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

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.

• diazepam nasal spray (Drug), also known as Diazepam
• diazepam rectal gel (Drug), also known as Diastat®, AcuDial™

Primary outcomes

• AUC 0-24h [24 hours]: Relative bioavailability based on area under time plasma concentration curve.
• Cmax [24 hours]: Relative bioavailability based on maximum observed plasma concentration.

Secondary outcomes

• Focused Nasal Exam (Part A) [pre-dose (day 1) up to 24 hours post-dose]: 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)
• Focused Nasal Exam (Part B) [pre-dose (day 1) up to 24 hours post-dose]: 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)
• Smell Identification Test (SIT) [day 1 up to day 31]: 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.
• Taste Change Questionnaire [Up to 24 hours]: 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.

Sex: All, ages: 12 Years to 65 Years

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

Participant flow

Outcome results

• AUC 0-24h (Primary), Mean, ng*h/mL: Single Dose of Diazapam Nasal Spray (DZNS) 1357.7 +/- 802.78; Single Dose of Diazapam Rectal Gel (DRG) 2117.9 +/- 996.27
• Cmax (Primary), Mean, ng/mL: Single Dose of Diazapam Nasal Spray (DZNS) 157.0 +/- 120.15; Single Dose of Diazapam Rectal Gel (DRG) 309.3 +/- 137.95
• Focused Nasal Exam (Part A) (Secondary), Count of participants, Participants: DZNS - At 24 Hours Post-Dose - NONE 64; DZNS - At 24 Hours Post-Dose - Grade 1a 6; DZNS - At 24 Hours Post-Dose - Grade 1b 0; DZNS - At 24 Hours Post-Dose - Grade 2 1; DZNS - At 24 Hours Post-Dose - Grade 3 0; DZNS - At 24 Hours Post-Dose - Grade 4 0; DZNS - At 24 Hours Post-Dose - Missing 0
• Focused Nasal Exam (Part B) (Secondary), Count of participants, Participants: DZNS - At 24 Hours Post-Dose None 70; DZNS - At 24 Hours Post-Dose Mild 3; DZNS - At 24 Hours Post-Dose Moderate 0; DZNS - At 24 Hours Post-Dose Severe 0; DZNS - At 24 Hours Post-Dose Missing 0
• Smell Identification Test (SIT) (Secondary), Count of participants, Participants: At Follow-Up Visit - Normosmia 19; At Follow-Up Visit - Mild Microsmia 10; At Follow-Up Visit - Moderate Microsmia 0; At Follow-Up Visit - Severe Microsmia 0; At Follow-Up Visit - Anosmia 0; At Follow-Up Visit - Probable Malingering 0; At Follow-Up Visit - Missing 1
• Taste Change Questionnaire (Secondary), Mean, units on a scale: Taste Change by Intensity in Cohort 1 6.5 +/- 3.57

Adverse events

Time frame: 31 Days

Other adverse events by term

• Lee Min Jae, Study director, SK Biopharmaceuticals Co, Ltd