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

• ClinicalTrials.gov Identifier: NCT02724423
• Recruitment Status: Recruiting
• First Posted: March 31, 2016
• Last Update Posted: March 13, 2019
• Sponsor: Neurelis, Inc.
• Information provided by (Responsible Party): Neurelis, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Acute Repetitive Seizures	Drug: NRL-1	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 45 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Masking Description: open-label
• Primary Purpose: Treatment
• Official Title: An Open-Label, Repeat-Dose Pharmacokinetics Study of NRL-1 in Epilepsy Subjects Under Seizure and Normal Conditions
• Actual Study Start Date: June 30, 2016
• Estimated Primary Completion Date: June 30, 2019
• Estimated Study Completion Date: June 30, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: NRL-1; 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; Other Name: Intranasal diazepam

Outcome Measures

Primary Outcome Measures :

1. Assess the Cmax of diazepam after intranasal dose of NRL-1 [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
2. Assess the AUC through up to 6 hours of diazepam after intranasal dose of NRL-1 [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
3. Assess the tmax of diazepam after intranasal dose of NRL-1 [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]

Secondary Outcome Measures :

1. Comparison of Cmax after single administration of NRL-1 [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
2. Comparison of tmax after single administration of NRL-1 [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
3. Comparison of AUC (0-6) after single administration of NRL-1 [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
4. Comparison of Cmax after single administration of NRL-1 between subjects 6 to 11 and greater than 12 years of age [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
5. Comparison of tmax after single administration of NRL-1 between subjects 6 to 11 and greater than 12 years of age [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
6. Comparison of AUC (0-6) after single administration of NRL-1 between subjects 6 to 11 and greater than 12 years of age [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
7. Comparison of Cmax after single administration of NRL-1 in subjects during the ictal and peri-ictal period to that of health normal subjects from PK data obtained in previous studies [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
8. Comparison of tmax after single administration of NRL-1 in subjects during the ictal and peri-ictal period to that of health normal subjects from PK data obtained in previous studies [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
9. Comparison of AUC (0-6) after single administration of NRL-1 in subjects during the ictal and peri-ictal period to that of health normal subjects from PK data obtained in previous studies [ Time Frame: 15 min, 30 min, 45 min, 1 hr, 1.25, 1.5 hrs, 1.75 hrs, 2 hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, optional 8 hrs, 12 hrs ]
10. Safety of NRL-1 assessed by collection of adverse events data [ Time Frame: 56 days ]
    Data regarding treatment-emergent AEs (TEAEs) will be collected in this study. All clinically significant abnormal changes from baseline in physical examination findings, vital signs, ECGs, and laboratory evaluations will be collected, graded with regards to severity or clinical significance and assessed for causal relationship.
11. Tolerability of NRL-1 assessed by smell test using the NIH Toolbox Odor Identification Test kit [ Time Frame: 1 hr, 4 hrs, and at discharge ]
12. Tolerability of NRL-1 assessed by examination of the nasal mucosa [ Time Frame: 30 min, 1 hr, 2 hrs, 4 hrs, and 6 hrs post dose, and at discharge (6 hrs or optional 8 and 12 hours) ]
13. Tolerability of NRL-1 assessed by nasal Irritation assessments [ Time Frame: 2 hrs, 4 hrs, and 6 hrs post dose, and at discharge (6 hrs or optional 8 and 12 hours) ]

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male and female subjects between the ages of 6 and 65 years, inclusive.
2. Written informed consent to participate in the study.
3. Body mass index (BMI) not to exceed 35 kg/m², inclusive.
4. Subject has a clinical diagnosis of Epilepsy and, in the opinion of the Investigator, may need benzodiazepine intervention for seizure control.
5. Subjects having either partial or generalized Epilepsy with motor seizures or seizures with clear alteration of awareness are eligible for enrollment.
6. 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).
7. 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.
8. 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:

1. Subject is undergoing intracranial EEG monitoring.
2. 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.
3. Subject has had significant traumatic injury, major surgery or open biopsy within 30 days prior to study screening.
4. 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.
5. Any Suicidal Ideation of 3, 4, or 5 or any Suicidal Behavior in Lifetime using C-SSRS.
6. A history of allergic or adverse responses to diazepam or any comparable or similar product.
7. 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.
8. Subjects who donated blood or plasma within 30 days of the first dose of study drug.
9. 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.
10. Inadequate or difficult venous access that may jeopardize the quality or timing of the PK samples.
11. Female subjects who are trying to conceive, are pregnant, or are lactating.
12. 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.
13. 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.
14. Treatment with phenobarbital or primidone within 30 days of the anticipated dosing visit (i.e., baseline).
15. Treatment with warfarin or dabigatran or other blood thinners within 30 days of the anticipated dosing visit (i.e., baseline).
16. Treatment with any diazepam containing products within 14 days of the anticipated dosing visit (i.e., baseline).
17. Use of nasal decongestants or nasal steroids within 7 days prior to the screening visit or during the study.
18. Subject does not have the flu, rhinitis or any other nasal condition that would impact absorption of intranasal diazepam.

Contacts and Locations

Contacts

Contact: Richard Lowenthal, MSc, MBA; 858-335-1300; richard@pacificlinkconsulting.com

Contact: Robert Hasson; 858-368-9925; rhasson@pacificlinkconsulting.com

Locations

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Robert E Hogan, MD

Principal Investigator: Robert E Hogan, MD

United States, Pennsylvania

Thomas Jefferson University; Recruiting

Philadelphia, Pennsylvania, United States, 19107

Contact: Michael Sperling, MD

Principal Investigator: Michael Sperling, MD

United States, Tennessee

Le Bonheur Children's Hospita; Recruiting

Memphis, Tennessee, United States, 38103

Contact: James Wheless, MD

Principal Investigator: James Wheless, MD

United States, Virginia

University of Virginia; Recruiting

Charlottesville, Virginia, United States, 22903

Contact: Nathan Fountain, MD

Principal Investigator: Nathan Fountain, MD

Sponsors and Collaborators

Neurelis, Inc.

More Information

• Responsible Party: Neurelis, Inc.
• ClinicalTrials.gov Identifier: NCT02724423 History of Changes
• Other Study ID Numbers: DIAZ.001.04
• First Posted: March 31, 2016
• Last Update Posted: March 13, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Neurelis, Inc.:

epilepsy; seizure

Additional relevant MeSH terms:

Epilepsy; Seizures; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Diazepam; Adjuvants, Anesthesia; Anticonvulsants; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Hypnotics and Sedatives; Central Nervous System Depressants; Muscle Relaxants, Central; Neuromuscular Agents; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action