Epilepsy
Conditions
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).
Interventions
single dose for inhalation
DRUGPlacebos
single dose for inhalation
Sponsors
Engage Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 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-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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
Australia, Jamaica, United States
Participant flow
Recruitment details
The study started to enroll participants in March 2018 and concluded in January 2020.
Pre-assignment details
Participant Flow refers to Enrolled Population.
Participants by arm
| Arm | Count |
|---|---|
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) 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. | 8 |
| Double-blind: Placebo 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. | 40 |
| Double-blind: Staccato Alprazolam 1.0 mg 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. | 38 |
| Double-blind: Staccato Alprazolam 2.0 mg 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. | 38 |
| Total Title | 124 |
| Total | 248 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 14.51 | 33.1 years STANDARD_DEVIATION 9.8 | 34.8 years STANDARD_DEVIATION 11.18 | 33.5 years STANDARD_DEVIATION 11.74 | 34.7 years STANDARD_DEVIATION 11.6 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 8 Participants | 2 Participants | 2 Participants | 12 Participants |
| Race/Ethnicity, Customized Declined to Answer | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian / Pacific Islander | 2 Participants | 2 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 0 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 26 Participants | 36 Participants | 28 Participants | 94 Participants |
| Sex: Female, Male Female | 8 Participants | 20 Participants | 21 Participants | 26 Participants | 75 Participants |
| Sex: Female, Male Male | 0 Participants | 20 Participants | 17 Participants | 12 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 40 | 0 / 38 | 0 / 38 |
| other Total, other adverse events | 3 / 8 | 10 / 40 | 14 / 38 | 19 / 38 |
| serious Total, serious adverse events | 0 / 8 | 2 / 40 | 1 / 38 | 0 / 38 |
Outcome results
Primary
Percentage of Participants in Each Treatment Group Achieving Seizure Activity Cessation Within 2 Minutes and no Recurrent Seizure Within 2 Hours
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants in Each Treatment Group Achieving Seizure Activity Cessation Within 2 Minutes and no Recurrent Seizure Within 2 Hours | 62.5 percentage of participants |
| Double-blind: Placebo | Percentage of Participants in Each Treatment Group Achieving Seizure Activity Cessation Within 2 Minutes and no Recurrent Seizure Within 2 Hours | 42.5 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants in Each Treatment Group Achieving Seizure Activity Cessation Within 2 Minutes and no Recurrent Seizure Within 2 Hours | 65.8 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants in Each Treatment Group Achieving Seizure Activity Cessation Within 2 Minutes and no Recurrent Seizure Within 2 Hours | 65.8 percentage of participants |
p-value: =0.039295% CI: [1.8, 44.8]Chi-squared
p-value: =0.039295% CI: [1.8, 44.8]Chi-squared
Secondary
Percentage of Participants With Secondary Generalization (Evolution to a Complex Partial Seizure and/or a Generalized Tonic-Clonic Seizure)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Secondary Generalization (Evolution to a Complex Partial Seizure and/or a Generalized Tonic-Clonic Seizure) | 12.5 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Secondary Generalization (Evolution to a Complex Partial Seizure and/or a Generalized Tonic-Clonic Seizure) | 0.0 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Secondary Generalization (Evolution to a Complex Partial Seizure and/or a Generalized Tonic-Clonic Seizure) | 0.0 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Secondary Generalization (Evolution to a Complex Partial Seizure and/or a Generalized Tonic-Clonic Seizure) | 0.0 percentage of participants |
Secondary
Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much worse than | 0 percentage of participants |
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Worse than | 0 percentage of participants |
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Same as | 12.5 percentage of participants |
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Better than | 50.0 percentage of participants |
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much better than | 25.0 percentage of participants |
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Not done | 12.5 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Not done | 7.5 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Better than | 35.0 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much worse than | 2.5 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Same as | 42.5 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Worse than | 5.0 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much better than | 7.5 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Worse than | 2.6 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Same as | 57.9 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Better than | 18.4 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Not done | 5.3 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much better than | 15.8 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much worse than | 0 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much better than | 5.3 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Not done | 5.3 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Worse than | 5.3 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Better than | 28.9 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Much worse than | 0 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Seizure Episode Severity Assessed by Seizure Episode Severity Scale | Same as | 55.3 percentage of participants |
Secondary
Percentage of Participants With Use of Rescue Medication
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Open-label: Staccato Alprazolam (STAP-001) 1.0 Milligram (mg) | Percentage of Participants With Use of Rescue Medication | 0 percentage of participants |
| Double-blind: Placebo | Percentage of Participants With Use of Rescue Medication | 7.5 percentage of participants |
| Double-blind: Staccato Alprazolam 1.0 mg | Percentage of Participants With Use of Rescue Medication | 15.8 percentage of participants |
| Double-blind: Staccato Alprazolam 2.0 mg | Percentage of Participants With Use of Rescue Medication | 7.9 percentage of participants |