Bioavailability, Safety and Tolerability of Diazepam Nasal Spray Versus Diazepam Rectal Gel (Diastat®)

Study Overview
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Brief Summary
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This is a multi-center, open-label, crossover, pharmacokinetic, bio-availability study involving adolescents and adults with refractory (drug-resistant) epilepsy. Cohort 1 comprises the subjects used to determine the relative bioavailability of DZNS versus DRG (Diastat)

Detailed Description
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To determine the bioavailability of diazepam nasal spray versus diazepam rectal gel (Diastat®) under conditions of use in adolescent and adult persons with epilepsy (PWE) meeting the definition of refractory epilepsy.

Official Title
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An Open-Label, Randomized, Crossover Pharmacokinetic Study to Determine the Bioavailability, Safety and Tolerability of Single Doses of Diazepam Nasal Spray Versus Diazepam Rectal Gel (Diastat®) in Patients With Refractory Epilepsy

Conditions
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Refractory Epilepsy

Intervention / Treatment
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* Drug: diazepam nasal spray
* Drug: diazepam rectal gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of refractory epilepsy Body weight 26 to 111 kilogram (kg) inclusive Other inclusion criteria apply Exclusion Criteria: Male or female subject who is not surgically sterile or female subject who is less than 2 years postmenopausal, and does not agree to use a highly effective birth control method during the study and up to 3 months after the last dose of investigational product Female subject who is pregnant, breastfeeding, or planning to become pregnant Presence or history of any abnormality or illness that may affect the absorption, distribution, metabolism or elimination of diazepam Other exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: diazepam nasal spray (DZNS)<br>One dose of diazepam nasal spray is administered as two intranasal sprays; one in each nostril using a nasal spray device. | Drug: diazepam nasal spray<br> <br> * Other names: Diazepam;|
| Active Comparator: diazepam rectal gel (DRG)<br>A single rectal dose of diazepam will be administered to subjects according to the Diastat prescribing information. | Drug: diazepam rectal gel<br> <br> * Other names: AcuDial™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC 0-24h | Relative bioavailability based on area under time plasma concentration curve. | 24 hours | 
| Cmax | Relative bioavailability based on maximum observed plasma concentration. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Focused Nasal Exam (Part A) | A focused nasal exam was completed by the Investigator in the treatment period(s) when diazepam nasal spray was administered, based on a visual inspection of the nasal mucosa. Nasal irritation will be graded none to Grade 4 septal perforation. Grade 1a= focal irritation, Grade 1b= superficial mucosal erosion, Grade 2= moderate mucosal erosion, Grade 3= ulceration, Grade 4= septal perforation. This exam may be conducted within a 5 minute window after the specified time point. Between the 12 and 24 h time points, the exam should be repeated every 4 hours as needed to follow any residual symptoms to resolution and the time of resolution should be documented. (Categories with no data were omitted) | pre-dose (day 1) up to 24 hours post-dose | 
| Focused Nasal Exam (Part B) | A focused nasal exam was completed by the Investigator in the treatment period(s) when diazepam nasal spray was administered, based on a visual inspection of the nasal mucosa. Focused Nasal Examination Part B - will show nasal mucosal symptoms that will be rated for severity will include discharge, mucosal edema, crusting, erythema, and epistaxis. This exam may be conducted within a 5 minute window after the specified time point. Between the 12 and 24 h time points, the exam was should be repeated every 4 hours as needed to follow any residual symptoms to resolution and the time of resolution should be documented. (Categories with no data were omitted) | pre-dose (day 1) up to 24 hours post-dose | 
| Smell Identification Test (SIT) | The SIT is a validated test of smell identification which scores patients into different levels of olfactory function normalized by age and gender, however it had not been validated for use in PWE. The Smell Identification Test (SIT) is a 40-item multiple-choice standardized test. The test can be self-administered and consists of four 10-page booklets with a different scratch and sniff strip on each page. A scratch with a pencil releases the scent from the strip, and the subject is then asked to match the scent to one of four choices on the page. An answer must be selected for each of the 40 items, even when the subject cannot detect a smell. The total score (i.e., number of correct answers, range: 0-40) can be compared against normative data collected from approximately 4000 normal individuals between ages 4 to 99 to determine the subject's percentile rank of olfactory dysfunction corrected for age and gender. | day 1 up to day 31 | 
| Taste Change Questionnaire | Questionnaire given to safety population in Cohort 1 for reporting taste change during the study. If the subject spontaneously reports an experience of taste change associated with diazepam nasal spray dosing, it will be evaluated qualitatively by the research staff using a taste change questionnaire. The subject will be asked to describe the type, intensity, and duration of the change in taste at multiple scheduled time points after dosing. Between the 12 and 24 h time points, the questionnaire should be repeated every 4 hours as needed to follow any residual symptoms to resolution, and time of resolution should be documented. | Up to 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seizures, Epilepsy