StATES: Inpatient, Dose-Ranging Study of Staccato Alprazolam in Epilepsy With Predictable Seizure Pattern

• Sponsor: Engage Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03478982
• Collaborator: (none)
• Enrollment: 156
• Locations: 67
• Arms: 3
• Actual Duration (Months): 21.7
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: Staccato Alprazolam; Drug: Placebos	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Mar 16, 2018
• Actual Primary Completion Date: Dec 22, 2019
• Actual Study Completion Date: Jan 4, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Staccato Alprazolam 1.0 mg single dose for inhalation	Drug: Staccato Alprazolam; single dose for inhalation; Other Names: STAP-001
Experimental: Staccato Alprazolam 2.0 mg single dose for inhalation	Drug: Staccato Alprazolam; single dose for inhalation; Other Names: STAP-001
Placebo Comparator: Placebo single dose for inhalation	Drug: Placebos; single dose for inhalation

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants in Each Treatment Group Achieving Seizure Activity Cessation Within 2 Minutes and no Recurrent Seizure Within 2 Hours [2 hours post-dosing on dosing day]

   Percentage of participants with onset of a predictable seizure through 2 minutes post dosing with study drug and no recurrence of seizure activity within 2 hours were reported for each treatment group based on clinical observation.

Secondary Outcome Measures

1. Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale [6 hours post-dosing on dosing day]

   Severity of on study seizure episode compared to previously experienced seizures was assessed with Seizure Episode Severity Scale. It is a 5-point scale with range from 1 to 5, where 1 indicates much worse than and 5 indicates much better than.

2. Percentage of Participants With Use of Rescue Medication [2 hours post-dosing on dosing day]

   Percentage of participants with use of rescue medication to stop a seizure episode at the discretion of the principal investigator were reported.

3. Percentage of Participants With Secondary Generalization (Evolution to a Complex Partial Seizure and/or a Generalized Tonic-Clonic Seizure) [24 hours post-dosing on dosing day]

   Percentage of participants who had seizures that evolved to a complex partial seizure and/or a generalized tonic-clonic seizure were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

1. 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.

2. 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.

3. Subject is able to comply by the requirements of the protocol, particularly the requirements and specific Institution policies during the in-clinic 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.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Hospital	Birmingham	Alabama	United States	35294
2	University of Arizona	Phoenix	Arizona	United States	85006
3	St. Joseph's Hospital and Medical Center - Barrow Neurological Institute	Phoenix	Arizona	United States	85013
4	Clinical Trials Inc	Little Rock	Arkansas	United States	72205
5	Rancho Research Institute Inc.	Downey	California	United States	90242
6	UCLA	Los Angeles	California	United States	90095
7	Hoag Hospital	Newport Beach	California	United States	92663
8	Stanford Neuroscience Health Center	Palo Alto	California	United States	94304
9	Havana Research Institute LLC.	Pasadena	California	United States	91105
10	University of Colorado	Aurora	Colorado	United States	80045
11	Yale University	New Haven	Connecticut	United States	06511
12	VA Connecticut Healthcare System	West Haven	Connecticut	United States	06516
13	Georgetown University Hospital	Washington	District of Columbia	United States	20007
14	GW Medical Faculty Associates	Washington	District of Columbia	United States	20037
15	NW FL Clinical Research Group LLC	Gulf Breeze	Florida	United States	32561
16	University of Florida Health Science Center Jacksonville	Jacksonville	Florida	United States	32209
17	Mayo Clinic Florida	Jacksonville	Florida	United States	32224
18	Clinical Translational Research Site	Miami	Florida	United States	33136
19	Advanced Pharma Cr, LLC	Miami	Florida	United States	33147
20	Nicklaus Children's Hospital	Miami	Florida	United States	33155
21	AdventHealth Orlando	Orlando	Florida	United States	32803
22	Research Institute of Orlando, LLC	Orlando	Florida	United States	32806
23	NeuroMedical Research Institute	Panama City	Florida	United States	33607
24	Center for Rare Neurological Diseases	Norcross	Georgia	United States	30093
25	Clinical Research Institute	Stockbridge	Georgia	United States	30281
26	Hawaii Pacific Neuroscience	Honolulu	Hawaii	United States	96817
27	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611
28	Rush University Medical Center	Chicago	Illinois	United States	60612
29	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
30	Ochsner Health System	New Orleans	Louisiana	United States	70121
31	Maine Medical Center	Scarborough	Maine	United States	04074
32	Mid-Atlantic Epilepsy And Sleep Center, LLC	Bethesda	Maryland	United States	20817
33	Harvard Medical School - Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
34	University of Michigan	Ann Arbor	Michigan	United States	48109
35	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
36	SRI International	West Bloomfield	Michigan	United States	48322
37	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
38	Impact Clinical Trials Las Vegas	Las Vegas	Nevada	United States	89106
39	JFK Medical Center	Edison	New Jersey	United States	08820
40	Institute of Neurology & Neurosurgery at St. Barnabas	Livingston	New Jersey	United States	07039
41	Rutgers University	New Brunswick	New Jersey	United States	08901
42	Dent Neurologic Institute	Amherst	New York	United States	14226
43	SUNY Downstate Medical Center - Comprehensive Epilepsy Center	Brooklyn	New York	United States	11203
44	Kaleida Health Oishei Children's Hospital	Buffalo	New York	United States	14203
45	NYU Comprehensive Epilepsy Center	New York	New York	United States	10016
46	Mount Sinai Health System	New York	New York	United States	10029
47	Lenox Hill Hospital	New York	New York	United States	10075
48	University of Rochester Medical Center	Rochester	New York	United States	14642
49	Carolinas Neurosciences Institute	Charlotte	North Carolina	United States	28207
50	OnSite Clinical Solutions, LLC	Concord	North Carolina	United States	28025
51	The Promedica-University of Toledo Neuroscience Center	Toledo	Ohio	United States	43606
52	Oregon Health & Science University - Brain Institute - Comprehensive Epilepsy Center	Portland	Oregon	United States	97239
53	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
54	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
55	Lewis Katz School of Medicine at Template University	Philadelphia	Pennsylvania	United States	19140
56	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
57	University of Texas Southwestern Medical Center - Neurology Clinic	Dallas	Texas	United States	75390
58	UT Houston	Houston	Texas	United States	77030
59	Clinical Trial Network	Houston	Texas	United States	77074
60	University of Utah Hospital	Salt Lake City	Utah	United States	84132
61	Centra Medical Group Neurology Center	Lynchburg	Virginia	United States	24502
62	Carilion Roanoke Memorial Hospital	Roanoke	Virginia	United States	24014
63	Multi-Care Institute for Research and Innovation	Tacoma	Washington	United States	98405
64	Austin Hospital	Heidelberg	Victoria	Australia	3084
65	The Alfred	Melbourne	Victoria	Australia	3004
66	The Royal Melbourne Hospital	Melbourne	Victoria	Australia	3050
67	The Tower	Kingston 5		Jamaica

Sponsors and Collaborators

• Engage Therapeutics, Inc.

Investigators

• Study Chair: J. Isojarvi, MD, PhD, Engage Therapeutics, Inc.

Study Documents (Full-Text)

• Study Protocol - Feb 1, 2019
• Statistical Analysis Plan - Jul 8, 2019

More Information

Publications

None provided.

• Responsible Party: Engage Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03478982
• Other Study ID Numbers: ENGAGE-E-001
• First Posted: Mar 27, 2018
• Last Update Posted: Feb 3, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Epilepsy; Seizures; Alprazolam

Study Results

Participant Flow

Recruitment Details	The study started to enroll participants in March 2018 and concluded in January 2020.
Pre-assignment Detail	Participant Flow refers to Enrolled Population.

Arm/Group Title	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)	Double-blind: Placebo	Double-blind: Staccato Alprazolam 1.0 mg	Double-blind: Staccato Alprazolam 2.0 mg
Arm/Group Description	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of placebo matching to alprazolam as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 2.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.
Period Title: Overall Study
STARTED	11	50	47	48
Enrolled Participants But Not Treated	3	10	9	10
Intent-to-treat (ITT) Population	8	40	38	38
COMPLETED	11	50	47	48
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)	Double-blind: Placebo	Double-blind: Staccato Alprazolam 1.0 mg	Double-blind: Staccato Alprazolam 2.0 mg	Total Title
Arm/Group Description	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of placebo matching to alprazolam as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 2.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.
Overall Participants	8	40	38	38	124
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.1 (14.51)	33.1 (9.80)	34.8 (11.18)	33.5 (11.74)	34.7 (11.60)
Sex: Female, Male (Count of Participants)
Female	8 100%	20 50%	21 55.3%	26 68.4%	75 60.5%
Male	0 0%	20 50%	17 44.7%	12 31.6%	49 39.5%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	1 2.5%	0 0%	0 0%	1 0.8%
Asian	0 0%	2 5%	0 0%	1 2.6%	3 2.4%
Black or African American	0 0%	8 20%	2 5.3%	2 5.3%	12 9.7%
Native Hawaiian / Pacific Islander	2 25%	2 5%	0 0%	1 2.6%	5 4%
White	4 50%	26 65%	36 94.7%	28 73.7%	94 75.8%
Declined to Answer	0 0%	1 2.5%	0 0%	2 5.3%	3 2.4%
Other	2 25%	0 0%	0 0%	4 10.5%	6 4.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants in Each Treatment Group Achieving Seizure Activity Cessation Within 2 Minutes and no Recurrent Seizure Within 2 Hours
Description	Percentage of participants with onset of a predictable seizure through 2 minutes post dosing with study drug and no recurrence of seizure activity within 2 hours were reported for each treatment group based on clinical observation.
Time Frame	2 hours post-dosing on dosing day

Outcome Measure Data

Analysis Population Description

The Modified Intent-to-treat (mITT) population consisted of all participants who had a seizure event, received study drug, and had at least one evaluation after study drug administration.

Arm/Group Title	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)	Double-blind: Placebo	Double-blind: Staccato Alprazolam 1.0 mg	Double-blind: Staccato Alprazolam 2.0 mg
Arm/Group Description	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of placebo matching to alprazolam as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 2.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.
Measure Participants	8	40	38	38
Number [percentage of participants]	62.5 781.3%	42.5 106.3%	65.8 173.2%	65.8 173.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind: Placebo, Double-blind: Staccato Alprazolam 1.0 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0392
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	23.3
	Confidence Interval	(2-Sided) 95%; 1.8 to 44.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-blind: Placebo, Double-blind: Staccato Alprazolam 2.0 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0392
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	23.3
	Confidence Interval	(2-Sided) 95%; 1.8 to 44.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale
Description	Severity of on study seizure episode compared to previously experienced seizures was assessed with Seizure Episode Severity Scale. It is a 5-point scale with range from 1 to 5, where 1 indicates much worse than and 5 indicates much better than.
Time Frame	6 hours post-dosing on dosing day

Outcome Measure Data

Analysis Population Description

The mITT population consisted of all participants who had a seizure event, received study drug, and had at least one evaluation after study drug administration.

Arm/Group Title	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)	Double-blind: Placebo	Double-blind: Staccato Alprazolam 1.0 mg	Double-blind: Staccato Alprazolam 2.0 mg
Arm/Group Description	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of placebo matching to alprazolam as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 2.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.
Measure Participants	8	40	38	38
Much worse than	0 0%	2.5 6.3%	0 0%	0 0%
Worse than	0 0%	5.0 12.5%	2.6 6.8%	5.3 13.9%
Same as	12.5 156.3%	42.5 106.3%	57.9 152.4%	55.3 145.5%
Better than	50.0 625%	35.0 87.5%	18.4 48.4%	28.9 76.1%
Much better than	25.0 312.5%	7.5 18.8%	15.8 41.6%	5.3 13.9%
Not done	12.5 156.3%	7.5 18.8%	5.3 13.9%	5.3 13.9%

3. Secondary Outcome

Title	Percentage of Participants With Use of Rescue Medication
Description	Percentage of participants with use of rescue medication to stop a seizure episode at the discretion of the principal investigator were reported.
Time Frame	2 hours post-dosing on dosing day

Outcome Measure Data

Analysis Population Description

The mITT population consisted of all participants who had a seizure event, received study drug, and had at least one evaluation after study drug administration.

Arm/Group Title	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)	Double-blind: Placebo	Double-blind: Staccato Alprazolam 1.0 mg	Double-blind: Staccato Alprazolam 2.0 mg
Arm/Group Description	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of placebo matching to alprazolam as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 2.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.
Measure Participants	8	40	38	38
Number [percentage of participants]	0 0%	7.5 18.8%	15.8 41.6%	7.9 20.8%

4. Secondary Outcome

Title	Percentage of Participants With Secondary Generalization (Evolution to a Complex Partial Seizure and/or a Generalized Tonic-Clonic Seizure)
Description	Percentage of participants who had seizures that evolved to a complex partial seizure and/or a generalized tonic-clonic seizure were reported.
Time Frame	24 hours post-dosing on dosing day

Outcome Measure Data

Analysis Population Description

The mITT population consisted of all participants who had a seizure event, received study drug, and had at least one evaluation after study drug administration.

Arm/Group Title	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)	Double-blind: Placebo	Double-blind: Staccato Alprazolam 1.0 mg	Double-blind: Staccato Alprazolam 2.0 mg
Arm/Group Description	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of placebo matching to alprazolam as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.	Participants received a single dose of alprazolam 2.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.
Measure Participants	8	40	38	38
Number [percentage of participants]	12.5 156.3%	0.0 0%	0.0 0%	0.0 0%

Adverse Events

Time Frame	From Screening up to 12 weeks
Adverse Event Reporting Description	The Safety Population included all participants who received study drug during the Treatment Period from either Open-label Feasibility or Double-blind Phase.
Arm/Group Title	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)		Double-blind: Placebo		Double-blind: Staccato Alprazolam 1.0 mg		Double-blind: Staccato Alprazolam 2.0 mg
Arm/Group Description	Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.		Participants received a single dose of placebo matching to alprazolam as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.		Participants received a single dose of alprazolam 1.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.		Participants received a single dose of alprazolam 2.0 mg as an oral inhalation using the Staccato delivery system at the onset of their predictable seizure episode from Day 1 through the end of Day 7.
All Cause Mortality
	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)		Double-blind: Placebo		Double-blind: Staccato Alprazolam 1.0 mg		Double-blind: Staccato Alprazolam 2.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/40 (0%)		0/38 (0%)		0/38 (0%)
Serious Adverse Events
	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)		Double-blind: Placebo		Double-blind: Staccato Alprazolam 1.0 mg		Double-blind: Staccato Alprazolam 2.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		2/40 (5%)		1/38 (2.6%)		0/38 (0%)
Infections and infestations
Pneumonia	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
Nervous system disorders
Generalised tonic-clonic seizure	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Seizure cluster	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
Status epilepticus	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
Other (Not Including Serious) Adverse Events
	Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg)		Double-blind: Placebo		Double-blind: Staccato Alprazolam 1.0 mg		Double-blind: Staccato Alprazolam 2.0 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)		10/40 (25%)		14/38 (36.8%)		19/38 (50%)
Cardiac disorders
Tachycardia	0/8 (0%)	0	1/40 (2.5%)	1	1/38 (2.6%)	1	0/38 (0%)	0
Eye disorders
Abnormal sensation in eye	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Diplopia	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Dry eye	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Gastrointestinal disorders
Nausea	0/8 (0%)	0	1/40 (2.5%)	2	1/38 (2.6%)	1	2/38 (5.3%)	2
Vomiting	0/8 (0%)	0	1/40 (2.5%)	1	1/38 (2.6%)	1	1/38 (2.6%)	1
Constipation	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Retching	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Abdominal pain	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
General disorders
Feeling abnormal	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Injury associated with device	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Fatigue	0/8 (0%)	0	2/40 (5%)	2	0/38 (0%)	0	0/38 (0%)	0
Infections and infestations
Urinary tract infection	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Gastroenteritis viral	1/8 (12.5%)	1	0/40 (0%)	0	0/38 (0%)	0	0/38 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
Skin abrasion	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
Investigations
Oxygen saturation decreased	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Urine analysis abnormal	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Urine phosphorus	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Metabolism and nutrition disorders
Hyperkalaemia	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Hyponatraemia	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Hypophosphataemia	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Myalgia	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Musculoskeletal chest pain	1/8 (12.5%)	1	0/40 (0%)	0	0/38 (0%)	0	0/38 (0%)	0
Nervous system disorders
Somnolence	0/8 (0%)	0	1/40 (2.5%)	1	7/38 (18.4%)	8	4/38 (10.5%)	4
Dysgeusia	0/8 (0%)	0	1/40 (2.5%)	1	6/38 (15.8%)	6	4/38 (10.5%)	4
Dizziness	0/8 (0%)	0	2/40 (5%)	2	2/38 (5.3%)	2	2/38 (5.3%)	3
Sedation	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	2/38 (5.3%)	2
Disturbance in attention	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Dizziness postural	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Headache	0/8 (0%)	0	2/40 (5%)	2	1/38 (2.6%)	1	0/38 (0%)	0
Lethargy	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Tremor	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Generalised tonic-clonic seizure	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
Psychiatric disorders
Anxiety	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Reproductive system and breast disorders
Dysmenorrhoea	1/8 (12.5%)	1	0/40 (0%)	0	0/38 (0%)	0	0/38 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/8 (12.5%)	1	0/40 (0%)	0	4/38 (10.5%)	4	7/38 (18.4%)	7
Throat irritation	1/8 (12.5%)	1	0/40 (0%)	0	0/38 (0%)	0	2/38 (5.3%)	2
Oropharyngeal pain	0/8 (0%)	0	0/40 (0%)	0	0/38 (0%)	0	1/38 (2.6%)	1
Pneumonia aspiration	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0
Skin and subcutaneous tissue disorders
Skin disorder	0/8 (0%)	0	1/40 (2.5%)	1	0/38 (0%)	0	0/38 (0%)	0
Vascular disorders
Hypertension	0/8 (0%)	0	0/40 (0%)	0	1/38 (2.6%)	1	0/38 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.