Epilepsy
Conditions
Brief summary
The purpose of this study is to determine whether people who usually have photosensitive epilepsy will show a reduction in epileptic activity when they take a single dose of Staccato Alprazolam as compared to placebo.
Detailed description
The purpose of this study is to determine whether people who usually have photosensitive epilepsy will show a reduction in epileptic activity when they take a single dose of Staccato Alprazolam as compared to placebo. People with photosensitive epilepsy have changes on their electroencephalogram (EEG) when shown flashing lights. Three dose levels of Staccato Alprazolam will be compared to placebo. This study will also assess the level of sedation of Staccato Alprazolam compared to placebo.
Interventions
DRUGA=Placebo
DRUGB=Inhaled Alprazolam 0.5 mg
DRUGC=Inhaled Alprazolam 1 m
DRUGD= Inhaled Alprazolam 2 mg
DRUGE=Placebo
Sponsors
Nova Pneuma Inc.
The Epilepsy Study Consortium
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male and female subjects between the ages of 18 to 60 years, inclusive * Body mass index (BMI) ≥18 and ≤35 kg/m2 * Able to speak, read, and understand English and willing and able to provide written informed consent on an IRB-approved form before the initiation of any study procedures * A diagnosis and history of a photoparoxysmal response on EEG with or without a diagnosis of epilepsy for which patients are on 0-2 concomitant antiepileptic drugs * At least 3 of the EEGs performed during the screen visit must have a reproducible IPS-induced photoparoxysmal response (PPR) on EEG of at least 3 points on a frequency assessment scale in at least one eye condition * In otherwise good general health as determined by a complete medical history, physical examination, 12-lead ECG, blood chemistry profile, hematology, and urinalysis * 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
Exclusion criteria
* History of non-epileptic seizures (e.g. metabolic, structural, or pseudo-seizures) * History of seizure worsening in response to narrow spectrum drugs * An active CNS infection, demyelinating disease, degenerative neurological disease or any CNS disease deemed to be progressive during the course of the study that may confound the interpretation of the study results * Use of more than 2 concomitant AEDs for epilepsy treatment * Subjects taking known inhibitors or inducers of CYP3A , including carbamazepine * Subjects with a history of allergic reactions to alprazolam or other benzodiazepines * Treatment with an investigational drug within 30 days (or within 5 half-lives of the investigational drug, if \>30 days) before Visit 2 * A history within the past 1 year of drug or alcohol dependence or abuse * Positive urine screen for drugs of abuse at Visit 1 - Screening * A history of HIV-positivity * Female subjects who have a positive pregnancy test at screening or prior to test sessions or are breastfeeding * History of acute narrow angle glaucoma, Parkinson's disease, hydrocephalus, or history of significant head trauma * Subjects who have a current history of asthma, chronic obstructive lung disease (COPD), or any lung disease associated with bronchospasm * Subjects who use medications to treat airways disease, such as asthma or COPD * Subjects who have any acute respiratory signs/symptoms (e.g., wheezing) * Clinically significant ECG abnormality including (but not limited to) any of the following conduction abnormalities or dysrhythmias: atrial fibrillation, mean QTcF (QT interval corrected for heart rate using Fridericia's method) interval \>450 msec, ventricular rate \<45 beats/min, second or third degree AV block, left bundle branch block, or evidence of prior myocardial infarction (MI) or acute ischemia * 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 * Significant hepatic, renal, gastroenterologic, cardiovascular (including ischemic heart disease and congestive heart failure), endocrine, neurologic (including history of seizures or stroke), or hematologic disease * Any other disease or condition, by history, physical examination, or laboratory abnormalities that in the investigator's opinion, would present undue risk to the subject, or may confound the interpretation of study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Change From Pretreatment Baseline in the Standardized Photosensitivity Range (SPR) | SPR was recorded pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration The maximum change from baseline occurred at: 10 min for alprazolam 2 mg, 1 hour for alprazolam 0.5 and 1 mg and placebo | Photosensitivity describes the presentation of an epileptiform EEG response (photoparoxysmal response) from exposure to intermittent photic stimulation (IPS). SPR is the number of frequency steps (2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50 and 60 Hz). between the upper and lower limits of sensitivity to IPS for that patient at that time, in order not to evoke seizures. Thus a reduction (-change) means the intervention is working (desired effect on sensitivity) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Sedation Using Visual Analog Scale (Sedated-Alert) | Sedation was recorded pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration The maximum change from baseline occurred at:: 30 min for alprazolam 1 mg, 1 hour for alprazolam 0.5 and 2 mg, and 4 hours for placebo | Maximum change (in mm) from pretreatment baseline in level of sedation reported by the patient on a 100 mm line anchored by Sedated (0) and Alert (100) |
| Maximum Sedation Using Visual Analog Scale (Sleepy-Awake) | Sleepiness was recorded pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration The maximum change from baseline occurred: at: 30 min for alprazolam 1 mg, 1 hour for alprazolam 0.5 and 2 mg and placebo | Maximum change (in mm) from pretreatment baseline in level of sedation reported by each subject on a 100 mm line anchored by Sleepy (0) and Awake (100) |
| Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Standardized Photosensitivity Range (SPR) | Pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration | Pearson correlation of all paired plasma concentrations of alprazolam (PK) with pharmacodynamic effect on SPR (PD) for each alprazolam dose |
| Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sedated-Alert) | Pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration | Pearson correlation of all paired plasma concentrations of alprazolam (PK) with pharmacodynamic effect on Sedation (PD) for each alprazolam dose |
| Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sleepy-Awake) | Pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration | Pearson correlation of all paired plasma concentrations of alprazolam (PK) with pharmacodynamic effect on Sleepiness (PD) for each alprazolam dose |
Countries
United States
Contacts
STUDY_CHAIRJ Isojarvi, MD
Engage Therapeutics, Inc.
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BEADC BEADC Patient receiving treatment sequence BEADC | 1 |
| CDAEB Patient receiving treatment sequence CDAEB | 1 |
| DEBAC Patient receiving treatment sequence DEBAC | 1 |
| EDBAC Patient receiving treatment sequence EDBAC | 1 |
| CABED Patient receiving treatment sequence CABED | 1 |
| Total | 5 |
Baseline characteristics
| Characteristic | BEADC BEADC | CDAEB | DEBAC | EDBAC | CABED | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 24 years STANDARD_DEVIATION 0 | 23 years STANDARD_DEVIATION 0 | 27 years STANDARD_DEVIATION 0 | 39 years STANDARD_DEVIATION 0 | 23 years STANDARD_DEVIATION 0 | 27.2 years STANDARD_DEVIATION 6.8 |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Race Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Race Not Hispanic or Latino | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Race Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 1 participants | 1 participants | 1 participants | 1 participants | 1 participants | 5 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 / 5 | 0 / 5 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 2 / 5 | 2 / 5 | 3 / 5 | 4 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 5 |
Outcome results
Primary
Maximum Observed Change From Pretreatment Baseline in the Standardized Photosensitivity Range (SPR)
Photosensitivity describes the presentation of an epileptiform EEG response (photoparoxysmal response) from exposure to intermittent photic stimulation (IPS). SPR is the number of frequency steps (2, 5, 8, 10, 13, 15, 18, 20, 23, 25, 30, 40, 50 and 60 Hz). between the upper and lower limits of sensitivity to IPS for that patient at that time, in order not to evoke seizures. Thus a reduction (-change) means the intervention is working (desired effect on sensitivity)
Time frame: SPR was recorded pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration The maximum change from baseline occurred at: 10 min for alprazolam 2 mg, 1 hour for alprazolam 0.5 and 1 mg and placebo
Population: All 5 patients received all 4 treatments (crossover design)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inhaled Placebo | Maximum Observed Change From Pretreatment Baseline in the Standardized Photosensitivity Range (SPR) | -0.2 Number of frequency steps |
| Staccato Alprazolam, 0.5 mg | Maximum Observed Change From Pretreatment Baseline in the Standardized Photosensitivity Range (SPR) | -4.4 Number of frequency steps |
| Staccato Alprazolam, 1 mg | Maximum Observed Change From Pretreatment Baseline in the Standardized Photosensitivity Range (SPR) | -5.2 Number of frequency steps |
| Staccato Alprazolam, 2 mg | Maximum Observed Change From Pretreatment Baseline in the Standardized Photosensitivity Range (SPR) | -4.8 Number of frequency steps |
Secondary
Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Standardized Photosensitivity Range (SPR)
Pearson correlation of all paired plasma concentrations of alprazolam (PK) with pharmacodynamic effect on SPR (PD) for each alprazolam dose
Time frame: Pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration
Population: PK-PD population pairs, All 5 crossover subjects by alprazolam treatment received~Number of PK-PD pairs per dose (n) = 35 (7 time points x 5 subjects)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Placebo | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Standardized Photosensitivity Range (SPR) | -0.454 correlation coefficient | Standard Deviation 0.206 |
| Staccato Alprazolam, 0.5 mg | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Standardized Photosensitivity Range (SPR) | -0.534 correlation coefficient | Standard Deviation 0.286 |
| Staccato Alprazolam, 1 mg | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Standardized Photosensitivity Range (SPR) | -0.410 correlation coefficient | Standard Deviation 0.168 |
Secondary
Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sedated-Alert)
Pearson correlation of all paired plasma concentrations of alprazolam (PK) with pharmacodynamic effect on Sedation (PD) for each alprazolam dose
Time frame: Pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration
Population: PK-PD population pairs, All 5 crossover subjects by alprazolam treatment received~Number of PK-PD pairs per dose (n) = 35 (7 time points x 5 subjects)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Placebo | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sedated-Alert) | -0.350 correlation coefficient | Standard Deviation 0.122 |
| Staccato Alprazolam, 0.5 mg | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sedated-Alert) | -0.567 correlation coefficient | Standard Deviation 0.322 |
| Staccato Alprazolam, 1 mg | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sedated-Alert) | -0.623 correlation coefficient | Standard Deviation 0.388 |
Secondary
Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sleepy-Awake)
Pearson correlation of all paired plasma concentrations of alprazolam (PK) with pharmacodynamic effect on Sleepiness (PD) for each alprazolam dose
Time frame: Pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration
Population: PK-PD population pairs, All 5 crossover subjects by alprazolam treatment received~Number of PK-PD pairs per dose (n) = 35 (7 time points x 5 subjects)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Placebo | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sleepy-Awake) | -0.449 correlation coefficient | Standard Deviation 0.201 |
| Staccato Alprazolam, 0.5 mg | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sleepy-Awake) | -0.582 correlation coefficient | Standard Deviation 0.339 |
| Staccato Alprazolam, 1 mg | Correlation of Plasma Concentrations of Alprazolam With Pharmacodynamic Effects on Visual Analog Scale (Sleepy-Awake) | -0.586 correlation coefficient | Standard Deviation 0.343 |
Secondary
Maximum Sedation Using Visual Analog Scale (Sedated-Alert)
Maximum change (in mm) from pretreatment baseline in level of sedation reported by the patient on a 100 mm line anchored by Sedated (0) and Alert (100)
Time frame: Sedation was recorded pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration The maximum change from baseline occurred at:: 30 min for alprazolam 1 mg, 1 hour for alprazolam 0.5 and 2 mg, and 4 hours for placebo
Population: All 5 patients received each of the 4 treatments after washout (crossover design)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inhaled Placebo | Maximum Sedation Using Visual Analog Scale (Sedated-Alert) | -5.3 units on a scale |
| Staccato Alprazolam, 0.5 mg | Maximum Sedation Using Visual Analog Scale (Sedated-Alert) | -58 units on a scale |
| Staccato Alprazolam, 1 mg | Maximum Sedation Using Visual Analog Scale (Sedated-Alert) | -67.4 units on a scale |
| Staccato Alprazolam, 2 mg | Maximum Sedation Using Visual Analog Scale (Sedated-Alert) | -70.6 units on a scale |
Secondary
Maximum Sedation Using Visual Analog Scale (Sleepy-Awake)
Maximum change (in mm) from pretreatment baseline in level of sedation reported by each subject on a 100 mm line anchored by Sleepy (0) and Awake (100)
Time frame: Sleepiness was recorded pretreatment, 2, 10, 30 min, 1, 2, 4, and 6 hr post each study drug administration The maximum change from baseline occurred: at: 30 min for alprazolam 1 mg, 1 hour for alprazolam 0.5 and 2 mg and placebo
Population: All 5 patients received each of the 4 treatments after washout (crossover design)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inhaled Placebo | Maximum Sedation Using Visual Analog Scale (Sleepy-Awake) | -9.2 units on a scale |
| Staccato Alprazolam, 0.5 mg | Maximum Sedation Using Visual Analog Scale (Sleepy-Awake) | -54 units on a scale |
| Staccato Alprazolam, 1 mg | Maximum Sedation Using Visual Analog Scale (Sleepy-Awake) | -58.8 units on a scale |
| Staccato Alprazolam, 2 mg | Maximum Sedation Using Visual Analog Scale (Sleepy-Awake) | -58.8 units on a scale |