Pharmacokinetics and Safety Study of Diazepam Buccal Film (DBF) in Pediatric Subjects With Epilepsy

A Multicenter,Open Label Crossover Study to Assess the Pharmacokinetics and Safety of Diazepam Buccal Soluble Film (DBSF) in Pediatric Subjects With Epilepsy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03222349

Enrollment

Registered

2017-07-19

Start date

2017-08-31

Completion date

2020-03-11

Last updated

2021-05-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Epilepsy

Keywords

interictal state, ictal/peri-ictal state

Brief summary

Open-label study to assess the pharmacokinetics of a single diazepam buccal film (DBF) dose in 3 age cohorts of pediatric patients with epilepsy (age 2-5 years, age 6-11 years, and age 12-16 years). Subjects in the 6-11 years and 12-16 years age cohorts received a single DBF dose during the interictal period (Period A) and ictal/peri-ictal period (Period B) with at least 14 days washout between doses. Subjects in the age 2-5 years age cohort received a single DBF dose only during the ictal/peri-ictal period (Period B).

Detailed description

This was a Phase 2 multicenter, open-label, two-way study conducted in male and female pediatric subjects (aged 2 to 16 years) with a clinical diagnosis of epilepsy who were scheduled to be admitted to an Epilepsy Monitoring Unit (EMU), a general clinical research center (GCRC), or similar facility for evaluation of seizures and who complied with all remaining protocol eligibility criteria. To ensure that 16 to 18 subjects would complete the study across 3 age ranges (2 to 5 years, 6 to 11 years, and 12 to 16 years), a minimum of 24 subjects were to be enrolled (8 in each age cohort). Subjects in the 6 to 11 years and 12 to 16 years age cohorts received a single dose of DBF during the interictal period (Period A) and ictal/peri-ictal period (Period B) with at least 14 days washout between doses. Subjects in the age 2 to 5 years age cohort received a single dose of DBF only during the ictal/peri-ictal period (Period B). DBF was provided in a range of doses from 5 to 17.5 mg. The appropriate dose of DBF was assigned on the basis of age and weight using an interactive web response system during check-in. Period A (interictal administration): 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) 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. Period B (ictal/peri-ictal administration): For the purpose of this study, the ictal state was defined as an ongoing clinically observable seizure or seizure activity as verified via EEG. The peri-ictal 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 monitoring, the peri-ictal state was to be defined as less than 5 minutes after cessation of seizure activity as verified via EEG. .

Interventions

DRUGDiazepam Buccal Film

Subjects received a single DBF dose determined by age and body weight during the interictal state and during the ictal/peri-ictal period with at least 14 days washout between doses.

Study design

Allocation

NON_RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

This was a multicenter study comprised of 2 treatment periods with a minimum 14 days between the 2 treatment periods.

Eligibility

Sex/Gender

ALL

Age

2 Years to 16 Years

Healthy volunteers

Inclusion criteria

Potential subjects meeting all of the following criteria may be included in the study: 1. Subjects have a clinical diagnosis of epilepsy (GTC seizures or focal seizures with impaired awareness) and were scheduled for admission to an Epilepsy Monitoring Unit (EMU), General Clinical Research Center (GCRC), or similar facility for evaluation. 2. Male and female subjects between 2 and 16 years of age, inclusive. 3. Subjects had a body weight of at least 6 kg and less than or equal to 111 kg. 4. Subjects had an average frequency of at least 1 clinically apparent seizure every 3 days or ≥10 clinically apparent seizures per month, with alteration of consciousness as documented by reliable subject report, personal seizure diary records, and/or by seizure diaries dispensed at screening and verified prior to study entry. 5. Female subjects of childbearing potential (i.e., were having periods, were not surgically sterile) must have had a negative serum pregnancy test (using Beta-hCG) at Screening and a negative urine pregnancy test on Study Day I prior to drug dosing. Female subjects of childbearing potential must have agreed to abstinence, have had a partner who was sterile, or have been practicing double barrier contraception or have been using an FDA-approved contraceptive (e.g., licensed hormonal or barrier methods) for greater than 2 months prior to screening visit, and must have committed to an acceptable form of birth control for the duration of the study and for 30 days after participation in the study. 6. Male subjects with a female sexual partner of childbearing potential must have agreed to abstinence or to practice adequate birth control during the study, including at least 1 barrier method such a condom, diaphragm, or spermicide for more than 2 months prior to the screening visit, and must have committed to an acceptable form of birth control for the duration of the study and for 30 days after participation in the study. Also, male subjects must have agreed not to donate sperm during the study and for 90 days after the follow-up visit. 7. Subjects were currently receiving at least one antiepileptic medication. 8. Subject's parent or legally authorized representative must have been willing and able to complete informed consent and HIPAA authorization. Subjects must have been willing to give assent as required by the Institutional Review Board (IRB). 9. Subject must have agreed to be available or subject's parent(s) or legally authorized representative(s) must have agreed to have the subject be available for both Treatment Periods and the Follow-up Visit, and must have been willing to comply with all required study procedures and adhere to all protocol requirements. 10. Subject or subject's parent(s) or legally authorized representative(s) must have been able to comprehend and be informed of the nature of the study, as assessed by the Investigator.

Exclusion criteria

Potential subjects meeting any of the following criteria were excluded from participating in the study: 1. Subjects with a progressive neurological disorder such as a brain tumor, demyelinating disease, or degenerative central nervous system (CNS) disease that was likely to progress in the 12 months after screening. 2. Subjects with respiratory failure (or is at risk for respiratory failure) or other severe cardiorespiratory disease with New York Heart Association Class Ill or IV functional status, or who required supplemental oxygen. 3. Female subjects who were lactating, had a positive serum pregnancy test (β-hCG) at screening, or had a positive urine pregnancy test at Check-in for treatment periods. 4. Subjects with psychiatric disease that in the Investigator's judgment would prevent the subject's successful completion of the study. 5. Subjects with recent history of suicide attempt (defined as an active, interrupted, or aborted attempt within the previous 5 years) or reported suicidal ideation in the previous 6 months as indicated by a positive response (Yes) to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale performed at the screening 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 Investigator or designee and confirmed by Sponsor via written communication prior to subject enrollment. Abnormal laboratory results considered clinically significant by the Investigator or designee were to be evaluated by the Investigator in consultation with the Medical Monitor. 7. Subjects with any clinically significant illness other than epilepsy within 30 days prior to study drug administration, as determined by the Investigator. 8. Subjects with any significant physical or organ abnormality or other condition that would interfere with study participation or constitute a safety risk in the judgment of the Investigator. 9. Subjects with any significant lesion of the oral cavity or having oral prophylactic or dental procedures within 30 days prior to study drug administration. 10. Subjects with a QT interval corrected by Fridericia's formula (QTcF) \>450 ms for males or QTcF \>470 ms 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, phencyclidine, or a positive breath alcohol test. Subjects who tested positive for tetrahydrocannabinol (THC) at screening were excluded unless the Investigator was able to affirm in writing that the use of a medical marijuana product was part of the subject's treatment plan as recommended by a physician for treatment of a medical condition. In such case, the subject was to be allowed to continue with screening, and the medical marijuana product was to be recorded as a concomitant medication. 12. Subjects with a known history or presence of any of the following: 1. Substance abuse or dependence (including alcohol) within 1 year prior to first study drug administration 2. Hypersensitivity or idiosyncratic reaction to diazepam, its excipients, sodium phosphates, and/or related substances, e.g., benzodiazepines 3. Glaucoma (open or acute narrow angle) 4. Severe allergic reactions (e.g., anaphylactic reactions, angioedema) to investigational product and excipients 13. Subjects who had participated in another clinical trial or who had received an investigational drug within 30 days prior to study drug administration or 5 half-lives of the investigational drug-whichever was the longer period. 14. Subjects with presence of mouth jewelry, dentures, oral implants, braces, or piercings in the mouth or tongue that, in the opinion of the Investigator, would have been likely to interfere with successful completion of the dosing procedure. 15. Subjects with a blood or plasma donation within 30 days prior to screening. 16. Subjects not willing or unable to tolerate blood draws. 17. Consumption of alcohol within 48 hours before dosing; or 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 study drug administration. 18. Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome (CYP) 450 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 prior to study drug administration. (Barbiturates, carbamazepine, phenytoin, and other enzyme-modifying antiepileptic drugs (AEDs) that were medically needed were permitted.) 19. Use of any monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine ), and/or phenothiazines (chlorpromazine) within 30 days prior to first study drug administration. 20. Employee or immediate relative of an employee of Aquestive Therapeutics, any of its affiliates or partners, or Syneos Health.

Design outcomes

Primary

Measure	Time frame	Description
Observed Maximum Plasma Concentration (Cmax) From Time 0 (Dosing) to 4 Hours Post-dose	Time 0 (dosing), 0.25, 0.5, 1, 1.5, 2, 4 hours post-dose	Maximum observed plasma concentration from Time 0 to 4 hours post-dose in Period A (interictal administration) and Period B (ictal/peri-ictal administration)
Area Under the Concentration Time Curve (AUC) From 0 to 2 Hours Post-dose	Time 0 (dosing), 0.25, 0.5, 1, 1.5, 2 hours post-dose	AUC calculated from time 0 (dosing) to 2 hours post-dose in both Period A (interictal administration) and Period B (ictal/peri-ictal administration)Period A (interictal administration) and Period B (ictal/peri-ictal administration)
Time When Maximum Plasma Concentration Was Observed (Tmax) 0 to 2 Hours Post-dose	Time 0 (dosing), 0.25, 0.5, 1, 1.5, 2 hours post-dose	Tmax calculated from time 0 (dosing) to 2 hours post-dose in both Period A (interictal administration) and Period B (ictal/peri-ictal administration)
Time When Maximum Plasma Concentration Was Observed (Tmax) 0-4 Hours Post-Dose	Time 0 (dosing), 0.25, 0.5, 1, 1.5, 2, 4 hours post-dose	Tmax calculated from dosing (Time 0) to 4 hours post-dose in both Period A (interictal administration) and Period B (ictal/peri-ictal administration)
Observed Maximum Plasma Concentration (Cmax) 0-2 Hours	Time 0 (dosing), 0.25, 0.5, 1, 1.5, 2 hours post-dose	Maximum observed plasma concentration measured from Time 0 to 2 hours post-dose in Period A (interictal administration) and Period B (ictal/peri-ictal administration)
Area Under the Concentration Time Curve (AUC) 0 to 4 Hours Post-dose	Time 0 (dosing), 0.25, 0.5, 1, 1.5, 2, 4 hours post-dose	AUC calculated from time 0 (dosing) to 4 hours post-dose in both Period A (interictal administration) and Period B (ictal/peri-ictal administration)

Secondary

Measure	Time frame	Description
Usability of Diazepam Buccal Film: Unsuccessful Attempts	Period A and Period B from the time of first attempt at DBF insertion to 15 minutes after insertion.	Number of subjects with any unsuccessful DBF insertion attempts (All analyzed subjects with an unsuccessful attempt ultimately had a successful attempt at dosing)
Usability Endpoint : Amount of Saliva That Exited the Mouth After DBF Dosing	Period A and Period B from the time of first attempt at DBF insertion to 15 minutes after insertion.	Estimation of the amount of saliva exiting the mouth in mL after DBF dosing in Period A and Period B
Number of Subjects Who Swallowed DBF After Initial Insertion	Period A and Period B from the time of first attempt at DBF insertion to 15 minutes after insertion.	Number of subjects who swallowed DBF during Period A and/or Period B
Usability of Diazepam Buccal Film: Number of Subjects Who Spit Out/Moved/Chewed the Film After it Adhered (Stuck) to Buccal Mucosa During Period A and Period B.	Period A and Period B from the time of first attempt at DBF insertion to 15 minutes after insertion.	Was DBF spit out or blown out by the subject after adherence to the buccal mucosa or did the subject chew, talk or move the DBF prior to complete disintegration/dissolution?

Countries

United States

Participant flow

Recruitment details

Planned enrollment was 24 male and female subjects with 8 subjects in each of 3 age ranges (2 to 5 years, 6 to 11 years, and 12 to 16 years) with a clinical diagnosis of epilepsy (generalized tonic clonic seizures or focal seizures with impaired awareness) currently receiving at least one epileptic medication who were scheduled for admission to an Epilepsy Monitoring Unit (EMU), General Clinical Research Center (GCRC), or similar facility for evaluation.

Pre-assignment details

A total of 24 subjects were enrolled and received at least 1 dose of study drug based on age and weight during the interictal and the ictal/peri-ictal period in either order as determined by seizure occurrence.

Participants by arm

Arm	Count
Safety Analysis Set A total of 24 subjects were enrolled and received at least 1 dose of DBF determined based on age and weight (6 in the 2-5 years age group, 9 in the 6-11 years age group, and 9 in the 12-16 years age group).	24
Total	24

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	2
Overall Study	Study terminated by sponsor	1	0
Overall Study	Treatment A not done	0	5
Overall Study	Treatment B not done	5	0
Overall Study	Withdrawal by Subject	1	0

Baseline characteristics

Characteristic	Safety Analysis Set
Age, Categorical <=18 years	24 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	0 Participants
Age, Continuous	14.0 years STANDARD_DEVIATION 1.58
Body Mass Index (kg/m^2)	22.166 kg/m^2 STANDARD_DEVIATION 10.198
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	1 Participants
Race (NIH/OMB) Black or African American	5 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants
Race (NIH/OMB) White	14 Participants
Region of Enrollment United States	24 Participants
Sex: Female, Male Female	14 Participants
Sex: Female, Male Male	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 17	2 / 16
other Total, other adverse events	9 / 17	7 / 16
serious Total, serious adverse events	0 / 17	2 / 16

Outcome results

Primary

Area Under the Concentration Time Curve (AUC) 0 to 4 Hours Post-dose

AUC calculated from time 0 (dosing) to 4 hours post-dose in both Period A (interictal administration) and Period B (ictal/peri-ictal administration)

Time frame: Time 0 (dosing), 0.25, 0.5, 1, 1.5, 2, 4 hours post-dose