birth control method throughout the study and for 1 
week following the end of the study. Medically acceptable methods of contraception that 
may be used by the participant and/or his/her partner include abstinence, birth control 
pills or patches, diaphragm with spermicide, intrauterine device (IUD), surgical 
sterilization, and progestin implant or injection. Prohibited methods include: the rhythm 
method, withdrawal, condoms alone, or diaphragm alone. 
6. Subject is able to comply by the requirements of the protocol, particularly the 
requirements and specific Institution policies during the in-patient stay. 
 
 
8.2. 
Subject Exclusion Criteria 
 
1. History or diagnosis of non-epileptic seizures (e.g. metabolic or pseudo-seizures). 
2. History of status epilepticus in the 6 months prior to Screening 
3. Has a progressive neurological disorder such as brain tumor, demyelinating disease, or 
degenerative central nervous system (CNS) disease that is likely to progress in the next 3 
months 


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4. Use of strong CYP 3A4 inhibitors; including azole antifungal agents (e.g., etoconazole, 
itraconazole), nefazodone, fluvoxamine, cimetidine, HIV protease inhibitors (e.g., 
ritonavir) 
5. Has severe chronic cardio-respiratory disease 
6. History of HIV-positivity. 
7. Pregnant or breast-feeding. 
8. Clinically significant renal or hepatic insufficiency (hepatic transaminases >2 times the 
upper limit of normal (ULN) or creatinine ≥ 1.5 x ULN). 
9. History of acute narrow angle glaucoma, Parkinson's disease, hydrocephalus, or history 
of significant head trauma. 
10. Subjects who use medications to treat airways disease, such as asthma or COPD or have 
any acute respiratory signs/symptoms (e.g., wheezing). 
11. Use of any investigational drug within 30 days or 5 half-lives of the investigational drug 
prior to administration of study medication, whichever is longer 
12. A history within the past 1 year of drug or alcohol dependence or abuse. 
13. Positive urine screen for drugs of abuse at Screening (positive Cannabis/Cannabinol 
results are acceptable if there is a documented history of stable use for medical purposes). 
14. Known allergy or hypersensitivity to alprazolam. 
15. History of glaucoma. 
16. Subjects who currently have an active major psychiatric disorder where changes in 
pharmacotherapy are needed or anticipated during the study. 
17. Hypotension (systolic blood pressure ≤90 mm Hg, diastolic blood pressure ≤50 mm Hg), 
or hypertension (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥100 mm 
Hg) measured while seated at screening or baseline. 
18.  Significant hepatic, renal, gastroenterologic, cardiovascular (including ischemic heart 
disease and congestive heart failure), endocrine, neurologic or hematologic disease. 
19. Subjects who, in the opinion of the Investigator, should not participate in the study for 
any reason, including if there is a question about the stability or capability of the subject 
to comply with the trial requirements. 
 
 
8.3. 
Subject Withdrawal Criteria 
All subjects are free to withdraw from participation in the study at any time, for any reason, and 
without prejudice. The Investigator must withdraw any subject from the study if the subject 
requests to stop participating in the study. The Investigator, Sponsor, or its designee may 
remove a subject from the study at any time and for any reason. In addition, subjects should be 
withdrawn if they: 
• Require a medication that is prohibited by the protocol 


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• Do not follow guidelines specified in the protocol (i.e., is noncompliant with protocol 
procedures) 
 
In addition, subjects may be withdrawn for any medically appropriate reason or significant 
protocol violation, in the opinion of the Investigator. 
Subjects who withdraw or are withdrawn from the study will not be replaced. 
 
8.3.1. 
Subject Withdrawal Procedures 
A subject who prematurely discontinues study participation should have all assessments 
performed per the Exit Procedures if possible. 
If a subject terminates early from the study, the Investigator will record the reason(s) for early 
termination on the relevant electronic case report form (eCRF). The specific reason for the 
withdrawal should be carefully documented on the eCRF. 
Adverse events resulting in subject early termination will be followed to the satisfactory 
resolution and determination of outcome, as ascertained by the Investigator (and/or Sponsor, or 
its designee); See Section 12.1.2: Adverse Events. The data will be recorded on the appropriate 
eCRF. 
 
 
8.4. 
Emergency Unblinding of Treatment Assignment 
In the case of a medical requirement to break the blind to determine appropriate treatment for an 
adverse event, unblinding of a subject’s treatment assignment can be achieved through the study- 
specific Interactive Web Response System (IWRS). If possible, the Investigator should discuss 
the circumstances with the Medical Monitor prior to accessing unblinding information. In the 
event of a blind break, the Medical Monitor will be notified through the electronic data capture 
system. The subject for whom the blind is broken should be subsequently withdrawn from the 
study. The details regarding the process of breaking the blind are outlined in the Pharmacy 
Manual. 


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9. 
STUDY SCHEDULE AND PROCEDURES 
Subjects enrolled in this study will undergo only those procedures described in this protocol. No 
study-related procedures can be performed prior to receiving informed consent from the subject 
or the subject’s LAR. See the Schedule of Events and Schedule of Events – Procedures in 
CRU/EMU (Appendix 1A and Appendix 1B) for a summary of the study procedures. 
 
9.1. 
Part 1: Open Label Feasibility 
9.1.1. 
Screening Visit 
At the Screening Visit, it will be confirmed that the subject meets all inclusion and exclusion 
criteria and the procedures described in the Schedule of Events (Appendix 1A) will be 
performed, including: a full neurological and physical examination; vital signs assessment; 
medical history; blood draw for routine labs; 12 lead ECG; and urine drug and alcohol screen. A 
urine pregnancy test will be performed on females of childbearing potential. 
After screening, the doses of the background AEDs should be kept stable if possible. If dose 
changes are deemed necessary, continued study participation of the subject should be discussed 
with the Medical Monitor. 
 
9.1.2. 
Qualification Phase 
Subjects meeting all the requirements during the Screening visit will be given a Seizure Diary 
and asked to record their seizure episodes over the next 4 weeks. In order for the subject to 
remain eligible and qualify for the study, they will have to have at least 4 predictable seizure 
episodes, within the 28-day Qualification Period. The Qualification Period may be extended 
beyond 28 days up to 56 total days to provide flexibility for scheduling of the Qualification Visit 
and Treatment Visit. The 28 days of the seizure diary activity immediately prior to the 
Qualification Visit will be assessed for qualification. There will be a visit at the end of the 
Qualification Period, during which the subject will turn in their seizure diary. At the end of the 
Qualification Period, the Medical Monitor will review the Seizure Diary to confirm acceptable 
seizure frequency and subject’s advancement into the Treatment Phase. Subjects meeting the 
qualification criteria will enter the CRU/EMU within 7 days from the end of the Qualification 
Period. 
 
9.1.3. 
Treatment Phase 
The first subjects enrolled in the study will participate in an open-label feasibility evaluation and 
enrollment in this phase will end when there are data from eight individual subjects having 
seizure events in the CRU/EMU. Subjects meeting eligibility and qualification criteria will be 
admitted to the CRU/EMU, be assessed for continued eligibility according to the procedures in 
the Schedule of Events – Procedures in CRU/EMU (Appendix 1B), and be hooked up with EEG 
recording electrodes which will remain in place for the duration of the study. It is required that a 
Staff Caregiver be present to provide 1:1 coverage with the subject while in the CRU/EMU to 
watch for signs of a seizure episode. After the EEG electrode hook-up is complete, each subject 


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will be assigned a single 1 mg STAP-001 device that will be removed from the pouch and 
dispensed to the Staff Caregiver until drug administration. At the onset of the predictable seizure 
episode, the Staff Caregiver will activate the device and give to the subject if the subject is 
capable of self-administration or will assist in helping the subject to administer the drug. The 
Staff Caregiver will signal the onset of the seizure event on the video EEG, start the stopwatch 
and mark the occurrence of the seizure event on a seizure diary. At 2 minutes after study drug 
administration, the Staff Caregiver will record whether the seizure event has ceased or is still 
ongoing. The Staff Caregiver will observe the subject for the next 2 hours and record seizure 
activity on a seizure diary during this time period. After this the Staff Caregiver will continue 
observation throughout the 24 hours following drug administration. If over the course of 7 days 
there is no treatable seizure episode, the subject will be dismissed, after completing Exit 
Procedures. Note that the procedures in the Schedule of Events for the treatment day are only 
conducted on the day there is a treatable seizure event and drug has been administered. 
The feasibility data (with special emphasis on the drug administration and clinical assessment 
procedures) from these eight subjects will be analyzed and reviewed by the Sponsor and study 
team before continuing to enroll subjects in the double-blind part of the study. If necessary, the 
study protocol will be amended (for example, to change the drug administration procedure or to 
redefine the time frame for primary endpoint assessment) before starting the double-blind part of 
the study. 
When multiple procedures are scheduled at the same time point, the VAS assessment should be 
performed first, immediately followed by the PK draw. 
All Staccato doses will be administered as one puff from a single inhalation device by the subject 
with or without the assistance of the study Staff Caregiver. The exact time of administration and 
correct intake of the medication will be noted and recorded in the CRF. 
Subjects should have minimal postural changes for the first 1.5 hours after administration of 
study drug. 
 
 
9.2. 
Part 2: Double-Blind 
9.2.1. 
Screening Visit 
At the Screening Visit, it will be confirmed that the subject meets all inclusion and exclusion 
criteria and the procedures described in the Schedule of Events (Appendix 1A) will be 
performed, including: a full neurological and physical examination; vital signs assessment; 
medical history; blood draw for routine labs; 12 lead ECG; and urine drug and alcohol screen. A 
urine pregnancy test will be performed on females of childbearing potential. Device training 
including study drug administration procedures will be conducted. Training may include subject 
use of a practice ‘dummy’ device that does not contain any active drug. 


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After screening, the doses of the background AEDs should be kept stable if possible. If the dose 
changes are deemed necessary, continued study participation of the subject should be discussed 
with the Medical Monitor. 
 
9.2.2. 
Qualification Phase 
Subjects meeting all the requirements during the Screening visit will be given a Seizure Diary 
and asked to record their seizure episodes over the next 4 weeks. In order for the subject to 
remain eligible and qualify for the study, they will have to have at least 4 predictable seizure 
episodes, within the 28-day Qualification Period. The Qualification Period may be extended 
beyond 28 days up to 56 total days to provide flexibility for scheduling of the Qualification Visit 
and Treatment Visit. The 28 days of seizure diary activity immediately prior to the Qualification 
Visit will be assessed for qualification. There will be a visit at the end of the Qualification 
Period, during which the subject will turn in their seizure diary. At the end of the Qualification 
Period the Medical Monitor will review the Seizure Diary to confirm acceptable seizure 
frequency and subject’s advancement into the Treatment Phase. Subjects meeting the 
qualification criteria will enter to the CRU/EMU within 7 days from end of the Qualification 
Period. 
 
9.2.3. 
Treatment Phase 
 
Subjects meeting eligibility criteria will be admitted to the CRU/EMU and be assessed for 
continued eligibility according to the procedures for CRU/EMU entry in the Schedule of Events 
– Procedures in CRU/EMU (Appendix 1B). Device training including study drug administration 
procedures will be conducted. Training may include subject use of a practice ‘dummy’ device 
that does not contain any active drug. Eligible subjects will be stratified for use of inducing vs. 
non-inducing AEDs and for the use of chronic daily benzodiazepines, and randomly assigned to 
a treatment arm and be hooked up with EEG recording electrodes which will remain in place for 
the duration of the study. It is required that a Staff Caregiver be present to provide 1:1 coverage 
with the subject while in the CRU/EMU to watch for signs of a seizure episode. After 
randomization and EEG electrode hook-up is complete, the study medication, assigned to the 
subject, will be removed from the pouch and dispensed to the Staff Caregiver until drug 
administration. At the onset of the predictable seizure event, the Staff Caregiver will activate the 
device and give to the subject if the subject is capable of self-administration or will assist in 
helping the subject to administer the drug. The Staff Caregiver will signal the onset of the seizure 
event on the video EEG, start the stopwatch and mark the occurrence of the seizure event on a 
seizure diary. At 2 minutes after study drug administration, the Staff Caregiver will record 
whether the seizure event has ceased or is still ongoing. The Staff Caregiver will observe the 
subject for the next 2 hours and record seizure activity on a seizure diary during this time period. 
After this the Staff Caregiver will continue observation throughout the 24 hours following 
blinded study medication administration. During the seizure episode period, study procedures 
will be conducted according to the schedule in the Schedule of Events – Procedures in 


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CRU/EMU (Appendix 1B). If over the course of 7 days there is no recordable seizure episode, 
the subject will be dismissed, after completing the Exit Procedures. Note that the procedures in 
the Schedule of Events for the treatment day are only conducted on the day there is a treatable 
seizure event and drug has been administered. 
When multiple procedures are scheduled at the same time point, the VAS assessment should be 
performed first, immediately followed by the PK draw. 
All Staccato doses will be administered as one puff from a single inhalation device by the subject 
with or without the assistance of the study Staff Caregiver. The exact time of administration and 
correct intake of the medication will be noted and recorded in the CRF. 
Subjects should have minimal postural changes for the first 1.5 hours after administration of 
study drug. 


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10. 
DESCRIPTION OF STUDY TREATMENTS 
10.1. 
Description of Treatments 
After admission to the in-patient unit subjects will be stratified by use of inducing vs. non- 
inducing AEDs and for use of chronic daily benzodiazepines, and randomly assigned (1:1:1) to 
one of 2 doses of STAP-001 (1 mg or 2 mg) or Staccato placebo. 
 
10.2. 
Study Drug Materials and Management 
Please consult the Pharmacy Manual for a complete description of the study drug and 
requirements for storage, handling, dispensing, accountability, returns and destruction. 
 
10.2.1. 
Physical Description of Study Drug 
Study drug will include STAP-001and matching Staccato placebo. Details regarding 
formulation and dosage are presented in Table 1: 
Investigational Product 
 
Table 1: Investigational Product 
 
 
Investigational Product 
(Staccato Alprazolam (STAP-001) or Staccato Placebo) 
Product Name: 
Staccato Alprazolam (STAP-001) or 
Matching Staccato placebo 
Dosage Form: 
Inhalation device 
Dosage Strength of STAP-001 
1 mg, 2 mg, or placebo, per device 
Route of Administration 
Oral inhalation 
Physical Description 
White to off-white plastic device 
 
 
 
10.2.2. 
Study Drug Packaging, Labeling, and Storage 
 
Study drug will be packaged inside a sealed foil pouch. Blinding of study medication will be 
done according to the randomization schedule and performed by an unblinded observer or 
vendor who shall not be involved in any other aspect of this study. 
Detailed instructions for unblinding will be provided to the site in the event of an emergency and 
it is necessary to find out the study treatment assigned to an individual subject. If feasible, the 
Medical Monitor should be consulted before breaking the blind, and if this is not feasible, the 
medical monitor should be advised of the unblinding within 24 hours. 
The label(s) for the investigational product and placebo will include sponsor name, address and 
telephone number, the protocol number, investigational product name, dosage form, storage 
conditions, and required caution statements and/or regulatory statements, as applicable. 
Additional information may be included on the label as applicable per local regulations. 


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Details of the packaging, labeling and dispensing instructions can be found in the Pharmacy 
Manual. 
Adequate supplies of study drug will be provided to each site. Study drug should be stored in the 
original package between 15°C to 25°C (59°F to 77°F), as stated on the product label, in a 
secure, temperature-monitored, locked area, under the responsibility of the Investigator or other 
authorized individual until dispensed to the subjects. 
 
10.2.3. 
Study Drug Preparation and Administration 
 
Each product is packaged inside a sealed foil pouch. Removal of a pull-tab from the product 
activates it and renders it ready for use, as indicated by illumination of a green light. Successful 
dosing is signaled by the extinguishing of the green light. 
 
10.2.4. 
Study Drug Return and Disposal 
The Sponsor (or designee) will review with the Investigator and relevant site personnel the 
process for study treatment return, disposal, and/or destruction, including responsibilities for the 
site versus the Sponsor (or designee). Specific requirements for destruction or return are defined 
in the Pharmacy Manual. 
 
10.2.5. 
Study Drug Accountability 
To satisfy regulatory requirements regarding drug accountability, all study drug will be 
reconciled in full. The Investigator or designee must maintain accurate records of the receipt of 
study drug, including date received, lot number, amount received, condition of the package, and 
the disposition of study drug. 
Current dispensing records will also be maintained, including the date and amount of medication 
dispensed to each individual subject. Returned study drug records will be maintained and final 
study drug reconciliation will also be recorded for each subject. 
10.3. 
Concomitant Medications and Procedures 
All medications, including over-the-counter therapies (e.g., vitamins, herbal, and nutritional 
supplements), taken at the time of the Screening Visit through the Follow-Up Visit will be 
recorded in the subject’s source documentation and documented in the eCRF. 
With the exception of acetaminophen or ibuprofen for pain, ongoing doses of oral 
contraceptives, and stable background AEDs, medications other than study drug are not allowed 
from 12 hours before entry into the CRU/EMU until the end of the Treatment Phase, unless 
medically required. 
After screening, the doses of the background AEDs should be kept stable if possible. If dose 
changes are deemed necessary, continued study participation of the subject should be discussed 
with the Medical Monitor. 
Any concomitant medications taken during the Treatment Phase (up to 24 h after study drug 
administration), including any medication taken for the treatment of adverse events, will be 
recorded on the appropriate CRF. Recording of the concomitant medication will include the 
medication name, indication, dose, route, frequency, and time. 


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If a seizure episode does not stop within 5 minutes, rescue medication may be administered at 
the discretion of the principal investigator per the protocol of the research unit. If seizure 
activity continues despite use of rescue medication, the standard treatment protocol of the 
institution should be applied as appropriate. 
In case a subject experiences respiratory distress, an inhaled short-acting beta-agonist 
bronchodilator should be available for use under standard dosing conditions as needed. Any 
concomitant medication deemed necessary for the wellbeing of the subject may be given at the 
discretion of the Investigator. Use of medications that are prohibited per protocol will require 
subject withdrawal from the study. 


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11. 
STUDY ASSESSMENTS DESCRIPTIONS 
The schedule of assessments and procedures is presented in the Schedule of Events (Appendix 
1A and 1B) and should be referenced for details regarding the collection of each assessment at 
each visit. 
 
11.1. 
Demographic Characteristics and Medical History 
Demographic characteristics (i.e., gender, race and ethnic origin, date of birth, and calculated 
body mass index) will be collected at the Screening Visit, and detailed on the eCRF. 
Thorough medical history, including EEG and brain imaging (MRI/CT) findings within the last 5 
years, history of seizures, seizure pattern, frequency and characteristics during the last 12 
months. Current medications, and co-morbidities will be collected at the Screening Visit and 
reviewed and updated at entry into the CRU/EMU for the Treatment Phase. Epilepsy history and 
seizure documentation are collated and submitted to the Epilepsy Study Consortium Review 
Board for review. 
11.2. 
Vital Signs, Weight, and Height 
Vital signs will be measured after the subject has been in a supine or semi-supine position for at 
least 5 minutes and will include blood pressure, pulse rate, respiratory rate, and oral temperature 
as defined in the Schedule of Events. 
Weight will be measured per institution standard of care. Subjects should wear light clothing and 
remove his/her shoes before weight is measured. Height will be measured per institution 
standard of care, after the subject has removed his/her shoes. Height will only be measured at the 
Screening Visit. Weight and vital signs will be measured at each study visit according to the 
Schedule of Events. Weight and height will be used to calculate the subject’s body mass index at 
Screening. Weight and height will be converted as needed to kilograms and centimeters, 
respectively, prior to statistical analyses. 
11.3. 
Physical and Neurological Examination 
A complete physical examination will include an examination of all major organ systems, and 
will be performed as indicated in the Schedule of Events (Appendix 1A and Appendix 1B). A 
complete neurological examination will be performed as indicated in the Schedule of Events 
(Appendix 1A and Appendix 1B). 
 
11.4. 
12-Lead Electrocardiogram 
 
Twelve-lead ECGs will be performed after the subject has rested in a supine or semi-supine 
position for at least 5 minutes. Individual parameters including heart rate, PR, QT, QTcF, QRS, 
and RR intervals will be collected. Repeat ECGs (if deemed necessary) should be performed at 
least 5 minutes apart. The Investigator should indicate review of the electrocardiogram reports 
throughout the study by signing and dating each report. 


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11.5. 
Seizure Assessment 
11.5.1. 
Staff Caregiver Seizure Episode Recording 
It is required that a Staff Caregiver be present to provide 1:1 coverage with the subject while in 
the CRU/EMU. At the onset of the predictable seizure episode, the Staff Caregiver will activate 
the device and give to the subject if the subject is capable of self-administration or will assist in 
helping the subject to administer the drug. The Staff Caregiver will signal the onset of the seizure 
episode on the video EEG, start a stopwatch and record the onset of the seizure episode. At 2 
minutes after study drug administration, the Staff Caregiver will record whether the seizure 
episode has ceased or is still ongoing. The Staff Caregiver will observe the subject for the next 2 
hours and record seizure activity on a seizure diary during this time period. After this the Staff 
Caregiver will continue observation throughout the 24 hours following drug administration. 
 
11.5.2. 
Video Electroencephalogram (EEG) 
A 19-21-channel recording system will be used with a bipolar derivation. The display montage 
will include T4-T6-O2-O1-T5-T3 and T4-P4-Pz-P3-T3, apart from 2x4 (8) frontal to occipital 
leads. 
Subjects will be fitted with EEG electrodes according to the international 10-20 system upon 
reporting to the CRU/EMU. The EEG electrodes will remain in place for the duration of the stay 
in the CRU/EMU. 
EEG data will be sent to a central reader and evaluated in a blinded fashion. 
 
11.5.3. 
Seizure Episode Severity Assessment 
At the 6 hour time point after dose administration the subject will assess the seizure episode just 
experienced in relation to previous seizures experienced by the subject using the assessment tool 
found in the Appendix 3. 
 
11.6. 
Pharmacokinetic Sampling 
Blood samples will be collected into evacuated K2 EDTA tubes, e.g., Vacutainer®, from each 
subject according to the times specified in the Schedule of Events – Procedures in CRU/EMU 
(Appendix 1B). An indwelling catheter inserted into the forearm, or direct venipuncture may be 
used during the blood sampling procedure. 
The total volume of blood drawn from each subject during this study will be approximately 100 
mL, which includes approximately 24 mL for pharmacokinetic analysis and approximately 70 
mL for standard pre-study and post study clinical laboratory tests. 
Specific sample collection, preparation and shipping instructions will be provided to the study 
site. Samples will be assayed using validated methods. Instructions for harvesting and preparing 
plasma samples prior to freezing and additional procedures for blood sample collection will be 
provided in separate study laboratory manual. 
 
11.7. 
Sedation Assessment - Visual Analog Scale (VAS) 
The visual analog scale is a distinct 100 millimeter line anchored on the left end at full degree of 
impairment and on the right end at no degree of impairment, where indication of the degree of 
impairment perceived at the time of assessment is captured by marking the appropriate position 


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on the line between the anchor points. The measured distance of the mark from the left anchor 
will be recorded in millimeters 
As specified in the Schedule of Events – Procedures in CRU/EMU (Appendix 1B), sedation will 
be measured using a 100-mm linear visual analogue scale (VAS). The subject will be given 2 
scales, 1 anchored by “Sedated” and “Alert, the other by “Sleepy and “Awake” and asked to 
“Place a vertical mark on the line indicating your feelings RIGHT NOW”. The location of the 
mark will be measured at a later time and the results will be recorded in mm from the left on the 
appropriate eCRF. 
An example of the subject VAS is provided in Appendix 2. The paper scales will be provided to 
the sites and only originals can be used for subject assessment. Photocopies cannot be provided 
for subject assessment. 
 
 
11.8. 
Clinical Laboratory Assessments 
Blood and urine samples will be collected according to standard medical guidelines and 
processed at a clinical laboratory. Sample collections, handling and shipping instructions are 
provided in the clinical laboratory document. Study-related clinical laboratory assessments are 
presented below in Table 2: 
Clinical Laboratory Assessments 
Clinical laboratory samples should be collected according to the Schedule of Events -Procedures 
in CRU/EMU (Appendix 1B). 
The results of clinical laboratory tests conducted at the Screening Visit (and prior to dosing) 
must be assessed by the Investigator to determine each subject’s eligibility for participation in 
the study. Laboratory values that are out of range at screening may be repeated at the 
investigator’s discretion. The Investigator should indicate review of the laboratory reports 
throughout the study by signing and dating each report. 
Following study drug administration, all clinical laboratory results that fall outside the reference 
range will be interpreted by the Investigator as Abnormal, not clinically significant, or 
Abnormal, clinically significant. Laboratory results deemed Abnormal, clinically significant 
should be fully investigated and repeated for verification. Additional tests and evaluations 
required to establish the significance or etiology of a clinically significant abnormal result or to 
monitor the course of an adverse event should be obtained when clinically indicated. All 
clinically significant out-of-range laboratory values will be followed until they return to normal 
or stabilize; the investigator will treat the subject as medically required at appropriate intervals 
until this occurs. 
Any significant laboratory abnormalities that are either serious or unexpected will be promptly 
reported to the Sponsor. Any additional relevant laboratory results obtained by the Investigator 
during the course of this study will be reported to the Sponsor or designee. 
Laboratory values will be reported as an adverse event following the guidelines in section 12.1.1. 


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Table 2: Clinical Laboratory Assessments 
 
 
Hematology (Blood) 
Chemistry (Serum) 
Pregnancy 
Females of childbearing potential only 
Complete blood count 
Alanine aminotransaminase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransaminase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase 
Glucose 
Lipase 
Total protein 
Phosphorus 
Potassium 
Sodium 
Uric Acid 
At screening: 
Platelet count 
White blood cell count with 
differential 
Hemoglobin 
Hematocrit 
Urine Human Chorionic Gonadotropin 
At CRU/EMU entry: 
Urine Human Chorionic Gonadotropin 
Drug Screen (Urine) 
Urinalysis 
delta-9-tetrahydrocannabinol 
barbiturates 
Bilirubin 
Blood 
opioids 
Clarity 
amphetamines 
Urobilirubin 
methamphetamines 
Glucose, Urine 
methylenedioxymethamphetamine 
cocaine 
phencyclidine 
ethanol 
propoxyphene 
Ketones 
Leukocyte Esterase 
Nitrate 
pH 
Protein, Urine 
Specific Gravity 


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12. 
ADVERSE EVENTS 
12.1.1. 
Definition of Adverse Event 
An adverse event is any untoward medical occurrence that may appear or worsen in a subject 
during the course of a study. It may be a new intercurrent illness, a worsening concomitant 
illness, an injury, or any concomitant impairment of the subject’s health, including laboratory 
test values, regardless of etiology. Any worsening (ie, any clinically significant adverse 
change in the frequency or intensity of a pre-existing condition) should be considered an 
adverse event. A diagnosis or syndrome should be recorded on the adverse event page of the 
eCRF rather than the individual signs or symptoms of the diagnosis or syndrome. A 
worsening of the condition under study will not be reported as an adverse event. 
All subjects will be monitored for adverse events during the study. Assessments may include 
monitoring of the following parameters:  the subject’s clinical symptoms, laboratory, 
physical examination findings, or findings from other tests and/or procedures. 
An adverse event reported after informed consent and occurring before the first dose of study 
drug in the CRU/EMU, will be considered a pretreatment adverse event and will be captured 
on the eCRF. Adverse events will be considered treatment-emergent if the onset is after the 
first dose of study drug. 
An abnormal laboratory value is considered to be an adverse event or a component of an 
adverse event if the abnormality: 
• results in discontinuation from the study; 
• is judged by the Investigator to be of significant clinical importance requiring 
treatment, modification/interruption of investigational product dose, or any other 
therapeutic intervention 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the adverse event eCRF. If the abnormality 
was not a part of a diagnosis or syndrome, then the laboratory abnormality should be 
recorded as the adverse event. If possible, the laboratory abnormality should be recorded as 
a medical term and not simply as an abnormal laboratory result (e.g., record 
thrombocytopenia rather than decreased platelets). 
12.1.2. 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to seriousness, severity/intensity, 
relationship to study drug, duration, action taken, and outcome. 
 
12.1.2.1. Serious Adverse Event 
A serious adverse event is an adverse event, as per Title 21 CFR 312.32 and ICH E2A.II.B 
that fulfills the following criteria: 


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• Is fatal (results in death); 
• Is life-threatening (Note: the term "life-threatening" refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an 
event that could hypothetically have caused death had it been more severe); 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• Results in persistent or significant disability/incapacity (a substantial disruption of 
the subject's ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; or 
• Constitutes an important medical event that may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes 
listed above. 
Important medical events are defined as those occurrences that may not be immediately 
life-threatening or result in death, hospitalization, or disability, but may jeopardize the 
subject or require medical or surgical intervention to prevent one of the other outcomes listed 
above. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization. 
Events not considered to be serious adverse events are hospitalizations for: 
• A procedure for protocol/disease-related investigations (e.g., sampling for 
laboratory, pharmacokinetic, and pharmacodynamic tests). However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable serious adverse event. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an adverse event. 
• A procedure that is planned (i.e., planned prior to the starting of treatment on 
study); must be documented in the source document and the eCRF. 
Hospitalization or prolonged hospitalization for a complication remains a 
reportable serious adverse event. 
• An elective treatment of or an elective procedure for a pre-existing medical 
condition that does not worsen. 
• Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
If an adverse event is considered serious, the adverse event eCRF must be completed. 
For each serious adverse event, the Investigator will provide information on severity, start 
and stop dates, relationship to investigational product, action taken regarding investigational 
product, and outcome. 


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Queries pertaining to serious adverse events will be handled through the electronic data 
capture system or other appropriate means. Urgent queries (e.g., missing causality 
assessment) may be handled by telephone. 
 
12.1.2.2. Severity/Intensity 
For both adverse events and serious adverse events, the Investigator must assess the 
severity/intensity of the event. 
The National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0 should be used to grade the severity/intensity of all events. These criteria will be 
provided in the Site Operations Manual.  If a CTCAE criterion does not exist, the 
Investigator should grade the severity according to the following criteria: 
• Grade 1 (mild): does not interfere with the subject’s usual function 
• Grade 2 (moderate): interferes to some extent with subject's usual function 
• Grade 3 (severe): interferes significantly with subject's usual function 
• Grade 4 (life-threatening): results in a threat to life or in an incapacitating 
disability 
• Grade 5 (death): results in death 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This criterion is not the same as 
“serious” which is based on subject/event outcome or action criteria associated with events 
that pose a threat to a subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
 
12.1.2.3. Relationship to Study Drug 
Relationship should be assessed and provided for every adverse event/serious adverse event 
based on currently available information. Relationship is to be reassessed and provided as 
additional information becomes available. Adverse events will be classified by the 
Investigator as follows: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The event would be 
considered as definitely related to the study drug upon results of a positive re-challenge 
procedure. 


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Probably Related: There is evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, the 
influence of other factors that may have contributed to the event (e.g., the subject’s clinical 
condition, other concurrent disease, concomitant medications or events) is unlikely. 
Possibly Related: There is evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the study drug). However, the influence of 
other factors may have contributed to the event (e.g., the subject’s clinical condition, other 
concurrent disease, concomitant medications or events). 
Unlikely Related: A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and 
in which other drugs or concurrent or underlying disease provide plausible explanations (e.g., 
the subject’s clinical condition, other concomitant treatments). 
Not related: The adverse event is completely independent of study drug administration, 
and/or evidence exists that the event is definitely related to another etiology. There must be 
an alternative, definitive etiology documented by the clinician. 
12.1.2.4. Duration 
For all adverse events whether or not considered serious, the Investigator will provide a 
record of the start and stop dates of the event. Every effort should be made to resolve all 
adverse events with continued follow-up with the subject until appropriate resolution can be 
achieved. If an event is unresolved at the end of the study it will be recorded as ongoing. 
 
12.1.2.5. Action Taken 
The Investigator will record the action taken with investigational product as a result of an 
adverse event or serious adverse event on the eCRF, as applicable (e.g., discontinuation, or 
interruption of investigational product, as appropriate) and record if concomitant and/or 
additional treatments were given for the event. 
 
12.1.2.6. Outcome 
The Investigator will record the outcome of adverse events on the eCRF, as applicable (e.g., 
recovered, recovered with sequelae, not recovered, or death (due to the adverse event). 
 
12.1.3. 
Follow-Up 
Adverse events assessed as not related to study drug, including clinically significant 
laboratory tests, electrocardiograms, or physical examination findings, must be followed until 
the event resolves, the condition stabilizes, the event is otherwise explained, or the final 
study visit occurs, whichever comes first. 
Adverse events assessed as related to study drug and serious adverse events will be followed 
for as long as necessary to adequately evaluate the subject’s safety, or until the event 
stabilizes, is otherwise explained, death occurs, or the subject is lost to follow up. If 
resolved, a resolution date should be provided. The Investigator is responsible for ensuring 


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Address: 
Phone: 
 
that follow-up includes any supplemental investigations indicated to elucidate the nature 
and/or causality of the adverse event. This may include additional clinical laboratory testing 
or investigations, examinations, or consultation with other health care professionals as is 
practical. 
 
12.1.4. 
Pregnancy 
The Sponsor must be informed within 24 hours upon learning that a subject, or male 
subject’s partner, has become pregnant any time after the first dose of study drug until 30 
days after the last dose of study drug. The Pregnancy Notification eCRF should be used to 
report the pregnancy to the Sponsor or its designee. Subject pregnancies (or pregnancy of a 
male subject’s partner) must be followed until termination of pregnancy or the birth of the 
child. The Pregnancy Outcome eCRF should be used to report information regarding the 
status of the infant. 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking the investigational product should notify the Investigator, and the 
pregnant female partner should be advised to call her healthcare provider immediately. 
 
12.1.5. 
Recording Adverse Events 
All adverse events (regardless of seriousness or relationship to study drug) including those 
from the time informed consent is obtained through to the final study visit are to be recorded 
in the eCRF. Each individual adverse event is to be listed as a separate entry. The 
Investigator will provide information about dates of onset and resolution, seriousness, 
severity, action(s) taken, outcome, and relationship to the study drug. All adverse events 
should be documented in the subject’s source documents. 
 
12.1.6. 
Reporting Adverse Events 
The Investigator must report to Sponsor or its designee all adverse events that occur during 
the study from the time written informed consent is given until the final study visit or early 
termination, regardless of their relationship to the study drug. Serious adverse events and 
pregnancies will be reported from the time written informed consent is given through 30 days 
beyond the last dose of study drug. 
12.1.6.1. Reporting Serious Adverse Events 
The Investigator is required to notify the Sponsor, and the Sponsor’s designated Drug Safety 
Unit within 24 hours after becoming aware of the occurrence of a serious adverse event. All 
serious adverse events will be reported through completion of the adverse event eCRF. The 
Investigator will be responsible for reporting serious adverse events to the IRB. 
 
Medical Monitor: 


 
 


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13. 
STATISTICAL METHODS 
13.1. 
Sample Size Rationale 
There are no studies in the literature to provide reliable estimates of active treatment or 
placebo response rates for this study. Assuming a 10% drop-out/protocol violation rate, 
approximately 115 subjects will be enrolled in the double-blind part of the study to provide 
approximately 35 evaluable subjects per treatment arm. Enrollment may be stopped after 105 
evaluable subjects have completed the study. 
Approximately 30% of the overall study population randomized in the study may be subjects 
being treated with chronic daily benzodiazepines as part of their epilepsy management. Since 
the effect of concomitant chronic daily benzodiazepines use on study treatment is unknown, a 
50% response rate for chronic benzodiazepines users on active treatment arms is assumed. 
For subjects who are not chronic benzodiazepines users, a response rate of 60% for active 
treatment arms is assumed. With up to 30% of study population being chronic 
benzodiazepines users and these response assumptions, a 57% response for the active 
treatment arm is targeted. 
Power calculations assume a 2-sided test and significance level of 0.05 with 90% power and 
are based on the assumption that the proportion of responders with STAP-001 is 57% (best 
active treatment arm) whereas the assumed placebo responder rate is 20%. 
 
13.2. 
Endpoints 
13.2.1. 
Efficacy 
Primary efficacy endpoint: 
The proportion of responders in each treatment group achieving seizure activity cessation 
within 2 minutes after the administration of the study drug and no recurrence of seizure 
activity within 2 hours. 
 
Secondary endpoints: 
• Seizure episode severity assessed by subject and/or Staff Caregiver 
• Use of rescue medication 
• Secondary generalization (evolution to a complex partial seizure and/or a generalized 
tonic-clonic seizure) 
Exploratory endpoints: 
• Number of seizures during the 4, 6 and 12 hour time periods after study drug 
administration 
• Time to next seizure event with start time >2 minutes after study drug administration 


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Additional exploratory statistical analyses to further assess for treatment effect will be 
outlined in the Statistical Analysis Plan finalized prior to database lock for the Primary 
Efficacy Analysis. 
 
13.2.2. 
Pharmacokinetic 
Blood samples will be collected for plasma alprazolam concentration measurement pre-dose 
and then at 10, 30, and 60 minutes, and 2 and 6 hours after the dosing of the study drug. 
 
13.2.3. 
Safety 
Safety and tolerability will be assessed by evaluating adverse events, vital signs, concomitant 
medications, clinical laboratory, and electrocardiogram results, as well as physical 
examinations. Sedation will also be assessed using a subject VAS. 
 
13.3. 
Analysis Populations 
13.3.1. 
Treatment Period 
The Efficacy Population (ITT population) will include all subjects who have a seizure event 
and receive study drug during the Treatment Period. Modified Intent to Treat (mITT) 
population will consist of all subjects who have a seizure event, receive study drug, and have 
had at least one evaluation after study drug administration. mITT will be used for primary 
efficacy analysis. 
The PK Population will include all subjects who receive study drug and have at least one 
pharmacokinetic data point during the Treatment Period. Subjects who receive placebo will 
be excluded from the PK Population. 
The Safety Population will include all subjects who receive study drug during the Treatment 
Period from both Part 1 Open-label Feasibility and Part 2 Double-blind. 
The Per Protocol Population will include all subjects in the Efficacy Population who were 
dosed according to protocol and have no major protocol deviations. 
13.4. 
Analyses 
For the Treatment Period, data will be summarized by active treatment by dose level versus 
placebo-treated subjects (i.e., by treatment group). All data for analysis will be listed by 
subject. 
Continuous measures will be summarized descriptively (mean, standard deviation, median, 
minimum value, and maximum value) and categorical measures will be presented as number 
and percentage. 
Additional details for statistical methods will be provided in the Statistical Analysis Plan. 
 
13.4.1. 
Disposition and Baseline Characteristics 
Disposition will be summarized by randomized treatment group. The number and percentage 
of subjects, who are randomized, treated, prematurely discontinued, and complete the study 
will be summarized. 


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Baseline characteristics will be summarized by treatment group. 
The number of subjects in each cohort’s treatment group will be summarized for each 
investigative site for the Treatment Period. Medical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. Concomitant medications will 
be summarized by World Health Organization Drug Dictionary Anatomical-Therapeutic- 
Chemical (WHODRUG_ATC) classification and preferred term. 
13.4.2. 
Efficacy 
All statistical tests will be 2-sided with a significance level of 0.05. Testing will be 
performed only for the Treatment Period. 
Data will be summarized by active treatment by dose level versus placebo-treated subjects 
(i.e., by treatment group). Continuous measures will be summarized descriptively (mean, 
standard deviation, median, minimum value, and maximum value) and categorical measures 
will be presented as number and percentage. 
The primary efficacy analysis will be conducted following completion of the Treatment 
Period for the last subject and data base lock. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the proportion of responders in each treatment group 
achieving seizure activity cessation within 2 minutes after the administration of the study 
drug and no recurrence of seizure activity within 2 hours. The primary endpoint will be 
analyzed with a chi-squared test. The overall treatment comparison, as well as pairwise 
comparisons between each dose level and placebo will be performed. The estimates of the 
treatment difference versus placebo and their 95% confidence interval will be presented. 
There will be no adjustment for multiple treatment group comparisons in this dose-ranging 
Phase 2b study. The dose-response relationship will be explored with a regression analysis. 
The handling of missing data will be summarized in the Statistical Analysis Plan. 
Secondary and Exploratory Efficacy Endpoints 
Secondary and exploratory endpoints will be summarized by treatment group and if 
applicable, by assessment time point. Exploratory statistical testing may be performed if 
warranted. The Cochran-Mantel-Haenszel (CMH) test for row mean score difference will be 
used to test the treatment difference in the seizure episode severity. The Kruskal-Wallis test 
will be used to compare seizure frequencies. The time-to-next-seizure data will be 
summarized and displayed with Kaplan-Meier plots. No multiplicity adjustment will be 
implemented for exploratory tests. 
 
13.4.3. 
Pharmacokinetics 
The collection status of PK samples will be listed for each visit with scheduled 
pharmacokinetic sampling. Plasma concentrations of study drug and the active metabolites 
may be summarized separately, as appropriate. PK parameters including maximum 
concentration (Cmax), time to maximum (Tmax), area under the concentration curve from 0 to 
the last measurable value (AUClast) will be estimated for each subject using 


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noncompartmental methods. Since the time point range is 0 to 6 hours and the alprazolam 
half-life is 11 hours, we do not plan to estimate half-life or AUCinf. 
 
13.4.4. 
Safety 
All safety summaries will be descriptive with no statistical hypothesis testing and based on 
the Safety Population. Subjects will be summarized according to the study drug received 
(i.e., as treated), should it differ from the randomized treatment arm. All safety endpoints will 
be listed in by-subject data listings. 
Adverse events will be coded using MedDRA and summarized by system organ class and 
preferred term. Clinically significant deteriorations in physical examination findings will be 
reported and summarized as adverse events. 
Laboratory values will be converted to the project-defined unit of measurement, as 
applicable, before analysis. Abnormal, clinically significant laboratory values will be 
reported and summarized as adverse events. 
Adverse Events 
An adverse event reported after informed consent and occurring before the first dose of study 
drug in the CRU/EMU will be considered a pre-treatment adverse event. Treatment- 
emergent adverse events (TEAEs) will be defined as any adverse event that occurs after 
administration of study drug. The number and percentage of subjects who report TEAEs will 
be summarized by system organ class and preferred term. 
Treatment emergent adverse events will also be summarized by intensity as well as 
relationship to study drug. 
Subjects who report the same preferred term on multiple occasions will be counted once for 
the preferred term: under the highest severity when summarized by severity and under the 
closest relationship to study drug when summarized by relationship. If a subject reports 
multiple preferred terms for a system organ class, the subject will be counted only once for 
that system organ class. 
Proportions for adverse events that are gender-specific (e.g., dysmenorrhea) will be based on 
the number of subjects from that gender. 
The number and percentage of subjects who experience TEAEs will be summarized by 
treatment group for the following: 
• By system organ class and preferred term 
• By severity/intensity, system organ class, and preferred term 
• By relationship to study drug, system organ class, and preferred term 
• Serious adverse events by system organ class and preferred term 
• Serious adverse events by relationship to study drug, system organ class, and 
preferred term 
• Adverse events resulting in discontinuation of study drug by system organ class 
and preferred term 


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• Adverse events that result in study drug dose interruption by system organ class 
and preferred term 
By subject listings will be provided for any deaths, serious adverse events, and adverse 
events leading to discontinuation of treatment. 
 
Sedation Assessment 
Sedation as measured by the dichotomous using a 100-mm linear VAS will be summarized 
by time point. 
Clinical Laboratory 
Clinical laboratory variables will be presented in 2 ways. First, change from Baseline to each 
scheduled assessment will be summarized descriptively. Baseline will be defined as the 
laboratory value obtained before the first dose of study drug on Day 1; if Day 1 values are 
unavailable, then values obtained at the Screening Visit will be used. 
Second, treatment-emergent potentially clinically significant (PCS) laboratory values will be 
identified. Potentially clinically significant values are defined as those that meet Grade 3 or 
Grade 4 toxicity criteria from the CTCAE criteria. Treatment-emergent PCS laboratory 
values are those in which the baseline value is not PCS and the post-baseline value is PCS. 
The number and percentage of subjects with treatment-emergent PCS laboratory values will 
be summarized by treatment group for each clinical laboratory variable. 
Vital Signs 
The mean change from baseline to each scheduled assessment will be summarized 
descriptively by treatment group for each vital sign variable specified in this protocol. 
Baseline will be defined as the last vital sign value obtained before the first dose of study 
drug on Day 1; if Day 1 values are unavailable, then values obtained at the Screening Visit 
will be used. 
Electrocardiogram 
The change from baseline in electrocardiogram intervals (PR, QT, QTcF, QRS, and RR) to 
each scheduled assessment will be summarized descriptively by treatment group. 


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14. 
REGULATORY CONSIDERATIONS 
It is the responsibility of the clinical site and staff to notify the Sponsor and Sponsor’s 
designee immediately upon becoming aware of a serious breach of GCP or of the study 
protocol. It is the responsibility of the Sponsor or its designee to notify appropriate 
regulatory authorities of any serious breach which is likely to effect, to a significant degree, 
the safety or mental integrity of the subjects of the study or the scientific value of the study. 
14.1. 
Good Clinical Practice 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by GCP, as described in ICH Guideline E6 and in 
accordance with the general ethical principles outlined in the Declaration of Helsinki. The 
study will receive approval from the IRB/EC prior to commencement. The Investigator will 
conduct all aspects of this study in accordance with applicable national, state, and local laws 
of the pertinent regulatory authorities. 
 
14.2. 
Sponsor’s Responsibilities 
The Sponsor or its designee is responsible for the following: 
• Selecting qualified Investigators 
• Providing Investigators with the information they need to properly conduct an 
investigation 
• Ensuring proper monitoring of the investigation 
• Ensuring that the applicable regulatory authorities, and all participating 
Investigators are properly informed of significant new information regarding 
adverse events or risks associated with the medication being studied 
Before an investigational site can enter a subject into the study, a representative of the 
Sponsor will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of the Sponsor or its representatives. 
This will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator. 
During the study, a monitor from Engage Therapeutics, Inc. or its representative will have 
regular contacts with the investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 


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• Perform source data verification. This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records for 
each subject (e.g., clinic charts). 
• Record and report any protocol deviations. 
• Confirm adverse events and serious adverse events have been properly documented 
on eCRFs and confirm any serious adverse events have been forwarded to the 
Sponsor and those serious adverse events that met criteria for reporting have been 
forwarded to the IRB/EC and other applicable country and/or local regulatory 
authorities. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
As the Sponsor, Engage Therapeutics, Inc. has delegated some responsibilities to a designee, 
or Contract Research Organization. 
 
14.3. 
Investigator’s Responsibilities 
Investigator responsibilities are set out in the ICH Guideline for GCP and in the local 
regulations. Each Investigator participating in this study is required to maintain complete 
and accurate study documentation in compliance with current GCP standards and all 
applicable local regulations related to the conduct of a clinical study. 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study drug, and their 
study-related duties and functions. The Principal Investigator will maintain a list of sub- 
Investigators and other appropriately qualified persons to whom he or she has delegated 
significant study-related duties. Individuals ineligible from conducting or working on 
clinical studies, including those ineligible as a result of debarment under the Generic Drug 
Enforcement Act of 1992, will not be allowed to conduct or work on studies sponsored by 
Engage Therapeutics, Inc. The Investigator is required to immediately disclose to the 
Sponsor in writing, if any person involved in the conduct of the study is debarred pursuant to 
a hearing by the FDA under this anti-fraud law, or if any proceeding for debarment is 
pending, or is (to the best of the Investigator’s knowledge) threatened. 
The Investigator is responsible for keeping a record of all subjects who sign an informed 
consent document and are screened for entry into the study. Subjects who fail screening 
must have the reason(s) recorded in the subject’s source documents. 
The Investigator should inform the IRB/EC of any event likely to affect the safety of subjects 
or the continued conduct of the study. Additionally, all updates to the Investigator’s 
Brochure will be sent to the IRB/EC. A progress report will be sent to the IRB/EC and the 
protocol will be reviewed annually (e.g., re-approved) or more frequently, as required by the 
IRB/EC or local regulations. 
The Investigator will maintain a copy of all correspondence with the IRB/EC, including 
copies of approved documents. The Investigator will also maintain a copy of the IRB/EC 


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membership list with occupation and qualification (or a statement confirming compliance 
with GCP requirements for committee composition). 
The Investigator will notify the IRB/EC of the conclusion of the clinical study within 1 
month of completion or termination of the study. The final report sent to the IRB/EC will 
also be sent to the Sponsor along with the completed electronic case report forms (eCRFs) 
and all necessary regulatory documents, thereby fulfilling the Investigator’s regulatory 
responsibility. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records 
(e.g., medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of eCRFs and 
queries. 
14.4. 
Protocol Amendments 
Any permanent change to the protocol, whether it is an overall change or a change for 
specific study center(s), must be handled as a protocol amendment. All amendments to the 
protocol will be written by the Sponsor. The Investigator will not make any changes to this 
protocol without prior written consent from the Sponsor and subsequent approval by the 
IRB/EC. Except for administrative amendments, Investigators must await IRB/EC approval 
of protocol amendments before implementing the change(s). The Sponsor will ensure 
submission of any protocol amendments to the appropriate regulatory agencies. 
Administrative amendments are defined as having no effect on the safety of the research 
subjects, scope of the investigation, or quality of the study. However, a protocol change 
intended to eliminate an apparent immediate hazard to subjects should be implemented 
immediately, and the IRB/EC notified within 5 days. 
When, in the judgment of the chairman of the local IRB/EC, the Investigators, and/or the 
Sponsor, the amendment to the protocol substantially alters the study design and/or increases 
the potential risk to the subject, the currently approved written ICF will require similar 
modification. In such cases, repeat informed consent will be obtained from subjects enrolled 
in the study before continued participation under the new amendment. 
14.5. 
Audits and Inspections 
The Sponsor’s Quality Assurance Unit (or representative) may conduct audits at the study 
site(s). Audits will include, but are not limited to: drug supply, presence of required 
documents, the informed consent process, laboratory specimen processing, and comparison 
of eCRFs with source documents. The Investigator agrees to cooperate with audits 
conducted at a reasonable time and in a reasonable manner. 
Regulatory authorities worldwide may also audit the Investigator during or after the study. 
The Investigator should contact the Sponsor immediately if this occurs, and must fully 
cooperate with the audits conducted at a reasonable time in a reasonable manner. 


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The Investigator is required to make all study documentation promptly available for 
inspection, review or audit at the study site upon request by Sponsor, its representatives, or 
any appropriate regulatory agencies. 
 
14.6. 
Quality Control and Quality Assurance 
All aspects of the study will be carefully monitored by the Sponsor or its authorized 
representative for compliance with applicable government regulations with respect to current 
GCP and standard operating procedures. 
A quality control and quality assurance plan addressing aspects of the study that may impact 
data integrity or the protection of human subjects may be instituted for this study. All audit 
findings will be summarized and placed on file with appropriate documentation of 
response/resolution. 


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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Confidentiality 
All information disclosed or provided by the Sponsor (or designee), or generated or produced 
during the study including, but not limited to, the protocol, the eCRFs, the Investigator’s 
Brochure, and the results obtained during the course of the study, are confidential. The 
Investigator or any person under his/her authority agrees to keep confidential and not to 
disclose the information to any third party without the prior written approval of the Sponsor. 
Submission of this protocol and any other necessary documentation to the IRB is expressly 
permitted, IRB/EC members having the same obligation of confidentiality. Authorized 
regulatory officials and sponsor personnel (or designee) will be allowed full access to inspect 
and copy the records. The copied and inspected records will remain at the site and will not 
be transmitted or removed from the site. Study drug, subject bodily fluids, and/or other 
materials collected shall be used solely in accordance with this protocol, unless otherwise 
agreed to in writing by the Sponsor and responsible ethics committee(s) or regulatory 
authorities. 
Subjects’ names may, however, be made known to a regulatory agency or other authorized 
officials in the event of inspections. Documents containing the full name or other personally 
identifiable information of the subject are to remain at the site. This information will not be 
transferred to the Sponsor nor be contained in regulatory filings. 
15.2. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., protected health information 
authorization). 
Subjects will be identified only by unique subject numbers in eCRFs and other datasets 
generated for this study. The subject will not be identified by name in the eCRF, in any 
study samples or study reports. All data generated in this study is for research purposes only. 
The Sponsor, its partner(s) and designee(s), and various government health agencies may 
inspect the records of this study. Every effort will be made to keep the subject’s personal 
medical data confidential. 
The Sponsor will protect individual subject information to the fullest extent possible during 
this study. At no time will a subject become identified in any publication or presentation. 
However, the subject may have to become identified in the event of a regulatory authority 
audit or inspection in order to verify the accuracy of the data. Access to subject information 
is at the discretion of the Sponsor and cannot occur prior to database lock or other specified 
events as determined solely by the discretion of the Sponsor. 
15.3. 
Data Collection 
All data obtained for analysis in the clinical study described in this protocol will use an 
electronic data capture system. Data reported in the eCRFs should be consistent with and 


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substantiated by the subject’s medical record and original source documents. Any 
discrepancies must be explained. 
Prior to the start of the study, the Principal Investigator will complete a Delegation of 
Authority form (Site Signature and Delegation Log), showing the signatures and handwritten 
initials of all individuals and the delegation of responsibilities, such as identifying those 
individuals who are authorized to make or change entries on eCRFs. 
 
15.4. 
Case Report Form Completion 
Data within the eCRF will be monitored by a Clinical Research Associate according to the 
Monitoring Plan. Queries will be generated based on discrepancies found while monitoring. 
Site personnel will review and respond to these queries appropriately. Additionally, the 
Sponsor’s designee and the Sponsor may periodically perform aggregate data reviews, which 
could result in queries being generated for site personnel resolution. The completed eCRF 
for each subject must be signed and dated by the Principal Investigator to signify that the 
Principal Investigator has reviewed the eCRF and certifies it to be complete and accurate. 
 
15.5. 
Database Management, Data Clarification, and Quality 
Assurance 
The Sponsor’s designee (i.e., a designated Contract Research Organization) will be 
responsible for data management. Data Management will develop a Data Management Plan 
(DMP) document, and provide it to the Sponsor for approval. The DMP document will 
define all activities in the data collection and cleaning process. The detailed DMP will be 
based on the protocol, work scope, contract, analysis plans, data-flows, eCRFs, data cleaning 
procedures, other supporting documents, and data management standards and practices. 
The programmed data validations will be run to check for database completeness and 
consistency, and queries will be generated upon data entry or via review by a Clinical Data 
Manager after entry. The sites will respond to the data queries in a timely manner. 
Quality control procedures will be conducted prior to database lock according to the 
designated Contract Research Organization standard operating procedures. 
When the database has been declared to be complete and accurate, it will be locked. Any 
changes to the database after that time will only be made by joint written agreement between 
the Sponsor, Statistician, Data Manager, and Quality Assurance Auditor according to 
designated standard operating procedures of the Contract Research Organization. 
 
15.6. 
Inspection of Records 
According to the ICH guidelines for GCP, the Sponsor or designee must verify data entered 
in the eCRF entries against the source documents. The objective of source document 
verification is to comply with GCP and international regulatory requirements and to reduce 
the risks of fraud. Source document verification means ensuring that source documents are 
an accurate and confirmable reflection of the subject’s evaluations during participation in the 
study and that all relevant information recorded in the source document is accurately entered 


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into the eCRF. All source documents should be correctly labeled and filed and associated 
with a single, verifiable subject. 
All data required for this study should be captured in source notes. No data obtained by the 
Investigator or other study personnel should be captured directly in the eCRF. All source 
documents pertaining to this study will be maintained by the Investigator and made available 
for inspection by authorized persons. If electronic progress notes and other electronic source 
documents are not compliant with applicable regulatory guidance, they are not considered a 
valid source for this study. All subject progress notes must be dated and signed at the time of 
the visit. The Sponsor reserves the right to terminate the study for refusal of the Investigator 
to supply original source documentation for this clinical study. 
The Investigator will note in a source independent from the eCRF the following information: 
• Information to confirm that the subject exists (e.g., initials, date of birth, and sex); 
• Confirmation that the subject satisfies the inclusion/exclusion criteria; 
• Confirmation that the subject is taking part in the clinical study; 
• Confirmation of the informed consent process; 
• Visit dates and documentation of protocol assessments and procedures; 
• Information concerning all adverse events; 
• Details of concomitant and investigational medications. 
Source document verification is not a substitute for clinical study monitoring, the purpose of 
which is to ensure that the protocol has been followed correctly, the eCRF has been fully and 
accurately completed, source document verification has been carried out, and the study 
timelines and enrollment goals and requirements have been met. 
 
15.7. 
Retention of Records 
For investigational drug studies, clinical Investigators must retain study records for a period 
of 2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indication, until two years after the investigation is 
discontinued and FDA is notified. 
The Investigator must maintain all study documentation as confidential, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator must notify the Sponsor prior to destroying any study essential documents. 
If the Investigator can no longer ensure archiving, he/she shall inform the Sponsor. The 
relevant records shall be transferred to a mutually agreed upon designee. 


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16. 
PUBLICATION POLICY 
The results of this study may be published in a medical publication, journal, or another public 
dissemination, or may be presented at a medical conference or used for teaching purposes. 
Additionally, this study and its results may be submitted for inclusion in all appropriate 
health authority study registries, as well as publication on health authority study registry 
websites, as required by local health authority regulations. Selection of first authorship will 
be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study. 


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17. 
REFERENCES 
 
De Sarro G, Gitto R, Rizzo M, Zappia M, De Sarro A (1996). 1,4-Benzodiazepine derivatives 
as anticonvulsant agents in DBA/2 mice. Gen Pharmacol. 27:935-941. 
Herink J (1997). Effect of alprazolam and ketamine on seizures induced by two different 
convulsants. Acta Medica (Hradec Kralove). 40:9-11. 
Jenck F, Moreau JL, Bonetti EP, Martin JR, Haefely WE (1992). Ro 19-8022, a 
nonbenzodiazepine partial agonist at benzodiazepine receptors: neuropharmacological 
profile of a potential anxiolytic. J Pharmacol Exp Ther. 262:1121-1127. 
Ueki S, Watanabe S, Yamamoto T, Kataoka Y, Tazoe N, Shibata S, Shibata K, Ohta H, 
Kawahara K, Takano M, Suwandi D, Lee SC, Liou SY (1981). Behavioral and 
electroencephalographic effects of alprazolam and its metabolites. Nihon Yakurigaku 
Zasshi. 77:483-509. 
Verster JC, Volkerts ER (2004). Clinical pharmacology, clinical efficacy, and behavioral 
toxicity of alprazolam: a review of the literature. CNS. Drug Rev. 10:45-76. 


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Appendix 1A: Schedule of Events 
(See Appendix 1B, Schedule of Events for detail of Treatment Period procedures) 
 
Qualification Phase 
Treatment 
Phase 
Exit 
Proceduresa 
Follow-up 
Phone Call 
Screen 
Visit 
Qualification 
Periodb 
Qualification 
Visit 
Procedures 
Day -35 
(May extend 
to Day -63) 
Day –35 to 
Day –8 
(May extend 
to Day -63) 
Day -7 to 
Day -1 
Day 1 up to Day 8 
14 ±2 days from 
Study Drug 
Administration 
Informed consent 
X 
Review of inclusion/exclusion criteria 
X 
X 
Xc 
Medical history 
X 
Xc 
Physical examination 
X 
Xc 
X 
Neurological examination 
X 
Xc 
X 
Temperature (oral) 
X 
Xc 
Height 
X 
Weight 
X 
Xc 
Respiratory rate and heart rate 
X 
X 
X 
Blood pressure 
X 
X 
X 
O2 saturation by pulse oximetry (SpO2) 
Xde 
Seizure Episode Severity Rating Scale 
Xf 
Sedation VAS 
Xg 
 
 
a 24 to 32 hours after the treatment administration for patients who receive dosing; and at the time of exit for 
those who didn’t seize 
b During the Qualification Period the subject will record their seizure activity on the seizure diary. The 
Qualification Period may be extended beyond 28 days up to 56 total days to provide flexibility for scheduling of 
the Qualification Visit and Treatment Visit. The 28 days of the seizure diary activity immediately prior to the 
Qualification Visit will be assessed for qualification. 
c At Entry to CRU/EMU 
d At timepoint 0 (+2 min), and 10 (±2 min), 30 (±2 min) and 60 (±5 min) minutes, 2 (±5 min) and 6 (±5 min) 
hours after the dosing of the study drug. 
e Attached at Entry into CRU/EMU 
f At 6 (±5 min) hours after the dosing of the study drug.i 
g When multiple procedures are scheduled at the same time point, the VAS assessment should be performed 
first, immediately followed by the PK draw. Collected at timepoints 10 (±2 min), 30 (±2 min) and 60 (±5 min) 
minutes, 2 (±5 min) and 6 (±5 min) hours after the dosing of the study drug. 


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Qualification Phase 
Treatment 
Phase 
Exit 
Proceduresa 
Follow-up 
Phone Call 
Screen 
Visit 
Qualification 
Periodb 
Qualification 
Visit 
Procedures 
Day -35 
(May extend 
to Day -63) 
Day –35 to 
Day –8 
(May extend 
to Day -63) 
Day -7 to 
Day -1 
Day 1 up to Day 8 
14 ±2 days from 
Study Drug 
Administration 
Dispense and begin Seizure Diary 
X 
Xh 
Seizure Diary Completion 
X 
X 
Seizure Diary Collection and Review 
X 
X 
12-Lead ECG 
X 
Xc 
X 
Chemistry, hematology and urinalysis 
X 
Xc 
X 
Urine drug screeni 
X 
Xc 
Urine Pregnancy test (if applicable) 
X 
Xc 
PK Sample collection 
Xj 
Device training 
X 
Xc 
EEG Recording 
Xek 
Study drug administrationl 
X 
Adverse event assessmentm 
X 
X 
X 
X 
X 
X 
Subject seizure events forms sent to 
Epilepsy Study Consortium Review 
Board 
Xn 
Completed seizure diary sent to Medical 
Monitor for review 
X 
 
 
 
 
 
 
 
 
h Staff Caregiver completes the seizure diary during the Treatment Phase 
i Drug Screen needs to be negative to allow entry into the CRU/EMU and dosing of the study drug. 
j PK samples will be collected at 10 (±2 min), 30 (±2 min) and 60 minutes (±5 min), 2 hours (±5 min) and 6 
hours (±5 min) after the dosing of the study drug. If the PK sample is drawn outside of the timeframe, the 
sample will still be collected and evaluated. 
k Video EEG Recording will be throughout the subject’s stay at the CRU/EMU 
l At the onset of the predictable seizure 
m Adverse Events will be collected throughout the study after Informed Consent is signed and through Follow- 
Up 
n Forms completed and sent to review board within 48 hours after the subject or the subject’s LAR signs 
informed consent at the Screening Visit. 


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Appendix 1B: Schedule of Events – Procedures in CRU/EMU 
 
 
Entry to 
CRU/EMU 
Treatment Day: 
Schedule for day of Seizure Episode only 
Time 0b 10 min 30 min 
1h 
2 h 
6 h 
24ha/ Exit 
Procedures 
Medication history 
X 
Review of eligibility criteria 
X 
Physical examination 
X 
X 
Neurological examination 
X 
X 
Urine pregnancy test (if applicable) 
X 
12-Lead ECG 
X 
X 
Chemistry, hematology and urinalysis 
X 
X 
Urine drug screen 
X 
Weight 
X 
Temperature (oral) 
X 
Vital Signs (BP, HR, RR) 
X 
Xe 
Xe 
Xf 
Xf 
Xf 
X 
Attach EEG electrodes 
X 
Device training 
X 
EEG Recording 
X  
X 
Study Med administration 
Xbcd 
Start Stopwatchd 
X ------------------------------------------------------------------------ X 
Insert Indwelling Catheter for PK 
samples 
X 
PK Sampling 
X 
Xe 
Xe 
Xf 
Xf 
Xf 
Sedation VASg 
Xe 
Xe 
Xf 
Xf 
Xf 
Pulse Oximetry (SpO2)h 
Xe 
Xe 
Xe 
Xf 
Xf 
Xf 
Adverse Event Assessmenti 
X -------------------------------------------------------------------- X 
Seizure Diary 
X  
X 
Seizure Episode Severity Rating Scale 
Xf 
 
 
 
a Patient can be discharged after 24 to 32 hr assessments at the discretion of the study staff 
b Time 0 is defined as the start of inhalation 
c Subjects should have minimal postural changes for the first 1.5 hours after administration of study drug 
d at seizure episode onset 
e  ± 2 minutes 
f  ± 5 minutes 
g When multiple procedures are scheduled at the same time point, the VAS assessment should be performed first, 
immediately followed by the PK draw. 
h Attached at Entry into CRU/EMU 
i Post treatment 
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Appendix 4: Alprazolam (XANAX®) Prescribing Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
Study:  ENGAGE-E-001 
Page 1 of 20 
Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc.
STATISTICAL ANALYSIS PLAN 
Final v1.0 
Protocol ENGAGE-E-001(Amendment 6, v7.0, 01FEB2019) 
A Double-Blind, Placebo-Controlled, Inpatient, Dose-Ranging Efficacy Study of 
Staccato Alprazolam (STAP-001) in Subjects with Epilepsy with a Predictable 
Seizure Pattern 
Date:  July 8, 2019 
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TABLE OF CONTENTS 
List of Abbreviations .............................................................................................................................. 3
1.
INTRODUCTION ............................................................................................................................ 4
1.1
Objectives ................................................................................................................................ 4
1.2
Design ..................................................................................................................................... 4
1.2.1 
Part 1: Open-Label Feasibility ........................................................................................... 4 
1.2.2 
Part 2: Double-Blind.......................................................................................................... 4 
2.
ELABORATION OF STUDY PROTOCOL ...................................................................................... 5
2.1
Study Populations .................................................................................................................... 5
2.2
Study Endpoints ...................................................................................................................... 5
2.2.1 
Efficacy ............................................................................................................................. 5 
2.2.2 
Pharmacokinetic ............................................................................................................... 6 
2.2.3 
Safety ............................................................................................................................... 6 
2.3
Sample Size ............................................................................................................................ 6
3.
STATISTICAL METHODS .............................................................................................................. 6
3.1
General .................................................................................................................................... 6
3.2
Subject Disposition, Demographics, Baseline Characters and Study Drug Compliance ........... 7
3.3
Analysis of Study Endpoints .................................................................................................... 7
3.3.1 
Efficacy ............................................................................................................................. 7 
3.3.2 
Pharmacokinetics ............................................................................................................. 8 
3.3.3 
Safety Analysis ................................................................................................................. 8 
3.3.4 
Multiplicity Adjustment ...................................................................................................... 9 
3.4
Handling of Missing Data ......................................................................................................... 9
3.5
Protocol Deviations ................................................................................................................ 10
3.6
Key Data Items ...................................................................................................................... 10
3.7
Change to Planned Protocol Analysis .................................................................................... 12
4.
OUTPUT PLANNED FOR THE STUDY REPORT (BLINDED PHASE) ........................................ 12
4.1
Tables to be Included in Study Report ................................................................................... 12
4.1.1 
Summary of Subject Information ..................................................................................... 12 
4.1.2 
Summary of Efficacy Endpoints ...................................................................................... 12 
4.1.3 
Summary of PK/PD Endpoints ........................................................................................ 13 
4.1.4 
Summary of Safety Endpoints ........................................................................................ 13 
4.2
Listings to be Included in the Clinical Study Report................................................................ 14
4.2.1 
Listings of Subject Information ........................................................................................ 14 
4.2.2 
Listings of Efficacy Data ................................................................................................. 14 
4.2.3 
Listings of PK Data ......................................................................................................... 14 
4.2.4 
Listings of Safety Data .................................................................................................... 14 
4.3
Figures to be Included in the Clinical Study Report ................................................................ 15
5.
REFERENCES ............................................................................................................................. 16
6.
ATTACHMENT: The Shells of Tables, Figures and Listings planned for Clinical Study Report ..... 16
7.
APPENDIX:  Common Terminology Criteria for Adverse Events (CTCAE, v4.03) ......................... 17
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LIST OF ABBREVIATIONS 
AE 
adverse events 
AED 
antiepileptic drugs  
ATC 
anatomical-therapeutic-chemical  
AUCinf 
area under the concentration curve from 0 to infinity  
AUClast 
area under the concentration curve from 0 to the last measurable value 
CI 
confidence interval 
Cmax 
maximum concentration  
CRU 
clinical research unit  
CTCAE  
Common Terminology Criteria for Adverse Events 
EMU 
epilepsy monitoring unit  
FDA 
Food and Drug Administration  
ITT 
intend-to-treat 
ICH 
International Committee for Harmonization 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PBRS   
Peachtree BioResearch Solution 
PCS 
potentially clinically significant 
PD  
pharmacodynamic 
PK  
pharmacokinetic 
PI  
principal investigator 
PP  
per-protocol 
SAE 
serious adverse events 
SAP 
statistical analysis plan 
SAS 
statistical analysis system 
SD  
standard deviation 
SOC 
system organ class 
Tmax   
time to maximum 
US  
United States 
VAS 
visual analog scale  
WHODRUG World Health Organization Drug Dictionary 
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1.
INTRODUCTION
1.1 Objectives 
The overall objectives of the study are to assess the efficacy and safety of a single administration of 
STAP-001 in subjects with epilepsy with a predictable seizure pattern. 
The primary objectives are: 

To assess the efficacy of STAP-001 (1.0 mg and 2.0 mg) compared to placebo in treating a
seizure episode

To assess the clinical feasibility and safety of the inhalation of STAP-001 (1.0 mg and 2.0
mg) compared to placebo in subjects during a seizure episode

To assess the sedation associated with administration of STAP-001 (1.0 mg and 2.0 mg)
compared to placebo
1.2 Design 
This is a multicenter, dose-ranging study to investigate the efficacy, safety, and clinical usability of 
STAP-001 in adult (18 years of age and older) subjects with epilepsy with a predictable seizure pattern. 
This is an in-patient study. Eligible and qualified subjects will be admitted to a Clinical Research Unit 
(CRU) or Epilepsy Monitoring Unit (EMU) for study participation. The duration of the stay in the in-
patient unit during the Treatment phase will be 2-8 days. The study consists of two parts: Part 1- Open-
Label Feasibility; Part 2 - Double-Blind.  
1.2.1 Part 1: Open-Label Feasibility
The first subjects enrolled in the study will participate in an open-label feasibility evaluation. Enrollment 
in this phase will end when there are data from at least 8 individual subjects with a treated single 
seizure episode in a CRU/EMU. Eligible subjects will receive a single dose of 1 mg STAP-001 at the 
onset of their predictable seizure episode. The subjects will undergo all study procedures and 
evaluations as outlined in this protocol. The feasibility data (with special emphasis on the drug 
administration and clinical assessment procedures) from these 8 subjects will be analyzed and 
reviewed by the Sponsor before starting the double-blind part of the study. If deemed necessary based 
on the feasibility data, the study protocol will be amended (for example, to change the drug 
administration procedure or to redefine the time frame for primary endpoint assessment), before 
starting the double-blind part of the study. 
1.2.2 Part 2: Double-Blind
After admission to the in-patient unit eligible and qualified subjects will be stratified by the use of 
inducing vs non-inducing AED and the use of chronic daily benzodiazepines (yes or no) and randomly 
assigned (1:1:1) to one of two doses of STAP-001 (1 mg or 2 mg) or Staccato placebo.  A blood sample 
for PK analysis (pre-dose) will be obtained.  For each subject, a single seizure episode will be treated 
and assessed. Study medication will be self-administered (when feasible) or administered by a Staff 
Caregiver when a predictable seizure episode starts.  Assessment of the seizure activity is based on 
clinical observation by the Staff Caregiver using a stop watch. In addition, a video EEG will record the 
occurrence, start time, and duration, of the seizure event. PK samples will be collected 10, 30 and 60 
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minutes, and 2 and 6 hours after the administration of the study drug. If possible, subjects will signal 
when they experience a seizure event.  Subject will be under video EEG surveillance throughout the 
Treatment Phase. The Staff Caregiver will signal the event for the video EEG recording, starts the stop 
watch at the time of drug administration, and mark the occurrence of the seizure event on a seizure 
diary. If the seizure episode does not stop within 5 minutes of the study drug administration, rescue 
medication other than alprazolam may be administered at the discretion of the principal investigator per 
the protocol of the research unit. The study exit procedures will be conducted 24 to 32 hours after the 
administration of study medication or when the subject discontinues from the study. 
After discharge from the in-patient unit there will be a safety-follow-up phone contact 14 ± 2 days after 
the subject received the study medication. 
2.
ELABORATION OF STUDY PROTOCOL
2.1 Study Populations 
Five analysis populations will be defined and analyzed: 
1.
The Efficacy Population (ITT population) will include all subjects who have a seizure event
and receive study drug during the Treatment Period.
2.
Modified Intent to Treat (mITT) population will consist of all subjects who have a seizure
event, receive study drug, and have had at least one evaluation after study drug
administration.  mITT will be used for primary efficacy analysis.
3.
The Per Protocol Population will include all subjects in the Efficacy Population who were
dosed according to protocol and have no major protocol deviations. Major protocol deviations
will be identified by Engage Therapeutics, Inc., before the database is locked and unblinded.
4.
The PK Population will include all subjects who receive study drug and have at least one
pharmacokinetic data point during the Treatment Period.  Subjects who receive placebo will
be excluded from the PK Population.  PK concentrations will be analyzed using PK
population.
5.
The Safety Population will include all subjects who receive study drug during the Treatment
Period from both Part 1 Open-label Feasibility and Part 2 Double-blind. All safety parameters
will be analyzed using safety population.
2.2 Study Endpoints 
2.2.1 Efficacy
Primary efficacy endpoint: 

The proportion of responders in each treatment group achieving seizure activity cessation
within 2 minutes after the administration of the study drug and no recurrence of seizure
activity within 2 hours
Secondary endpoints: 

Seizure episode severity assessed by subject and/or Staff Caregiver

Use of rescue medication
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 
Secondary generalization (evolution to a complex partial seizure and/or a generalized tonic-
clonic seizure) 
Exploratory endpoints: 
 
Number of seizures during the 4, 6, and 12 hour time periods after study drug administration 
 
Time to next seizure event with start time >2 minutes after study drug administration  
2.2.2 Pharmacokinetic 
Blood samples will be collected for plasma alprazolam concentration measurement pre-dose and then 
at 10, 30, and 60 minutes, and 2 and 6 hours after the dosing of the study drug. 
2.2.3 Safety 
Safety and tolerability will be assessed by evaluating adverse events (AEs), vital signs, concomitant 
medications, clinical laboratory, and electrocardiogram (ECG) results, as well as neurological and 
physical examinations. Sedation will also be assessed using a subject visual analog scale (VAS).  
2.3 Sample Size 
There are no studies in the literature to provide reliable estimates of active treatment or placebo 
response rates for this study. Assuming a 10% drop-out/protocol violation rate, approximately 115 
subjects will be enrolled in the double-blind part of the study to provide approximately 35 evaluable 
subjects per treatment arm. Enrollment may be stopped after 105 evaluable subjects have completed 
the study. 
Approximately 30% of the overall study population randomized in the study may be subjects being 
treated with chronic daily benzodiazepines as part of their epilepsy management. Since the effect of 
concomitant chronic daily benzodiazepines use on study treatment is unknown, a 50% response rate 
for chronic benzodiazepines users on active treatment arms is assumed. For subjects who are not 
chronic benzodiazepines users, a response rate of 60% for active treatment arms is assumed. With up 
to 30% of study population being chronic benzodiazepines users and these response assumptions, a 
57% response for the active treatment arm is targeted. 
Power calculations assume a 2-sided test and significance level of 0.05 with 90% power and are based 
on the assumption that the proportion of responders with STAP-001 is 57% (best active treatment arm) 
whereas the assumed placebo responder rate is 20%. 
3. STATISTICAL METHODS  
3.1 General 
All data will be analyzed using the Statistical Analysis System (SAS®; Version 9.4).  
Safety and efficacy data will be summarized and presented by treatment group and time point in 
summary tables.  Continuous variables will be presented by descriptive statistics: n, mean, standard 
deviation (SD), median, minimum, and maximum.  Categorical variables will be tabulated by frequency 
count and percentage. 
When the actual treatment received by a subject is different from the randomized treatment assigned, 
the subject will be analyzed per the randomized treatment for the efficacy parameters (using the ITT, 
and mITT populations); while the subject will be analyzed per actual treatment that was taken for the 
safety parameters (using the safety population). 
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Unless otherwise stated, all statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance for main effects and all confidence intervals (CIs) will be 2-sided 95% confidence intervals. 
For the Treatment Period, data will be summarized by active treatment by dose level versus placebo-
treated subjects (i.e., by treatment group). All data for analysis will be listed by subject. 
3.2 Subject Disposition, Demographics, Baseline Characters and Study Drug Compliance 
 
Disposition will be summarized by randomized treatment group. The number and percentage 
of subjects, who are randomized, treated, prematurely discontinued, and complete the study 
will be summarized. 
 
Baseline characteristics will be summarized by treatment group. 
 
The number of subjects in each cohort’s treatment group will be summarized for each 
investigative site for the Treatment Period.  
 
Medical history will be listed with reported terms.  
 
Concomitant medications will be summarized by World Health Organization Drug Dictionary 
Anatomical-Therapeutic-Chemical (WHODRUG_ATC) classification and preferred term. 
3.3 Analysis of Study Endpoints 
3.3.1 Efficacy 
All statistical tests will be 2-sided with a significance level of 0.05. Testing will be performed only for the 
Treatment Period.  
Data will be summarized by active treatment by dose level versus placebo-treated subjects (i.e., by 
treatment group).  Continuous measures will be summarized descriptively (mean, standard deviation, 
median, minimum value, and maximum value) and categorical measures will be presented as number 
and percentage.   
The primary efficacy analysis will be conducted following completion of the Treatment Period for the 
last subject and data base lock. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the proportion of responders in each treatment group achieving 
seizure activity cessation within 2 minutes after the administration of the study drug and no recurrence 
of seizure activity within 2 hours.  The primary endpoint will be analyzed with a chi-squared test. The 
overall treatment comparison, as well as pair-wise comparisons between each dose level and placebo 
will be performed. The estimates of the treatment difference versus placebo and their 95% confidence 
interval will be presented. 
There will be no adjustment for multiple treatment group comparisons in this dose-ranging Phase 2b 
study. The dose-response relationship will be explored with a regression analysis. 
Secondary and Exploratory Efficacy Endpoints 
Secondary and exploratory endpoints will be summarized by treatment group and if applicable, by 
assessment time point. Exploratory statistical testing may be performed if warranted. The Cochran-
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Mantel-Haenszel (CMH) test for row-mean score difference will be used to test the treatment difference 
in the seizure episode severity. The Kruskal-Wallis test will be used to compare seizure frequencies. 
The time-to-next-seizure data will be summarized and displayed with Kaplan-Meier plots. No multiplicity 
adjustment will be implemented for exploratory tests. 
3.3.2 Pharmacokinetics 
The collection status of PK samples will be listed for each visit with scheduled pharmacokinetic 
sampling. Plasma concentrations of study drug and the active metabolites may be summarized 
separately, as appropriate.  
PK parameters including maximum concentration (Cmax), time to maximum (Tmax), area under the 
concentration curve from 0 to the last measurable value (AUClast) will be estimated for each subject 
using non-compartmental methods. Since the time point range is 0 to 6 hours and the alprazolam half-
life is 11 hours, we do not plan to estimate half-life or AUCinf.  
3.3.3 Safety Analysis 
All safety summaries will be descriptive with no statistical hypothesis testing and based on the Safety 
Population. Subjects will be summarized according to the study drug received.  (i.e., as treated), should 
it differ from the randomized treatment arm. All safety endpoints will be listed in by-subject data listings. 
Adverse Events 
An adverse event reported after informed consent and occurring before the first dose of study drug in 
the CRU/EMU will be considered a pre-treatment adverse event. Treatment-emergent adverse events 
(TEAEs) will be defined as any adverse event that occurs after administration of study drug.  
 
The number and percentage of subjects who experience TEAEs will be summarized by 
treatment group for the following: 
o 
By system organ class and preferred term 
o 
By severity, system organ class, and preferred term 
o 
By relationship  to study drug, system organ class, and preferred term 
o 
Serious adverse events by system organ class and preferred term 
o 
TEAE by preferred term and overall frequency. 
 
Subjects who report the same preferred term on multiple occasions will be counted once for 
the preferred term: under the highest severity when summarized by severity and under the 
closest relationship to study drug when summarized by relationship.  
 
If a subject reports multiple preferred terms for a system organ class, the subject will be 
counted only once for that system organ class. 
 
Subject listings will be provided for any deaths, serious adverse events, and adverse events 
leading to withdrawal. 
Sedation Assessment 
 
Sedated and alert scale as measured using a 100-mm linear VAS will be summarized by time 
point. 
 
Sleepy and Awake scale as measured using a 100-mm linear VAS will be summarized by 
time point. 
Clinical Laboratory 
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Clinical laboratory variables will be presented in 3 ways.  
1. 
Change from Baseline to each scheduled assessment will be summarized descriptively. 
Baseline will be defined as the laboratory value obtained before the first dose of study drug 
on Day 1; if Day 1 values are unavailable, then values obtained at the Screening Visit will be 
used. 
2. 
The number and percentage of subjects with abnormal laboratory values will be summarized 
by treatment group for each clinical laboratory variable. 
3. 
The number and percentage of subjects with treatment-emergent potentially clinically 
significant (PCS) laboratory values will be summarized by treatment group for each clinical 
laboratory variable. Potentially clinically significant lab values are defined as those that 
toxicity grade are ≥ 3 from the common terminology criteria for adverse events (CTCAE) 
criteria (See Section 7 Appendix). Treatment-emergent PCS laboratory values are those in 
which the baseline value is not PCS and the post-baseline value is PCS. 
Vital Signs 
The mean change from baseline to each scheduled assessment will be summarized descriptively by 
treatment group for each vital sign variable specified in this protocol. 
Baseline will be defined as the last vital sign value obtained before the first dose of study drug on Day 
1; if Day 1 values are unavailable, then values obtained at the Screening Visit will be used. 
Electrocardiogram 
The change from baseline in ECG intervals (PR, QT, QTcF, QRS, and RR) to each scheduled 
assessment will be summarized descriptively by treatment group. 
Neurological and Physical Examinations 
 
The number (%) of subjects of baseline neurological and physical examination results will be 
provided by categories of Normal/Abnormal/Not Done and treatment group for each 
examination item. 
 
The number (%) of subjects of post-baseline results will be summarized by categories of 
Normal/Abnormal/Not Done/No Change and treatment group for each examination item at 
scheduled assessment. 
3.3.4 Multiplicity Adjustment 
 
Multiplicity adjustment will not be applied for multiple testing in this study.  
3.4 Handling of Missing Data  
3.4.1 Imputation Rules for AE Records 
For safety analyses, the incomplete date and time for the safety events will not be imputed. However, 
the following imputation rule will be applied for AEs. 
 
If the start date of an AE is missing, then the AE will be considered as Treatment-Emergent 
AE (TEAE). 
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 
If the end date of an AE is missing and the ongoing flag is missing, then the AE status will be 
considered as ongoing. 
 
If the severity of an AE is missing, then the AE will be considered as “Severe” (CTCAE grads 
3).  
 
If the relationship to the study agent of an AE is missing, then the AE will be considered as 
“related” to study agent.  
3.4.2 Imputation Rules for Epilepsy Onset Date 
To calculate duration of seizure history, the incomplete epilepsy onset date will be imputed as following. 
 
Completely missing epilepsy onset date (UNK-UNK-UNK) will not be imputed, and hence no 
duration of seizure history will be calculated. 
 
If epilepsy onset date recoded as yyyy-UNK-UNK, then epilepsy onset date will be imputed as 
yyyy-07-01.  July 1 will be used for unknown month and date.  
 
If epilepsy onset date recoded as yyyy-MM-UNK, then epilepsy onset date will be imputed as 
yyyy-MM-15. 15 will be used for unknown onset data. 
3.5 Protocol Deviations  
Listing for all protocol deviations will be provided. 
Listing for major deviations that result in excluding from the PP population will also be provided for 
blinded phase.  
3.6 Key Data Items 
Study Analysis Population Definition: 
 
Intend-To-Treat (ITT) population:  All subjects who have seizure events and received 
study drug.   
 
Modified Intend-to Treat(mITT) population: All ITT subjects have had at least one efficacy 
evaluation after study drug dosed 
 
Per-Protocol (PP) population:  All ITT subjects without any major protocol deviations. 
 
PK Population: All ITT subjects who provided at least one PK data point.   
 
Safety Population:  All ITT subjects who receive at least one dose of study drug.  
Important Derived Variables: 
 
Age (year) = (Screening Date – Date of Birth +1)/365.25. 
 
Duration of Seizure History (year) = (Screening Date – Epilepsy Onset Date +1)/365.25. 
 
Prior Medications and Treatments: the medications and treatments started before enrolled 
to the study without any change after the enrollment. 
 
Concomitant Medication and Treatments:  the medications and treatments started on or 
after the time of the first dose of the study drug.  Any medications and treatments started 
before but changed after the first dose of the study drug will be considered as concomitant 
medications and treatments. 
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 
Baseline:  All clinical measurements (safety and efficacy data) collected at Day 1 or before 
the first dose will be analyzed as baseline.   
 
Post Baseline:  All clinical measurements (safety and efficacy data) collected after the first 
dose will be analyzed as post baseline.   
 
Treatment emergent Adverse Events (TEAE):  Any AEs started on or after the time of the 
first study drug dosed. 
Flags for Efficacy Endpoints: 
 
Treatment Response Flag 
= ‘Yes’, if treated seizure stopped within 2 minutes and there are no seizure events within 
2 hours (120 minutes); 
= ‘No’, otherwise; 
 
Secondary Generalization Flag 
= ‘Yes’, if at least one post-treatment seizure event was categorized as “a complex partial 
seizure” or “partial seizures evolving to secondarily generalized seizures” and/or “a 
generalized tonic-clonic seizure”; 
= ‘No’, otherwise; 
 
Number of Post-Treatment Seizures 
a. N_4h = #  of seizures observed during 0 – 4  hours post-treatment 
b. N_6h = #  of seizures observed during 0 – 6  hours post-treatment 
c. N_12h = #  of seizures observed during 0 – 12  hours post-treatment 
 
Time to the next seizure event 
= the next seizure event start time, if the start time > 2 minutes after study drug dosed 
= censored (left censored at 2 minutes), if the start time ≤ 2 minutes after study drug 
dosed     
Formulas of Metric Conversion:   
 
1 inch = 2.54 cm  
 
1 lb = 0.4536 kg 
 
 oC = (oF – 32)x5/9 
LABORATORY ASSESSMENTS 
Chemistry (Serum) 
Alanine aminotransaminase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransaminase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Blood urea nitrogen 
Calcium 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase 
Hematology (Blood)  
Complete blood count 
Platelet count 
White blood cell count with differential 
Hemoglobin 
Hematocrit 
 
Urinalysis 
Bilirubin 
Blood 
Clarity 
Urobilirubin 
Glucose, Urine 
Ketones 
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Glucose 
Lipase 
Total protein 
Phosphorus 
Potassium 
Sodium 
Uric Acid  
Leukocyte Esterase 
Nitrate 
pH 
Protein, Urine 
Specific Gravity 
 
 
3.7 Change to Planned Protocol Analysis 
Not applicable. 
4. OUTPUT PLANNED FOR THE STUDY REPORT (BLINDED PHASE)  
4.1 Tables to be Included in Study Report  
In the following sections, the different results are presented in the order in which it is planned to make 
them appear in the study report.  
The table templates are available in the Appendix of the SAP. The content shown in the templates does 
only mean as an example. It is not based on real study data or details concerning design.  
4.1.1 Summary of Subject Information 
Table 14.1.1 Subject Disposition – All Subjects 
 
Table 14.1.2 Summary of Demographics – ITT Population 
Table 14.1.3 Summary of Seizure History – ITT Population 
Table 14.1.4.1 Summary of Concomitant Medications – Safety Population 
Table 14.1.4.2 Summary of Concomitant Procedures – Safety Population 
Table 14.1.4.3 Summary of Rescue Medications – ITT Population 
4.1.2 
Summary of Efficacy Endpoints 
Table 14.2.1.1 Result of Treatment Response – mITT Population 
Table 14.2.1.2 Result of Treatment Response – PP Population 
Table 14.2.2.1 Results of Seizure Episode Severity Scale – mITT Population  
Table 14.2.2.2 Results of Seizure Episode Severity Scale – PP Population  
Table 14.2.3.1 Result of Use of Rescue Medication – mITT Population 
Table 14.2.3.2 Result of Use of Rescue Medication – PP Population 
Table 14.2.4.1 Result of Secondary Generalization Evolution – mITT Population 
Table 14.2.4.2 Result of Secondary Generalization Evolution – PP Population 
Table 14.2.5.1 Summary of Seizure Number after Study Drug Administration – mITT Population 
Table 14.2.5.2 Summary of Seizure Number after Study Drug Administration – PP Population 
Table 14.2.5.3 Treatment Comparison of Seizure Number after Study Drug Administration – mITT 
Population 
Table 14.2.5.4 Treatment Comparison of Seizure Number after Study Drug Administration – PP 
Population 
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Table 14.2.6.1 Kaplan-Meier Analysis of Time to Next Seizure Event after Study Drug Administration – 
mITT Population 
Table 14.2.6.2 Kaplan-Meier Analysis of Time to Next Seizure Event after Study Drug Administration – 
PP Population 
4.1.3 
Summary of PK/PD Endpoints 
Table 14.2.7.1 Summary of Plasma PK Concentration by Sample Time Point – PK Population 
Table 14.2.7.2 Summary of PK Parameter – PK Population 
4.1.4 
Summary of Safety Endpoints 
Table 14.3.1.1 Summary of Adverse Events – Safety Set 
 
Table 14.3.1.2 Summary of Adverse Events by MedDRA System Organ Class and Preferred Term – 
Safety Set 
 
Table 14.3.1.3 Summary of Serious Adverse Events by MedDRA System Organ Class and Preferred 
Term – Safety Set 
 
Table 14.3.1.4 Summary of Adverse Events by Severity, MedDRA System Organ Class and Preferred 
Term – Safety Set 
Table 14.3.1.5 Summary of Adverse Events by Relationship to Study Agent, MedDRA System Organ 
Class and Preferred Term – Safety Set 
 
Table 14.3.1.6 Summary of Adverse Events by MedDRA Preferred Term and Overall Frequency – 
Safety Set 
Table 14.3.2.1 Summary of Vital Signs by Time Point – Safety Set 
Table 14.3.2 2 Summary of Vital Signs Change from Baseline by Time Point – Safety Set 
 
Table 14.3.3.1 Summary of ECG by Time Point – Safety Set 
Table 14.3.3.2 Summary of ECG Change from Baseline by Time Point– Safety Set 
Table 14.3.3.3 Summary of ECG Category Results by Time Point – Safety Set 
Table 14.3.3.4 Summary of ECG Interpretation by Category and Time Point – Safety Set 
Table 14.3.4.1 Summary of Physical Examination by Visit – Safety Set 
Table 14.3.4.2 Summary of Neurological Examination by Visit – Safety Set 
Table 14.3.5.1 Summary of Laboratory (Hematology) Test Results – Safety Set 
Table 14.3.5.2 Summary of Laboratory (Blood Chemistry) Test Results – Safety Set 
Table 14.3.5.3 Summary of Laboratory (Urine) Continuous Test Results – Safety Set 
Table 14.3.5.4 Summary of Laboratory (Urine) Category Test Results – Safety Set 
Table 14.3.5.5 Number and Percentage Subjects with TEPCS Laboratory (Hematology) Test Results – 
Safety Set 
Table 14.3.5.6 Number and Percentage Subjects with TEPCS Laboratory (Blood Chemistry) Test 
Results – Safety Set 
Table 14.3.5.7 Number and Percentage Subjects with TEPCS Laboratory (Urine) Test Results – Safety 
Set 
Table 14.3.5.8 Number and Percentage Subjects with Abnormal Laboratory (Hematology) Test Results 
– Safety Set 
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Table 14.3.5.9 Number and Percentage Subjects with Abnormal Laboratory (Blood Chemistry) Test 
Results – Safety Set 
Table 14.3.5.10 Number and Percentage Subjects with Abnormal Laboratory (Urine) Continuous Test 
Results – Safety Set 
Table 14.3.6.1 Summary of Sedation and Alert Scale VAS – Safety Set  
Table 14.3.6.2 Summary of Sleepy and Awake Scale VAS – Safety Set 
4.2 
Listings to be Included in the Clinical Study Report  
4.2.1 
Listings of Subject Information 
Listing 16.1 Discontinued Subjects – Safety Set 
 
Listing 16.2 Demographic Characteristics – Safety Set 
Listing 16.3.1 General Medical History – Safety Set 
Listing 16.3.2 Seizure History – Safety Set 
Listing 16.4.1 Concomitant Medications – Safety Set 
Listing 16.4.2 Concomitant Procedures – Safety Set 
Listing 16.4.3 Rescue Medications – Safety Set 
Listing 16.5 Study Drug Administration – Safety Set  
Listing 16.6 Protocol Deviations – Safety Set 
Listing 16.7 Visit Date – Safety Set 
4.2.2 
Listings of Efficacy Data 
Listing 16.8.1 Clinical Response – Safety Set  
Listing 16.8.2 Seizure Episode Severity Scale – Safety Set 
Listing 16.8.3 Use of Rescue Medication – Safety Set 
Listing 16.8.4 Secondarily Generalized Evolution – Safety Set 
Listing 16.8.5 Number of Post Treatment Seizure – Safety Set 
Listing 16.8.6 Post-Treatment Seizure – Safety Set 
Listing 16.8.7 Time to Next Seizure Event – Safety Set 
4.2.3 
Listings of PK Data 
Listing 16.9.1 Plasma PK Concentrations (unit) – Safety Set 
Listing 16.9.2 PK Parameter – Safety Set 
4.2.4 
Listings of Safety Data 
Listing 16.10.1 Adverse Events – Safety Set 
Listing 16.10.2 Serious Adverse Events – Safety Set 
Listing 16.10.3 Severe (≥3 CTCAE Grade) Adverse Events – Safety Set 
Listing 16.10.4 Study Drug Related Adverse Events – Safety Set 
Listing 16.10.5 Adverse Events Leading to Death or Withdrawal – Safety Set 
Listing 16.11.1 Results of Laboratory (Hematology) Tests – Safety Set 
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Listing 16.11.2 Results of Laboratory (Blood Chemistry) Tests – Safety Set 
Listing 16.11.3 Results of Laboratory (Urine) Tests – Safety Set 
Listing 16.11.4 Results of Urine Drug and Alcohol Tests – Safety Set 
Listing 16.11.5 Results of Urine Pregnancy Tests – Safety Set 
Listing 16.12 Results of Vital Signs – Safety Set  
 
Listing 16.13 Results of ECG – Safety Set   
Listing 16.14 Abnormalities of Physical Examination – Safety Set 
Listing 16.15 Abnormalities of Neurological Examination – Safety Set 
Listing 16.16 Sedation and Alert VAS – Safety Set 
Listing 16.17 Sleepy and Awake VAS – Safety Set 
Listing 16.18 Randomization List – Safety Set 
4.3 
Figures to be Included in the Clinical Study Report  
Figure 14.4.1 Kaplan-Meier Plot of Time to Next Seizure Event with Start Time >2 Minutes after Study 
Drug Administration – mITT Population 
Figure 14.5.1 Plasma PK Concentrations (in Linear Scale) – PK Evaluable 
Figure 14.5.2 Plasma PK Concentrations (in Semi-log Scale) – PK Evaluable 
 
 
 
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5. REFERENCES 
(1) Protocol Engage-E-001: A Double-Blind, Placebo-Controlled, Inpatient, Dose-Ranging 
Efficacy Study of Staccato Alprazolam (STAP-001) in Subjects with Epilepsy with a 
Predictable Seizure Pattern, Amendment 6 (v7.0), February 1, 2019, Engage Therapeutics, 
Inc. 
(2) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03: June 14, 2010,  
U.S. Department of Health and Human Services  
 
6. ATTACHMENT: THE SHELLS OF TABLES, FIGURES AND LISTINGS PLANNED FOR 
CLINICAL STUDY REPORT 
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7. 
APPENDIX:  COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE, V4.03) 
Test 
Test 
Code 
Standard 
Units 
Direction 
of Change 
Toxicity Grade 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acidosis 
PH 
n/a 
Decrease/Acidosis 
WNL 
≥7.3 - 
<LLN 
 
<7.3 
 
Activated Partial 
Thromboplastin Time 
APTT 
n/a 
Increase/Activated 
partial thromboplastin 
time prolonged 
WNL 
>ULN- 
≤1.5 xULN 
>1.5 xULN 
- ≤2.5xULN 
>2.5 xULN 
 
Alanine Aminotransferase 
(ALT/SGPT) 
ALT 
n/a 
Increase/ Alanine 
aminotransferase 
increased 
WNL 
>ULN - 
≤3.0 xULN 
>3.0 xULN 
- ≤5.0 
xULN 
>5.0 xULN 
- ≤20.0 
xULN 
>20.0 
xULN 
Albumin 
ALB 
g/L 
Decrease/Hypoalbumine
-mia 
WNL 
≥30 - <LLN 
≥20 - <30 
<20 
 
Alkaline Phosphatase 
ALP 
n/a 
Increase/Alkaline 
phosphatase increased 
WNL 
>ULN - 
≤2.5 xULN 
>2.5 xULN 
- ≤5.0 
xULN 
>5.0 xULN 
- ≤20.0 
xULN 
>20.0 
xULN 
Alkalosis 
PH 
n/a 
Increase/Alkalosis 
WNL 
>ULN- 
≤7.5 
 
>7.5 
 
Amylase 
AMYLAS
E 
n/a 
Increase/Serum 
amylase increased 
WNL 
>ULN - 
≤1.5 xULN 
>1.5 xULN 
- ≤2.0 
xULN 
>2.0 xULN 
- ≤5.0 
xULN 
>5.0 xULN 
Aspartate 
Aminotransferase 
AST 
n/a 
Increase/Aspartate 
aminotransferase 
increased 
WNL 
>ULN - 
≤3.0 xULN 
>3.0 xULN 
- ≤5.0 
xULN 
>5.0 xULN 
- ≤20.0 
xULN 
>20.0 
xULN 
Bilirubin 
BILI 
n/a 
Increase/Blood bilirubin 
increased 
WNL 
>ULN - 
≤1.5 xULN 
>1.5 xULN 
- ≤3.0 
xULN 
>3.0 xULN 
- ≤10.0 
xULN 
>10.0 
xULN 
Calcium 
CA 
mmol/L 
Increase/Hypercalcemia 
WNL 
>ULN - 
≤2.9 
>2.9 - ≤3.1 
>3.1 - ≤3.4 
>3.4 
Calcium 
CA 
mmol/L 
Decrease/Hypocalcemia 
WNL 
≥2.0 - 
<LLN 
≥1.75 - 
<2.0 
≥1.5 - 
<1.75 
<1.5 
Calcium Corrected 
CACOR 
mmol/L 
Increase/Hypercalcemia 
WNL 
>ULN - 
≤2.875 
>2.875 - 
≤3.125 
>3.125 - 
≤3.375 
>3.375 
Calcium Corrected 
CACOR 
mmol/L 
Decrease/Hypocalcemia 
WNL 
≥2.0 - 
<LLN 
≥1.75 - 
<2.0 
≥1.5 - 
<1.75 
<1.5 
Calcium Ionized 
CAION 
mmol/L 
Increase/Hypercalcemia 
WNL 
>ULN - 
≤1.5 
>1.5 - ≤1.6 
>1.6 - ≤1.8 
>1.8 
Calcium Ionized 
CAION 
mmol/L 
Decrease/Hypocalcemia 
WNL 
≥1.0 - 
<LLN 
≥0.9 - < 1.0 
≥0.8 - < 0.9 
<0.8 
CD4 
CD4 
x10E9/L 
Decrease/CD4 
lymphocytes decreased 
WNL 
≥0.5 - 
<LLN 
≥0.2 - < 0.5 
≥0.05 - 
<0.2 
<0.05 
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Page 18 of 20 
 
 
 
Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
Test 
Test 
Code 
Standard 
Units 
Direction 
of Change 
Toxicity Grade 
0 
1 
2 
3 
4 
Cholesterol 
CHOL 
mmol/L 
Increase/Cholesterol 
high 
WNL 
>ULN - 
≤7.75 
>7.75 -≤ 
10.34 
>10.34 - 
≤12.92 
>12.92 
Creatine Kinase 
CK 
n/a 
Increase/CPK increased 
WNL 
>ULN - 
≤2.5 xULN 
>2.5 xULN 
- ≤5 xULN 
>5 xULN - 
≤10 xULN 
>10 xULN 
Creatinine 
CREAT 
n/a 
Increase/Creatinine 
increased 
WNL 
>ULN - 
≤1.5 xULN 
>1.5 xULN 
- ≤3.0 
xULN 
>3.0 xULN 
- ≤6.0 
xULN 
>6.0 xULN 
Fibrinogen 
FIBRINO 
umol/L 
Decrease/Fibrinogen 
decreased 
WNL 
<1.0 - 0.75 
x LLN 
<0.75 - 0.5 
x LLN 
<0.5 - 0.25 
x LLN 
0.25xLLN 
Gamma Glutamyl 
Transferase (GGT) 
GGT 
n/a 
Increase/GGT increased 
WNL 
>ULN - 
≤2.5 xULN 
>2.5 xULN 
- ≤5.0 
xULN 
>5.0 xULN 
- ≤20.0 
xULN 
>20.0 
xULN 
Glucose (fasting) 
GLUC 
mmol/L 
Increase/Hyperglycemia 
WNL 
>ULN - 
≤8.9 
>8.9 - 
≤13.9 
>13.9 - 
≤27.8 
>27.8 
Glucose 
GLUC 
mmol/L 
Decrease/Hypoglycemia 
WNL 
≥3.0 - 
<LLN 
≥2.2 - <3.0 
≥1.7 - <2.2 
<1.7 
Glucose (fasting) 
GLUC 
mmol/L 
Increase/Hyperglycemia 
WNL 
>ULN - 
≤8.9 
>8.9 - 
≤13.9 
>13.9 - 
≤27.8 
>27.8 
Glucose 
GLUC 
mmol/L 
Decrease/Hypoglycemia 
WNL 
≥3.0 - 
<LLN 
≥2.2 - <3.0 
≥1.7 - <2.2 
<1.7 
Glucose (fasting) 
GLUC 
mmol/L 
Increase/Hyperglycemia 
WNL 
>ULN - 
≤8.9 
>8.9 - 
≤13.9 
>13.9 - 
≤27.8 
>27.8 
Glucose 
GLUC 
mmol/L 
Decrease/Hypoglycemia 
WNL 
≥3.0 - 
<LLN 
≥2.2 - <3.0 
≥1.7 - <2.2 
<1.7 
Granulocytes 
GRAN 
x10E9/L 
Decrease/Neutrophil 
count decreased 
WNL 
≥1.5 - 
<LLN 
≥1.0 - <1.5 
≥0.5 - <1.0 
<0.5 
Haptoglobin 
HAPTOG 
μmol/L 
Decrease/Haptoglobin 
decreased 
WNL 
>0 - < LLN 
 
 
 
Hemoglobin 
HGB 
g/L 
Increase/Hemoglobin 
increased 
WNL 
Increase in 
>0 - 20 g/L 
above ULN 
or above 
baseline if 
baseline is 
above ULN 
Increase in 
>20 - 40 
g/L above 
ULN or 
above 
baseline if 
baseline is 
above ULN 
Increase in 
>40 g/L 
above ULN 
or above 
baseline if 
baseline is 
above ULN 
 
Hemoglobin 
HGB 
g/L 
Decrease/Anemia 
WNL 
≥100 - 
<LLN 
≥80 - 
<100.0 
<80 
 
Leukocytes (WBC) 
WBC 
x10E9/L 
Decrease/White blood 
cell decreased 
WNL 
≥3.0 - 
<LLN 
≥2.0 - <3.0 
≥1.0 - <2.0 
<1.0 
Lymphocytes 
LYM 
x10E9/L 
Decrease/Lymphocyte 
count decreased 
WNL 
≥0.8 - 
<LLN 
≥0.5 - <0.8 
≥0.2 - <0.5 
<0.2 
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Page 19 of 20 
 
 
 
Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
Test 
Test 
Code 
Standard 
Units 
Direction 
of Change 
Toxicity Grade 
0 
1 
2 
3 
4 
Magnesium 
MG 
mmol/L 
Increase/Hypermagnese
-mia 
WNL 
>ULN - 
≤1.23 
 
>1.23 - 
≤3.30 
>3.30 
Magnesium 
MG 
mmol/L 
Decrease/Hypomagnes
e-mia 
WNL 
≥0.5 - 
<LLN 
≥0.4 - <0.5 
≥0.3 - <0.4 
<0.3 
Neutrophils 
NEUT 
x10E9/L 
Decrease/Neutrophil 
count decreased 
WNL 
≥1.5 - 
<LLN 
≥1.0 - <1.5 
≥0.5 - <1.0 
<0.5 
Phosphate (Phosphate, 
Inorganic) 
PHOS 
mmol/L 
Decrease/Hypophospha
te-mia 
WNL 
≥0.8 - 
<LLN 
≥0.6 - <0.8 
≥0.3 - <0.6 
<0.3 
Platelets 
PLAT 
x10E9/L 
Decrease/Platelet count 
decreased 
WNL 
≥75.0 - 
<LLN 
≥50.0 - 
<75.0 
≥25.0 - 
<50.0 
<25.0 
Potassium 
K 
mmol/L 
Increase/Hyperkalemia 
WNL 
>ULN - 
≤5.5 
>5.5 - ≤6.0 
>6.0 - ≤7.0 
>7.0 
Potassium 
K 
mmol/L 
Decrease/ Hypokalemia 
WNL 
 
≥3.0 - 
<LLN 
≥2.5 - <3.0 
<2.5 
Protein (Urine, >16yr) 
PROT 
 
Increase/Proteinuria 
WNL 
1+ 
2+ 
 
 
Protein (Urine, <=16yr) 
PROT 
 
Increase/Proteinuria 
WNL 
1+ 
 
 
 
Protein/Creatinine (Urine) 
PROTCR
T 
 
Increase/Proteinuria 
WNL 
 
>=0.5 - 
<=1.9 
>1.9 
 
 
Prothrombin Intl. 
Normalized Ratio 
INR 
n/a 
Increase/INR increased 
WNL 
>ULN - 
≤1.5 xULN 
>1.5 xULN 
- ≤2.5 
xULN 
>2.5 xULN 
 
Sodium 
SODIUM 
mmol/L 
Increase/Hypernatremia 
WNL 
>ULN - 
≤150 
>150 - 
≤155 
>155 - 
≤160 
>160 
Sodium 
SODIUM 
mmol/L 
Decrease/Hyponatremia 
WNL 
≥130 - 
<LLN 
 
≥120 - 
<130 
<120 
Triacylglycerol Lipase 
(Lipase) 
LIPASE 
n/a 
Increase/Lipase 
increased 
WNL 
>ULN - 
≤1.5 xULN 
>1.5 xULN 
- ≤2.0 
xULN 
>2.0 xULN 
- ≤5.0 
xULN 
>5.0 xULN 
Triglycerides 
TRIG 
mmol/L 
Increase/Hypertriglycer-
idemia 
WNL 
>1.71- 
≤3.42 
>3.42 - 
≤5.7 
>5.7 - 
≤11.4 
>11.4 
WNL = Within Normal range, LLN = Lower Limit of Normal Range, ULN = Upper Limit of Normal Range 
 
 
 
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Statistical Analysis Plan 
Study:  ENGAGE-E-001 
 
 
 
Page 20 of 20 
 
 
 
Confidential & Proprietary Information of Peachtree BioResearch Solutions, Inc. 
Approval for  
Statistical Analysis Plan 
 
Title: 
A Double-Blind, Placebo-Controlled, Inpatient, Dose-Ranging 
Efficacy Study of Staccato Alprazolam (STAP-001) in Subjects with 
Epilepsy with a Predictable Seizure Pattern 
 
 
 
 
Reference: 
ENGAGE-E-001/SAP 
 
Version: 
1.0 
 
Date effective: 
 
 
 
 
 
Author: 
 PhD. Biostatistics, Peachtree BRS, Inc. 
 
Author’s signature: 
 
 
 
 
Date: 
 
 
 
The above Statistical Analysis Plan has been reviewed and approved by the Sponsor: 
 
 
 
 
 
Name of 
Reviewer/Approver 
, RN, BSN 
 
 
 
Position:   
VP Clinical Operations, Engage Therapeutics, Inc. 
Signature for 
sponsor: 
 
 
 
Date: 
 
 
 
 
 
  
Name of 
Reviewer/Approver 
 
 
 
 
Position: 
 
 
 
 
Signature for 
sponsor: 
 
 
 
Date: 
 
 
 
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