Study of Diazepam Buccal Film Administered in the Interictal and in the Ictal-Periictal States to Adults With Epilepsy

This was a Phase 2 multicenter, open-label, two-way study conducted in adult subjects to assess the bioavailability, pharmacokinetics, and safety of DBF during the Interictal Period and during the Ictal/peri-ictal Period, with a minimum of 14 days of washout between periods. Subjects had a clinical diagnosis of epilepsy (with generalized tonic-clonic seizures or focal seizures with impaired awareness) who were on stable regimens of anti-epileptic drugs and were scheduled for admission to an EMU, GCRC, or similar facility for evaluation.

All subjects were to receive a single 12.5-mg dose of study drug, without regard to meals, during both Interictal Period and Ictal/peri-ictal Period. The treatment was identical for both periods. Treatment sequence was not randomized. The interictal period and ictal/peri-ictal could occur in either order as determined by seizure occurrence.

Interictal Period: Subjects were considered to be in an interictal state if an interval of at least 3 hours had elapsed since any clinically observable postictal signs or symptoms (from the last observed seizure) and the subject had been seizure-free over this period. Subjects on electroencephalogram (EEG) video monitoring were to be considered to be in an interictal state if an interval of at least 3 hours had elapsed since there were any postictal electrical findings on EEG.

Ictal/peri-ictal Period: For the purposes of this study, the ictal state was defined as an ongoing clinically observable seizure or seizure activity as verified via EEG. The periictal state was defined clinically as the subject's immediate postictal state following a generalized tonic-clonic (GTC) seizure or focal seizure with impaired awareness, and within 5 minutes following the last clonic jerk. For subjects on EEG video monitoring, the periictal state was to be defined as less than 5 minutes after cessation of seizure activity as verified via EEG.

• Diazepam Buccal Film 12.5 mg (Drug), also known as DBF 12.5mg: All subjects received a single dose of DBF 12.5 mg during the interictal state and during the ictal/peri-ictal state with at least 14 days washout between the 2 treatment periods

Primary outcomes

• Tmax Pharmacokinetic EndPoints [-2 to 0, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 192, 240 hours]: Observed time to reach maximum drug concentration (Tmax)
• Cmax Pharmacokinetic EndPoints [-2 to 0, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 192, 240 hours]: Observed Peak Drug Concentration (Cmax)
• Area Under the Plasma Concentration Curve Pharmacokinetic EndPoints [-2 to 0, 0.25, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 192, 240 hours]: Area under the Plasma Concentration -time curve from time zero until the last measured time (AUC0-t)

Secondary outcomes

• Usability Endpoint - Successful Insertion/Placement of the Diazepam Buccal Film (DBF) on First Attempt [Subject was observed for 15 minutes after initial film placement/adhesion]: Number of subjects with unsuccessful insertion/placement of the DBF on first attempt at administration Number of subjects with successful insertion/placement of the DBF on first attempt at administration Placement is judged to be successful when film adheres to the center of buccal mucosa of either right or left cheek. Unsuccessful placements were followed by a subsequent successful insertion/placement of DBF
• Usability Endpoint: Swallowing the Film Before Complete Disintegration/Dissolution [Subject was observed for 15 minutes immediately following DBF placement/adhesion]: Was the film noted to have been swallowed by the subject ? Yes No Subjects were instructed to swallow any remnants of film still present in oral cavity 15 minutes after initial film placement. Results include subjects who swallowed film at any point during the 15 minutes immediately after initial film placement.
• Usability Endpoint: Retention of Diazepam Buccal Film (DBF) From Placement to Complete Disintegration [Subject was observed for 15 minutes immediately following DBF placement/adhesion]: Was the DBF spit out or blown out by the subject after placement on buccal mucosa or did the subject chew, talk, or move the DBF prior to complete disintegration/dissolution? Yes No
• Usability Endpoint: Exit of Saliva During the Time the Diazepam Buccal Film (DBF) Was Adhered to Buccal Mucosa [Subject was observed for 15 minutes immediately following DBF placement/adhesion]: The observer documented if any saliva was seen to exit the mouth during the time the DBF was adhered to buccal mucosa
• Usability Endpoint: Amount of Saliva That Exited the Mouth After Film Placement [Subject was observed for 15 minutes immediately following DBF placement/adhesion]: If Yes - saliva exited the mouth during the time, estimate in milliliters of the amount of saliva that exited the mouth after DBF placement on the buccal surface

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

Potential subjects meeting all of the following criteria may be included in the study:

1. Subjects scheduled for admission to the institution's EMU, GCRC (General Clinical Research Center) or similar facility for evaluation within 28 days.
2. Male and female subjects between 18 to 65 years of age, inclusive.
3. Subjects having a body weight of ≥ 40 kg to 111 kg.
4. Subjects have a clinical diagnosis of epilepsy and are scheduled to be admitted to an Epilepsy Monitoring Unit (EMU) for extracranial video-Electroencephalogram (EEG) recording of a seizure event for evaluation of their epilepsy.
5. Subjects have an average frequency of > 1 seizure every 3 days or > 10 seizures / month as documented by seizure diaries dispensed at the Screening Visit and verified prior to initiation of Period A or Period B.
6. Female subjects have a negative serum pregnancy test at Screening. Female subjects of childbearing potential (i.e., not surgically sterile or 2 years postmenopausal) must have a negative pregnancy test at screening and a partner who is sterile, agree to abstinence, be practicing double barrier contraception or using an FDA approved contraceptive (e.g., licensed hormonal or barrier methods) for greater than 2 months prior to screening visit and commit to an acceptable form of birth control for the duration of the study and for 30 days after participation in the study.
7. Subjects are currently receiving at least one antiepileptic medication.
8. Subjects or subject's legally authorized representative (LAR) must be willing and able to complete informed consent/assent and HIPAA authorization.
9. Subjects must agree and must be willing to comply with all required study procedures while in the EMU or GCRC.
10. Ability to comprehend and be informed of the nature of the study, as assessed by the PI or Sub-Investigator.
11. Ability to consume standard meals.
12. Availability to volunteer for the entire study duration and willing to adhere to all protocol requirements.

Exclusion Criteria:

Potential subjects meeting any of the following criteria will be excluded:

1. Subjects having 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 12 months.
2. Subjects having respiratory failure (or is at risk for respiratory failure) or other severe cardiorespiratory disease with New York Heart Association Class III or IV functional status, or requires supplemental oxygen.
3. Female subjects who are lactating or positive serum pregnancy test (ß-hCG) at screening for female subjects ≥12 years of age.
4. Subjects with severe psychiatric disease that in the Investigator's judgment would prevent the patient's successful completion of the study.
5. Subjects who have an episode of status epilepticus, as determined by the Principal Investigator/Sub-Investigator, at any time during Period B (EMU, GCRC or similar facility Visit
6. Subjects with known history or presence of any clinically significant hepatic (e.g. hepatic impairment), renal/genitourinary (renal impairment, kidney stones), psychiatric, dermatological or hematological disease or condition unless determined as not clinically significant by the Principal Investigator/Sub-Investigator and confirmed by Sponsor via written communication prior to subject enrollment.
7. Subjects with any clinically significant illness other than epilepsy within 30 days prior to first dosing, as determined by the Principal Investigator/Sub-Investigator.
8. Subjects with any significant physical or organ abnormality as determined by the Principal Investigator/Sub-Investigator.
9. Subjects with any significant lesion of the oral cavity or having oral prophylactic procedures within 30 days prior to first dosing.
10. Subjects with a QTc interval QTcF>450 msec for males and QTcF>470 msec for females on screening ECG, unless determined as not clinically significant by the Investigator.
11. Subjects with a positive test result for any of the following: drugs of abuse (amphetamines, cocaine, opiates, or phencyclidine), a positive breath alcohol test.
12. Subjects with a known history or presence of: a. Alcohol abuse or dependence within one year prior to first drug administration; b. Drug abuse or dependence; c. Hypersensitivity or idiosyncratic reaction to diazepam, its excipients, sodium phosphates; and/or related substances, e.g. benzodiazepines; d. Glaucoma (open or acute narrow angle); e. Severe allergic reactions (e.g. anaphylactic reactions, angioedema
13. Subjects who have participated in another clinical trial or who received an investigational drug within 30 days prior to first drug administration or 5 half-lives of the investigational drug-whichever is the longer period.
14. Blood or plasma donation within 30 days prior to Screening
15. Subjects not willing or unable to tolerate blood draws.
16. Subjects who have received any other dosage form of diazepam or benzodiazepines within 2 weeks prior to entering Period A or Period B.
17. Consumption of alcohol within 48 hours before dosing and food or beverages containing grapefruit, star fruit, Seville oranges, and/or pomelo or their derived products (e.g., fruit juice) within 10 days prior to first drug administration.
18. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (e.g. cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, or HIV antivirals) and strong inducers of CYP enzymes (e.g. glucocorticoids, St. John´s Wort, or rifampicin) in the previous 30 days before first drug administration \[barbiturates, carbamazepine, and phenytoin are allowed since these are common AEDs (Anti-epileptic drugs)\].
19. Use of any monoamine oxidase (MAO) inhibitors (e.g. phenelzine, tranylcypromine), phenothiazines (chlorpromazine) within 30 days prior to first drug administration.
20. Employee or immediate relative of an employee of the investigator, MonoSol Rx LLC, any of its affiliates or partners, or inVentiv Health.

Participant flow

Outcome results

• Tmax Pharmacokinetic EndPoints (Primary), Median, hours: Interictal State 1.000 (0.249 to 4.017); Ictal/Peri-ictal State 0.525 (0.250 to 2.033)
• Cmax Pharmacokinetic EndPoints (Primary), Mean, ng/mL: Interictal State 230.32 +/- 89.00; Ictal/Peri-ictal State 209.49 +/- 120.18
• Area Under the Plasma Concentration Curve Pharmacokinetic EndPoints (Primary), Mean, h*ng/mL: Interictal State 560.18 +/- 219.70; Ictal/Peri-ictal State 498.78 +/- 319.09
• Usability Endpoint - Successful Insertion/Placement of the Diazepam Buccal Film (DBF) on First Attempt (Secondary), Count of participants, Participants: Interictal State 0; Ictal/Peri-ictal State 2
• Usability Endpoint: Swallowing the Film Before Complete Disintegration/Dissolution (Secondary), Count of participants, Participants: Interictal State 4; Ictal/Peri-ictal State 2
• Usability Endpoint: Retention of Diazepam Buccal Film (DBF) From Placement to Complete Disintegration (Secondary), Count of participants, Participants: Interictal State 0; Ictal/Peri-ictal State 3
• Usability Endpoint: Exit of Saliva During the Time the Diazepam Buccal Film (DBF) Was Adhered to Buccal Mucosa (Secondary), Count of participants, Participants: Interictal State 0; Ictal/Peri-ictal State 2
• Usability Endpoint: Amount of Saliva That Exited the Mouth After Film Placement (Secondary), Count of participants, Participants: Interictal State 33; Ictal/Peri-ictal State 31

Adverse events

Time frame: Adverse events were collected throughout the course of the study for each subject (approximately 1 month for each subject - beginning with the first DBF dose until 14 ± 2 days following the second DBF dose).

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2017-08-04)
• Statistical Analysis Plan (PDF, 2018-09-14)

• Gary Slatko, Study director, Aquestive Therapeutics