Repeat-Dose Pharmacokinetics Study of NRL-1 in Epilepsy Subjects

Study Overview
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Brief Summary
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This study evaluates the pharmacokinetic and safety of NRL-1 in epilepsy subjects. Subjects will receive a single intranasal dose of NRL-1 of either 5 mg, 10 mg, 15 mg or 20 mg and will be based on the subject's body weight.

Detailed Description
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Diazepam rectal gel (Diastat) is the only formulation of diazepam indicated for the management of selected, refractory patients with epilepsy on stable regimens of antiepileptic drugs (AEDs) who require intermittent use of diazepam to control bouts of increased seizure activity, i.e., Acute Repetitive Seizures (ARS). A diazepam nasal spray is being developed for patients who experience ARS to provide an alternative more convenient and acceptable route of diazepam administration.

Official Title
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An Open-Label, Repeat-Dose Pharmacokinetics Study of NRL-1 in Epilepsy Subjects Under Seizure and Normal Conditions

Conditions
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Acute Repetitive Seizures

Intervention / Treatment
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* Drug: NRL-1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects between the ages of 6 and 65 years, inclusive. Written informed consent to participate in the study. Body mass index (BMI) not to exceed 35 kg/m², inclusive. Subject has a clinical diagnosis of Epilepsy and, in the opinion of the Investigator, may need benzodiazepine intervention for seizure control. Subjects having either partial or generalized Epilepsy with motor seizures or seizures with clear alteration of awareness are eligible for enrollment. Female subjects of childbearing potential, defined as having a menstrual cycle and who are not surgically sterile or less than two (2) years postmenopausal, must complete a pregnancy screen and agree to utilize one of the following forms of contraception during the trial and for 21 days after the last dose of study drug: abstinence, hormonal (oral, transdermal, implant, or injection), barrier (condom, diaphragm with spermicide), intrauterine device (IUD), or vasectomized partner (six months minimum). No clinically significant abnormal findings in the medical history, on the physical examination, ECG (corrected QT interval [QTcF] < 450 msec for males and QTcF < 470 msec for females), or clinical laboratory results during screening. Subjects and caregivers must agree to return to the study site for all study visits and must be willing to comply with all required study procedures. Exclusion Criteria: Subject is undergoing intracranial EEG monitoring. A history of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease, severe seasonal or non-seasonal allergies, nasal polyps or any nasal passage abnormality that could interfere with nasal spray administration, or any other condition which, in the opinion of the Investigator, would jeopardize the safety of the subject or impact the validity of the study results. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days prior to study screening. Subjects with active major depression or a past suicide attempt documented on the Baseline/Screening C-SSRS. The children C-SSRS should be used for subjects age 6 to 11. The adult C-SSRS should be used for subjects 12 and greater years of age. Any Suicidal Ideation of 3, 4, or 5 or any Suicidal Behavior in Lifetime using C-SSRS. A history of allergic or adverse responses to diazepam or any comparable or similar product. Subjects who (for whatever reason) have been on an abnormal diet (such as one that severely restricts specific basic food groups [e.g., ketogenic diet], limits calories [e.g., fast], and/or requires the use of daily supplements as a substitute for the foods typically eaten at mealtimes), during the four (4) weeks preceding the study. Subjects who donated blood or plasma within 30 days of the first dose of study drug. Participation in a clinical trial within 30 days prior to the first dose of study drug. Participation in an observational (non-interventional) study is not excluded as long as there are no scheduling conflicts with this study. Inadequate or difficult venous access that may jeopardize the quality or timing of the PK samples. Female subjects who are trying to conceive, are pregnant, or are lactating. Positive serum pregnancy test (ß-hCG) at screening or urine pregnancy test prior to each administration of study drug for all women of childbearing potential. Positive blood screen on subjects age 12 or greater for human immunodeficiency virus (HIV), Hepatitis B surface antigen (HbSAg), or Hepatitis C, or a positive urine screen for alcohol, drugs of abuse, or cotinine. When marijuana was used for medical reasons in the opinion of the investigator, it is not considered as drug abuse and the patient can be enrolled even if the marijuana metabolites in the urine revealed as positive. Treatment with phenobarbital or primidone within 30 days of the anticipated dosing visit (i.e., baseline). Treatment with warfarin or dabigatran or other blood thinners within 30 days of the anticipated dosing visit (i.e., baseline). Treatment with any diazepam containing products within 14 days of the anticipated dosing visit (i.e., baseline). Use of nasal decongestants or nasal steroids within 7 days prior to the screening visit or during the study. Subject does not have the flu, rhinitis or any other nasal condition that would impact absorption of intranasal diazepam.

Ages Eligible for Study
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Minimum Age: 6 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NRL-1 Ictal<br>During the ictal or peri-ictal setting, a single intranasal dose of NRL-1 will be administered at either 5 mg, 10 mg, 15 mg, or 20 mg based on the subject's body weight. | Drug: NRL-1<br> <br> * Other names: Intranasal diazepam;|
| Experimental: NRL-1 Inter-Ictal<br>During the inter-ictal setting, a single intranasal dose of NRL-1 will be administered at either 5 mg, 10 mg, 15 mg, or 20 mg based on the subject's body weight. | Drug: NRL-1<br> <br> * Other names: Intranasal diazepam;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Diazepam After Single Intranasal Doses of NRL-1 (Diazepam Nasal Spray) Administered to Epilepsy Subjects During the Ictal or Peri-ictal Period | Evaluate the pharmacokinetics (PK), in terms of Cmax, of diazepam following a single intranasal dose of NRL-1 (diazepam nasal spray) administered to epilepsy subjects in the ictal or peri-ictal state (defined as either during or immediately following a seizure), where the seizure involved motor activity or alteration of awareness compared with the normal (non-seizing) state. The epileptic condition (ictal/peri-ictal, interictal) had minimal impact on diazepam nasal spray pharmacokinetics. | Blood samples were obtained at 0, 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours after dosing. If feasible, samples were drawn at 8 and 12 hours post-dose but were excluded from PK analysis. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The AUC of Diazepam After Single Intranasal Doses of NRL-1 (Diazepam Nasal Spray) Administered to Epilepsy Subjects During the Ictal or Peri-ictal Period | Evaluate the pharmacokinetics (PK), in terms of AUC, of diazepam following a single intranasal dose of NRL-1 (diazepam nasal spray) administered to epilepsy subjects in the ictal or peri-ictal state (defined as either during or immediately following a seizure), where the seizure involved motor activity or alteration of awareness compared with the normal (non-seizing) state. The epileptic condition (ictal/peri-ictal, interictal) had minimal impact on diazepam nasal spray pharmacokinetics. | Blood samples were obtained at 0, 15, 30, and 45 minutes, and 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, and 6 hours after dosing. If feasible, samples were drawn at 8 and 12 hours post-dose but were excluded from PK analysis. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epilepsy, seizure