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

An Open-Label, Safety and Tolerability Study of Chronic Intermittent Use of Diazepam Buccal Film (DBF) in Pediatric, Adolescent and Adult Subjects With Epilepsy

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03428360

Acronym

DBF

Enrollment

149

Registered

2018-02-09

Start date

2018-01-23

Completion date

2020-06-25

Last updated

2021-08-05

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

Conditions

Epilepsy

Keywords

Seizure

Brief summary

This Phase 3, multicenter, open-label study of chronic, intermittent use of study drug (DBF) is designed to evaluate the safety and tolerability of the buccal formulation of diazepam in children, adolescents and adults with intermittent, stereotypic episodes of frequent seizure activity (eg, seizure clusters) that are distinct from the subject's usual seizure pattern.

Detailed description

The Primary objective of the study is to assess the safety and tolerability of DBF (study drug) administered a minimum of 3 times to subjects with epilepsy for the treatment of seizures over a minimum 6-month period. Secondary objectives: * To evaluate the usability of study drug as assessed by the ability of caregivers/subjects to administer study drug based on the Instructions for Use (IFU). * To evaluate the Quality of Life (QoL) of the subjects during the study drug treatment period as assessed by use of age-appropriate epilepsy scales over a minimum 6-month period.

Interventions

DRUGDiazepam Buccal Soluble Film 5, 7.5,10, 12.5,15 or 17.5 mg with individual dose determined according to age and weight category

The subjects in this study administered DBF themselves or with the help of a caregiver, (trained by the study site staff in study drug administration and documentation) in the same setting as they typically used the diazepam rectal gel or other rescue medication, without the presence of study staff.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

The study population was male or female pediatric, adolescent, and adult subjects with a clinical diagnosis of epilepsy and with bouts of increased seizure activity, frequent breakthrough seizures, seizure clusters, or cluster seizures and who were on chronic, intermittent use of rescue medication (eg, Diastat AcuDial or other benzodiazepine).

Eligibility

Sex/Gender

ALL

Age

2 Years to 65 Years

Healthy volunteers

Inclusion criteria

1. Female or male subject between the ages of 2 and 65 years of age, inclusive 2. Written informed consent to participate in the study 3. Subject has an established diagnosis of epilepsy either partial or generalized epilepsy with motor seizures with clear alteration of awareness, and while on a regimen of anti-epileptic medication(s), still experiences bouts of seizures (frequent break through seizures, e.g. Acute Repetitive Seizures (ARS) or seizure clusters) and who, in the opinion of the Investigator, may need benzodiazepine intervention for seizure control at least 1 time a month on average. 4. Caregiver, if needed for subject, provides written informed consent and is able to administer study drug in the event of a seizure. 5. Female subjects ≥12 years of age have a negative serum pregnancy test at screening. Female subjects of childbearing potential, (not surgically sterile or less than 2 years postmenopausal), must have a partner who is sterile, agrees 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 the study 6. No aspects of the medical history and/or the physical-neurological examination that at the judgment of the Investigator, in consultation with the Sponsor, will interfere with administration or absorption of study drug, or could evolve into a safety issue 7. No clinically significant abnormal findings on the electrocardiogram (QTcF≤450 msec for males and QTcF≤470 msec for females) 8. Subject and caregiver must be willing to comply with all study visits and all required study procedures

Exclusion criteria

1. A history of clinically significant gastrointestinal, renal/genitourinary, hepatic, hematologic, dermatologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, or any other clinically significant abnormalities, such as physical examination, vital signs, laboratory tests or ECG at Screening or Baseline which in the opinion of the investigator require further investigation or treatment or which may interfere with study procedures or safety or other medical conditions (e.g., cardiac, respiratory, gastrointestinal, psychiatric, renal disease) which are not adequately and stably controlled, or which in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments or any other condition which, in the opinion of the Investigator, would jeopardize the safety of the subject 2. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days prior to study screening 3. Subject with an active major depression or a past suicide attempt, or any suicidal ideation of 4, or 5 or any suicidal behavior in lifetime using Columbia-Suicide Severity Rating Scale(C-SSRS). The pediatric C-SSRS should be used for subjects 6 to 11 years of age. The adult C-SSRS should be used for subjects ≥12 years of age. Note that this exclusion is only applicable to cognitive-appropriate subjects who are able to understand and complete the Suicide Rating Scale 4. A history of allergic or adverse responses to diazepam or any other benzodiazepine 5. Participation in a clinical trial other than MonoSol Rx Phase 2 studies 160325 and 160326 within 30 days prior to Day 0. Participation in an observational (non-interventional) study is not an exclusion, provided that there are no scheduling conflicts with this study. Received any other investigational medication (unless it can be documented that the subject received only placebo) or device within 8 weeks or 5 half-lives (whichever is longer) before assignment to study drug treatment 6. Lactating female or positive serum pregnancy test (ß-hCG) at screening for female subjects ≥12 years of age 7. Positive blood screen for HIV, HbSAg, or Hepatitis C, or a positive urine screen for alcohol or drugs of abuse, except marijuana use for medicinal indications. When marijuana is or was used for medicinal indications in the opinion of the Investigator, it is not considered as drug abuse and the subject can be enrolled in states where medical marijuana use is legal, even if the marijuana metabolites in the urine revealed as positive

Design outcomes

Primary

Measure	Time frame	Description
Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)	Adverse events (AEs) were recorded from Day 1 through the last study contact (Month 7 telephone contact).	A TEAE was defined as any adverse event with onset date on the day of or after administration of study drug including relationship and severity.
Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)	AESIs were recorded from Day 1 through the last study contact (Month 7 telephone contact).	A.Oral irritation related AEs including but not limited to: buccal mucosal swelling, mouth ulceration, injuries to oral cavity (such as tongue or mucosal laceration, broken tooth, bleeding), erythema, stomatitis, gingivitis, xerostomia, staining, dysphagia, dysgeusia, burning, stinging, tingling. B. Abuse related AEs including euphoria, euphoric mood, feeling of relaxation, anger, dissociative effects, hallucinations, psychosis, changes in mood, impaired cognition, attention, psychomotor effects, inappropriate affect, overdose, and misuse. C. Other: Respiratory disorders, nervous system disorders

Secondary

Measure	Time frame	Description
Usability Assessment: Ability to Remove Study Drug From Foil Pouch on Each Use Occasion	Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months	For each use occasion the following question was asked: Did you have difficulty in removing study drug from foil pouch on this occasion? Yes or No
Number of Occasions With Successful Insertion/Retention in Cheek	Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months	Of the total number of use occasions over the course of the study, the number of use occasions that were successfully inserted/retained in the cheek
Usability Assessment: Number of Use Occasions Where Difficulty in Opening the Outer Packaging Was Recorded.	Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months	For each use occasion the following question was asked: Did you have difficulty in opening the outer plastic packaging on this use occasion? Yes
Usability Assessment: Number of Occasions Where DBF Was Not Placed or Retained on the Inner Cheek Until Dissolution	Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months	Number of occasions where the study drug was not successfully placed and or retained in cheek until the film fully dissolved.
Usability Assessment: Reasons for Multiple Placement/Insertion Attempts During a Use Occasion	Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months	Reasons for multiple attempts at insertion Multiple choice answer was: Excessive drooling, Clenching jaw / Won't open mouth, Spit out before sticking, Other/None of the above
Usability Assessment: Difficulty Inserting DBF Against the Buccal Mucosa (Number of Attempts to Insert Film for Each Use Occasion)	Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months	Number of occasions where it took 1 attempt to insert film, Number of occasions where it took 2 attempts to insert film, Number of occasions where it took 3 attempts to insert film, Number of occasions where it took \>3 attempts to insert film
Usability Assessment: Ability to Open Foil Pouch on Each Use Occasion	Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months	For each use occasion the following question was asked: Did you have difficulty in opening the foil pouch on this use occasion? Yes or No

Countries

United States

Participant flow

Recruitment details

150 subjects with epilepsy passed screening but 1 was never enrolled

Pre-assignment details

149 were enrolled but only 130 received at least 1 dose of study drug and were included in the analyses

Participants by arm

Arm	Count
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug Male or female subjects between the ages of 2 and 65 years who had an established diagnosis of epilepsy exhibited by motor seizures with clear alteration of awareness, and while on a regimen of anti-epileptic medication(s), still experienced bouts of seizures (frequent breakthrough seizures, eg, seizure clusters) and who, in the opinion of the Investigator, could need benzodiazepine intervention for seizure control at least 1 time a month on average. Subjects must have been on at least 1 concomitant anti-epileptic drug at screening. Diazepam Buccal Soluble Film 5, 7.5,10, 12.5,15 or 17.5 mg with individual dose determined according to age and weight category: The subjects in this study administered DBF themselves or with the help of a caregiver, (trained by the study site staff in study drug administration and documentation) in the same setting as they typically used the diazepam rectal gel or other rescue medication, without the presence of study staff.	130
Total	130

Arm

Count

Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug

Male or female subjects between the ages of 2 and 65 years who had an established diagnosis of epilepsy exhibited by motor seizures with clear alteration of awareness, and while on a regimen of anti-epileptic medication(s), still experienced bouts of seizures (frequent breakthrough seizures, eg, seizure clusters) and who, in the opinion of the Investigator, could need benzodiazepine intervention for seizure control at least 1 time a month on average. Subjects must have been on at least 1 concomitant anti-epileptic drug at screening. Diazepam Buccal Soluble Film 5, 7.5,10, 12.5,15 or 17.5 mg with individual dose determined according to age and weight category: The subjects in this study administered DBF themselves or with the help of a caregiver, (trained by the study site staff in study drug administration and documentation) in the same setting as they typically used the diazepam rectal gel or other rescue medication, without the presence of study staff.

130

Total

130

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	1
Overall Study	Death	3
Overall Study	Informed consent withdrawn	5
Overall Study	Lost to Follow-up	5
Overall Study	Non-compliant with study	1
Overall Study	Non-compliant with study drug	3
Overall Study	Not on antiepileptic drug	1
Overall Study	Physician Decision	2
Overall Study	Study terminated by sponsor	10
Overall Study	Withdrawal by Subject	4

Baseline characteristics

Characteristic	Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug
Age, Continuous	25.9 years STANDARD_DEVIATION 13.28
Body Mass Index (kg/m^2	24.108 kg/m^2 STANDARD_DEVIATION 6.8148
Ethnicity (NIH/OMB) Hispanic or Latino	29 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	99 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	5 Participants
Race (NIH/OMB) Black or African American	12 Participants
Race (NIH/OMB) More than one race	8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	6 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	99 Participants
Sex: Female, Male Female	66 Participants
Sex: Female, Male Male	64 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	3 / 130
other Total, other adverse events	84 / 130
serious Total, serious adverse events	17 / 130

Outcome results

Primary

Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)

A.Oral irritation related AEs including but not limited to: buccal mucosal swelling, mouth ulceration, injuries to oral cavity (such as tongue or mucosal laceration, broken tooth, bleeding), erythema, stomatitis, gingivitis, xerostomia, staining, dysphagia, dysgeusia, burning, stinging, tingling. B. Abuse related AEs including euphoria, euphoric mood, feeling of relaxation, anger, dissociative effects, hallucinations, psychosis, changes in mood, impaired cognition, attention, psychomotor effects, inappropriate affect, overdose, and misuse. C. Other: Respiratory disorders, nervous system disorders

Time frame: AESIs were recorded from Day 1 through the last study contact (Month 7 telephone contact).

Population: Subjects who received at least 1 dose of study drug

Arm	Measure	Group	Value (NUMBER)
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)	Any adverse event of special interest	32 participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)	Any oral safety adverse event	8 participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)	Any other adverse event of special interest	8 participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)	Any oral irritation adverse event	3 participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)	Any potential abuse related adverse event	21 participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)	Any abuse related adverse event	1 participants

Primary

Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)

A TEAE was defined as any adverse event with onset date on the day of or after administration of study drug including relationship and severity.

Time frame: Adverse events (AEs) were recorded from Day 1 through the last study contact (Month 7 telephone contact).

Population: Subjects who received at least 1 dose of study drug

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)	At least 1 TEAE	84 Participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)	At least 1 severe TEAE	14 Participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)	At least 1 study drug related TEAE	10 Participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)	At least 1 severe and related TEAE	1 Participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)	At least 1 serious TEAE	18 Participants
Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug	Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)	At least 1 serious and related TEAE	1 Participants

Secondary

Number of Occasions With Successful Insertion/Retention in Cheek

Of the total number of use occasions over the course of the study, the number of use occasions that were successfully inserted/retained in the cheek