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

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ClinicalTrials.gov Identifier: NCT03428360
Recruitment Status : Completed
First Posted : February 9, 2018
Results First Posted : August 5, 2021
Last Update Posted : August 5, 2021
Sponsor:
Collaborators:
Syneos Health
Covance
Information provided by (Responsible Party):
Aquestive Therapeutics

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Epilepsy
Intervention Drug: 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
Enrollment 149
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
Arm/Group Title Safety Set
Hide Arm/Group Description

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 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.

Period Title: Overall Study
Started 130
Completed 90
Not Completed 40
Reason Not Completed
Informed consent withdrawn             5
Withdrawal by Subject             4
Lost to Follow-up             5
Physician Decision             2
Informed consent withdrawn             5
Study terminated by sponsor             10
Non-compliant with study             1
Non-compliant with study drug             3
Death             3
Adverse Event             1
Not on antiepileptic drug             1
Arm/Group Title Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug
Hide Arm/Group Description

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.

Overall Number of Baseline Participants 130
Hide Baseline Analysis Population Description
Safety Analysis Set: Enrolled subjects with epilepsy who received at least 1 dose of study drug
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 130 participants
25.9  (13.28)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants
Female
66
  50.8%
Male
64
  49.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants
Hispanic or Latino
29
  22.3%
Not Hispanic or Latino
99
  76.2%
Unknown or Not Reported
2
   1.5%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants
American Indian or Alaska Native
0
   0.0%
Asian
5
   3.8%
Native Hawaiian or Other Pacific Islander
6
   4.6%
Black or African American
12
   9.2%
White
99
  76.2%
More than one race
8
   6.2%
Unknown or Not Reported
0
   0.0%
Body Mass Index (kg/m^2  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 130 participants
24.108  (6.8148)
1.Primary Outcome
Title Number of Subjects in the Safety Analysis Set With at Least 1 Treatment-emergent Adverse Event (TEAE)
Hide Description 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).
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug
Arm/Group Title Safety Analysis Set: Enrolled Subjects With Epilepsy Who Received at Least 1 Dose of Study Drug
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 130
Measure Type: Count of Participants
Unit of Measure: Participants
At least 1 TEAE
84
  64.6%
At least 1 severe TEAE
14
  10.8%
At least 1 study drug related TEAE
10
   7.7%
At least 1 severe and related TEAE
1
   0.8%
At least 1 serious TEAE
18
  13.8%
At least 1 serious and related TEAE
1
   0.8%
2.Primary Outcome
Title Number of Subjects in Safety Analysis Set With Adverse Events of Special Interest (AESI)
Hide Description

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).
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug
Arm/Group Title Subjects With Epilepsy
Hide Arm/Group Description:

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.

Overall Number of Participants Analyzed 130
Measure Type: Number
Unit of Measure: participants
Any adverse event of special interest 32
Any oral irritation adverse event 3
Any oral safety adverse event 8
Any potential abuse related adverse event 21
Any abuse related adverse event 1
Any other adverse event of special interest 8
3.Secondary Outcome
Title Usability Assessment: Number of Use Occasions Where Difficulty in Opening the Outer Packaging Was Recorded.
Hide Description For each use occasion the following question was asked: Did you have difficulty in opening the outer plastic packaging on this use occasion? Yes
Time Frame Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug (Safety Analysis Set)
Arm/Group Title Total Use Occasions
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Analysis is based upon the total number times the study drug was used over the course of the study - subjects could have multiple use occasions during the study: Total number of use occasions reported was 1348 for the total 130 subjects in the Safety Population
Overall Number of Participants Analyzed 130
Overall Number of Units Analyzed
Type of Units Analyzed: Total number of use occasions
1348
Measure Type: Number
Unit of Measure: total number of use occasions
211
4.Secondary Outcome
Title Usability Assessment: Ability to Open Foil Pouch on Each Use Occasion
Hide Description 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
Time Frame Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Number of subjects reporting use occasions
Arm/Group Title Study Drug Use Occasions
Hide Arm/Group Description:
Total number of use occasions reported over the course of the study; each subject could report multiple use occasions during the study
Overall Number of Participants Analyzed 130
Overall Number of Units Analyzed
Type of Units Analyzed: Total number of use occasions
1348
Count of Units
Unit of Measure: total number of use occasions
Yes, I had difficulty opening the foil pouch
391
  29.0%
No, I did not have difficulty opening the foil pouch
957
  71.0%
5.Secondary Outcome
Title Usability Assessment: Ability to Remove Study Drug From Foil Pouch on Each Use Occasion
Hide Description 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
Time Frame Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug (Safety Analysis Set)
Arm/Group Title Study Drug Use Occasions
Hide Arm/Group Description:
Total number of use occasions reported during the study; each subject could report multiple use occasions over the course of the study
Overall Number of Participants Analyzed 130
Overall Number of Units Analyzed
Type of Units Analyzed: Total number of use occasions rpoeted
1348
Count of Units
Unit of Measure: total number of use occasions rpoeted
Yes, I had difficulty removing study drug from pouch on this occasion
47
   3.5%
No, I did not have difficulty removing study drug from the pouch on this occasion
1301
  96.5%
6.Secondary Outcome
Title Number of Occasions With Successful Insertion/Retention in Cheek
Hide Description 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
Time Frame Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug (Safety Analysis Set)
Arm/Group Title Study Drug Use Occasions
Hide Arm/Group Description:
Total number of use occasions reported during the study; each subject could report multiple use occasions over the course of the study
Overall Number of Participants Analyzed 130
Overall Number of Units Analyzed
Type of Units Analyzed: Total number of use occasions
1348
Measure Type: Number
Unit of Measure: Number of events
1330
7.Secondary Outcome
Title Usability Assessment: Difficulty Inserting DBF Against the Buccal Mucosa (Number of Attempts to Insert Film for Each Use Occasion)
Hide Description 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
Time Frame Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug (Safety Analysis Set)
Arm/Group Title Study Drug Use Occasions
Hide Arm/Group Description:
Total number of use occasions reported during the study; each subject could report multiple use occasions over the course of the study
Overall Number of Participants Analyzed 130
Overall Number of Units Analyzed
Type of Units Analyzed: Total number of use occasions
1348
Measure Type: Number
Unit of Measure: Number of events
Number of occasions where it required 1 attempt to insert film 1268
Number of occasions that required 2 attempts to insert film 38
Number of occasions that required 3 attempts to insert film 18
Number of occasions that required >3 attempts to insert film 6
8.Secondary Outcome
Title Usability Assessment: Number of Occasions Where DBF Was Not Placed or Retained on the Inner Cheek Until Dissolution
Hide Description Number of occasions where the study drug was not successfully placed and or retained in cheek until the film fully dissolved.
Time Frame Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug (Safety Analysis Set)
Arm/Group Title Study Drug Use Occasions
Hide Arm/Group Description:
Total number of use occasions reported over the course of the study; each subject could report multiple use occasions during the study
Overall Number of Participants Analyzed 130
Overall Number of Units Analyzed
Type of Units Analyzed: Total number of use occasions
1348
Count of Units
Unit of Measure: total number of use occasions
16
   1.2%
9.Secondary Outcome
Title Usability Assessment: Reasons for Multiple Placement/Insertion Attempts During a Use Occasion
Hide Description 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
Time Frame Recorded in an electronic diary after each use of study drug, throughout the course of the study; approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects who received at least 1 dose of study drug (Safety Analysis Set)
Arm/Group Title Study Drug Use Occasions
Hide Arm/Group Description:
Total number of use occasions reported during the study; each subject could report multiple use occasions over the course of the study
Overall Number of Participants Analyzed 130
Overall Number of Units Analyzed
Type of Units Analyzed: Total number of use occasions
1348
Measure Type: Number
Unit of Measure: total number of use occasions
Clenching jaw / won't open mouth 21
Excessive drooling 24
Spit out before sticking 17
Other (none of the above) 33
Time Frame Adverse events that started after the first intake of DBF through the Final Visit were considered treatment-emergent adverse events (TEAEs).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Safety Analysis Set
Hide Arm/Group Description

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.

All-Cause Mortality
Safety Analysis Set
Affected / at Risk (%)
Total   3/130 (2.31%)    
Hide Serious Adverse Events
Safety Analysis Set
Affected / at Risk (%) # Events
Total   17/130 (13.08%)    
Gastrointestinal disorders   
Enterocolitis  1  1/130 (0.77%)  1
Nausea  1  1/130 (0.77%)  1
Small bowel obstruction  1  1/130 (0.77%)  1
Vomiting  1  1/130 (0.77%)  1
General disorders   
Death  1  1/130 (0.77%)  1
Infections and infestations   
Pneumonia  1  1/130 (0.77%)  1
Injury, poisoning and procedural complications   
Joint dislocation  1  1/130 (0.77%)  1
Toxicity to various agents  1  1/130 (0.77%)  1
Metabolism and nutrition disorders   
Hypokalaemia  1  1/130 (0.77%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Brain neoplasm malignant  1  1/130 (0.77%)  1
Nervous system disorders   
Seizure  1  1/130 (0.77%)  1
Epilepsy  1  1/130 (0.77%)  1
Partial seizure  1  1/130 (0.77%)  1
Respiratory, thoracic and mediastinal disorders   
Aspiration  1  1/130 (0.77%)  3
Acute respiratory failure  1  1/130 (0.77%)  1
Pneumonitis  1  1/130 (0.77%)  1
Respiratory failure  1  1/130 (0.77%)  1
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Safety Analysis Set
Affected / at Risk (%) # Events
Total   84/130 (64.62%)    
Gastrointestinal disorders   
Vomiting  1  7/130 (5.38%)  8
Nausea  1  5/130 (3.85%)  5
Diarrhoea  1  4/130 (3.08%)  6
General disorders   
Pyrexia  1  7/130 (5.38%)  12
Infections and infestations   
Upper respiratory tract infection  1  8/130 (6.15%)  8
Sinusitis  1  6/130 (4.62%)  6
Ear infection  1  4/130 (3.08%)  4
Injury, poisoning and procedural complications   
Fall  1  5/130 (3.85%)  7
Skin abrasion  1  4/130 (3.08%)  5
Investigations   
Weight decreased  1  4/130 (3.08%)  6
Weight increased  1  4/130 (3.08%)  6
Nervous system disorders   
Seizure  1  26/130 (20.00%)  98
Somnolence  1  6/130 (4.62%)  6
Lethargy  1  4/130 (3.08%)  5
Dizziness  1  4/130 (3.08%)  4
Headache  1  4/130 (3.08%)  4
Respiratory, thoracic and mediastinal disorders   
Cough  1  5/130 (3.85%)  6
Pneumonia aspiration  1  4/130 (3.08%)  4
1
Term from vocabulary, MedDRA (19.1)
Indicates events were collected by systematic assessment
Only those subjects who received at least one dose of DBF (130 out of 149) for a breakthrough seizure were included in the Safety Analysis Set.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Clinical Project Manager
Organization: Aquestive Therapeutics
Phone: 9089411896
EMail: cbuan@aquestive.com
Layout table for additonal information
Responsible Party: Aquestive Therapeutics
ClinicalTrials.gov Identifier: NCT03428360    
Other Study ID Numbers: 42-1703
First Submitted: December 18, 2017
First Posted: February 9, 2018
Results First Submitted: June 24, 2021
Results First Posted: August 5, 2021
Last Update Posted: August 5, 2021