Brief Summary: This is a multi-center, double-blind, randomized, parallel group, dose-ranging study to investigate the efficacy and clinical usability of staccato alprazolam 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).

Primary Outcome Measure: Cessation of seizure activity [time frame: 2 hours post-dosing].

Anticipated Study Start Date: March 2018
Anticipated Study Completion Date: May 2019

Eligibility Criteria

Inclusion Criteria

1. Subject is able to provide, personally signed, and dated informed consent to participate in the study before completing any study related procedures.
2. Male or female ? 18 years of age.
3. Has an established diagnosis of focal or 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) focal 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 the Screening Visit.
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. Receiving chronic benzodiazepine treatment (defined as an average of ? 4 administrations per week) prior to admission to the in-patient unit
5. Use of strong CYP 3A4 inhibitors; including azole antifungal agents (e.g., etoconazole, itraconazole), nefazodone, fluvoxamine, cimetidine, HIV protease inhibitors (e.g., ritonavir)
6. Has severe chronic cardio-respiratory disease
7. History of HIV-positivity.
8. Pregnant or breast-feeding.
9. Clinically significant renal or hepatic insufficiency (hepatic transaminases >2 times the upper limit of normal (ULN) or creatinine ? 1.5 x ULN).
10. History of acute narrow angle glaucoma, Parkinson’s disease, hydrocephalus, or history of significant head trauma.
11. Subjects who use medications to treat airways disease, such as asthma or COPD or have any acute respiratory signs/symptoms (e.g., wheezing).
12. 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
13. A history within the past 1 year of drug or alcohol dependence or abuse.
14. Positive urine screen for drugs of abuse at Screening.
15. Known allergy or hypersensitivity to alprazolam.
16. History of glaucoma.
17. Subjects who currently have an active major psychiatric disorder where changes in pharmacotherapy are needed or anticipated during the study.
18. 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.
19. Significant hepatic, renal, gastroenterologic, cardiovascular (including ischemic heart disease and congestive heart failure), endocrine, neurologic or hematologic disease.
20. 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.

Brief Summary: This is a multi-center, double-blind, randomized, parallel group, dose-ranging study to investigate the efficacy and clinical usability of staccato alprazolam 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).

Primary Outcome Measure: Cessation of seizure activity [time frame: 2 hours post-dosing].

Anticipated Study Start Date: March 2018
Anticipated Study Completion Date: May 2019

Eligibility Criteria

Inclusion Criteria

1. Subject is able to provide, personally signed, and dated informed consent to participate in the study before completing any study related procedures.
2. Male or female ? 18 years of age.
3. Has an established diagnosis of focal or 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) focal 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 the Screening Visit.
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. Receiving chronic benzodiazepine treatment (defined as an average of ? 4 administrations per week) prior to admission to the in-patient unit
5. Use of strong CYP 3A4 inhibitors; including azole antifungal agents (e.g., etoconazole, itraconazole), nefazodone, fluvoxamine, cimetidine, HIV protease inhibitors (e.g., ritonavir)
6. Has severe chronic cardio-respiratory disease
7. History of HIV-positivity.
8. Pregnant or breast-feeding.
9. Clinically significant renal or hepatic insufficiency (hepatic transaminases >2 times the upper limit of normal (ULN) or creatinine ? 1.5 x ULN).
10. History of acute narrow angle glaucoma, Parkinson’s disease, hydrocephalus, or history of significant head trauma.
11. Subjects who use medications to treat airways disease, such as asthma or COPD or have any acute respiratory signs/symptoms (e.g., wheezing).
12. 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
13. A history within the past 1 year of drug or alcohol dependence or abuse.
14. Positive urine screen for drugs of abuse at Screening.
15. Known allergy or hypersensitivity to alprazolam.
16. History of glaucoma.
17. Subjects who currently have an active major psychiatric disorder where changes in pharmacotherapy are needed or anticipated during the study.
18. 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.
19. Significant hepatic, renal, gastroenterologic, cardiovascular (including ischemic heart disease and congestive heart failure), endocrine, neurologic or hematologic disease.
20. 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.

Pairnomix, LLC announced on March 26, 2018 that results from a comprehensive drug repurposing screen performed for a patient with SCN8A epilepsy were published as an original research article online and in an upcoming print issue of Epilepsia, the official journal of the International League Against Epilepsy (ILAE) and a leading, authoritative source for current research results on all aspects of epilepsy.

The study, A Comprehensive Approach to Identifying Repurposed Drugs to Treat SCN8A Epilepsy details rigorous efforts to identify repurposed drug options for a patient with epileptic encephalopathy caused by the SCN8A R1872Q genetic mutation. Whereas most drug repurposing studies focus on one or a few select compounds, this research highlights a broader approach using high-throughput technologies to screen hundreds of on-market drugs in a single experiment. In this study, 90 drugs were identified to have a significant effect in cellular studies; the majority of these drugs have never been implicated as having effects on ion channels or epilepsy and therefore represent potentially novel mechanistic activity.

Gregory Stewart, PhD, Chief Scientific Officer at Pairnomix, remarked, “We are very pleased to share these results and the research approach we have undertaken to identify drug options for physicians to consider in their medical management of patients with the SCN8A R1872Q variant. Our work demonstrates the utility of comprehensive, high-throughput drug screens to identify new drug options for patients that are available for immediate clinical use.”

Pairnomix, LLC announced on March 26, 2018 that results from a comprehensive drug repurposing screen performed for a patient with SCN8A epilepsy were published as an original research article online and in an upcoming print issue of Epilepsia, the official journal of the International League Against Epilepsy (ILAE) and a leading, authoritative source for current research results on all aspects of epilepsy.

The study, A Comprehensive Approach to Identifying Repurposed Drugs to Treat SCN8A Epilepsy details rigorous efforts to identify repurposed drug options for a patient with epileptic encephalopathy caused by the SCN8A R1872Q genetic mutation. Whereas most drug repurposing studies focus on one or a few select compounds, this research highlights a broader approach using high-throughput technologies to screen hundreds of on-market drugs in a single experiment. In this study, 90 drugs were identified to have a significant effect in cellular studies; the majority of these drugs have never been implicated as having effects on ion channels or epilepsy and therefore represent potentially novel mechanistic activity.

Gregory Stewart, PhD, Chief Scientific Officer at Pairnomix, remarked, “We are very pleased to share these results and the research approach we have undertaken to identify drug options for physicians to consider in their medical management of patients with the SCN8A R1872Q variant. Our work demonstrates the utility of comprehensive, high-throughput drug screens to identify new drug options for patients that are available for immediate clinical use.”