Cannabidiol Oral Solution in Pediatric Participants With Treatment-Resistant Childhood Absence Seizures

• ClinicalTrials.gov Identifier: NCT03336242
• Recruitment Status: Terminated
• First Posted: November 8, 2017
• Last Update Posted: November 13, 2020
• Sponsor: Benuvia Therapeutics Inc.
• Information provided by (Responsible Party): Benuvia Therapeutics Inc.

Study Description

Brief Summary:

The primary purpose of this study is to assess the efficacy of Cannabidiol Oral Solution in the treatment of pediatric participants with treatment-resistant childhood absence seizures. This study will also assess safety, tolerability and pharmacokinetics of Cannabidiol Oral Solution, and any improvement in qualitative assessments of participant status over the duration of the study in pediatric participants with treatment-resistant childhood absence seizures. The study will include a 4-week Screening Period, a 5 or 10 day Titration Period (depending study Cohort), a 4-week Treatment Period followed by 5-day Tapering for doses >20 mg/kg/day and a 4-week Follow-up Period.

Condition or disease	Intervention/treatment	Phase
Childhood Absence Epilepsy	Drug: Cannabidiol Oral Solution	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label, Dose-finding Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Pediatric Patients With Treatment-Resistant Childhood Absence Seizures
• Actual Study Start Date: December 15, 2017
• Actual Primary Completion Date: June 3, 2019
• Actual Study Completion Date: June 3, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1: Cannabidiol Oral Solution 20 mg/kg/day; Treatment Period: Cannabidiol Oral Solution 20 milligrams per kilogram per day (mg/kg/day) divided twice daily (BID) for 4 weeks.	Drug: Cannabidiol Oral Solution; An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).
Experimental: Cohort 2: Cannabidiol Oral Solution 30 mg/kg/day; Titration Period: Cannabidiol Oral Solution 20 mg/kg/day divided BID for 5 days. Treatment Period: Cannabidiol Oral Solution 30 mg/kg/day divided BID for 4 weeks.	Drug: Cannabidiol Oral Solution; An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).
Experimental: Cohort 3: Cannabidiol Oral Solution 40 mg/kg/day; Titration Period: Cannabidiol Oral Solution 20 mg/kg/day divided BID for 5 days, followed by 30 mg/kg/day divided BID for 5 days. Treatment Period: Cannabidiol Oral Solution 40 mg/kg/day divided BID for 4 weeks.	Drug: Cannabidiol Oral Solution; An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).

Outcome Measures

Primary Outcome Measures :

1. Percent Change from Baseline in Absence Seizure Counts Assessed by Video-electroencephalogram (EEG) at Visit 5 [ Time Frame: Baseline (Visit 2, Day 1 of Titration Period) and Visit 5 (Week 4, Day 6 of Treatment Period) ]
   A 4-hour video-EEG will be performed for all participants at Baseline, during the Treatment Period, and at the End of Study/Early Withdrawal Visit. Hyperventilation will be conducted during the video-EEG to count the number of absence seizures.
2. Percent Change from Baseline in Time to Absence Seizure During Hyperventilation Testing on Video-EEG at Visit 5 [ Time Frame: Baseline (Visit 2, Day 1 of Titration Period) and Visit 5 (Week 4, Day 6 of Treatment Period) ]
   A 4-hour video-EEG will be performed for all participants at Baseline, during the Treatment Period, and at the End of Study/Early Withdrawal Visit. Hyperventilation will be conducted during the video-EEG to count the number of absence seizures.
3. Percentage of Participants Seizure-Free at Visit 5 [ Time Frame: Screening (Visit 1, Day -28 to -1 of Screening Period) Up to Visit 5 (Week 4, Day 6 of Treatment Period ]
   Daily seizure activity will be recorded in a diary. Each day, the patient or parent/caregiver will respond to the question: "How many absence seizures did the patient have today?".
4. Clinical Global Impression of Improvement (CGI-I) Score at Visit 5 [ Time Frame: Visit 5 (Week 4, Day 6 of Treatment Period) ]
   The CGI-I will be completed by the parents/caregivers and the investigator and will be used to assess participants global status of their condition at Week 4 of the Treatment Period using a 7-point scale, where 1=very much improved and 7=very much worse since the initiation of treatment.

Secondary Outcome Measures :

1. Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Screening (Visit 1, Day -28 to -1 of Screening Period) up to Visit 7 (Week 4 of the Follow-Up Period) ]
   An AE is defined as any untoward medical occurrence in a patient administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. A TEAE is an AE with onset that occurs after receiving study drug. A SAE is any untoward medical occurrence that results in death, is life-threatening, requires the participant be at a risk of death at the time of the event, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality/birth defect, or other serious event that requires medical or surgical intervention.
2. Change from Baseline in Vital Signs During the Treatment Period [ Time Frame: Baseline (Visit 2, Day 1 of Titration period) and Visit 6 (Week 4, Day 7 of Treatment period) ]
3. Change from Screening in Laboratory Values During the Treatment Period [ Time Frame: Screening (Visit 1, Day -28 to -1 of Screening period) and Visit 6 (Week 4, Day 7 of Treatment period) ]
4. Maximum Plasma Concentration (Cmax) and Dose-normalized Cmax (Cmax/D) for Cannabidiol Under Fed and Fasted Conditions [ Time Frame: Visit 3 (Week 1, Day 1 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose), Visit 5 (Week 4, Day 6 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose), and Visit 6 (Week 4, Day 7 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose) ]

   Fed: Patient will arrive at the site on Day 1 of Week 4 of the Treatment Period without food and the morning dose. Site will provide a high fat/high calorie food then doses patient. Blood samples will be collected pre-dose (before meal/morning dose) and 2, 4, 6 hours after the morning dose (but before next dose).

   Fasted (2 hours before dose until 2 hours after dose): Patients will arrive at the site on Day 2 of Week 4 of the Treatment Period without food and the morning dose. Site will provide a standard meal 2 hours after dose. Blood samples will be collected pre-dose and 2 (before meal), 4, 6 hours after the morning dose (but before next dose).

5. Area Under the Plasma Concentration Curve from Time 0 to the Last Measured Concentration (AUC(0-t)) and Dose Normalized AUC(0-t) [AUC(0-t)/Dose] for Cannabidiol Under Fed and Fasted Conditions [ Time Frame: Visit 3 (Week 1, Day 1 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose), Visit 5 (Week 4, Day 6 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose), and Visit 6 (Week 4, Day 7 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose) ]

   Fed: Patient will arrive at the site on Day 1 of Week 4 of the Treatment Period without food and the morning dose. Site will provide a high fat/high calorie food then doses patient. Blood samples will be collected pre-dose (before meal/morning dose) and 2, 4, 6 hours after the morning dose (but before next dose).

   Fasted (2 hours before dose until 2 hours after dose): Patients will arrive at the site on Day 2 of Week 4 of the Treatment Period without food and the morning dose. Site will provide a standard meal 2 hours after dose. Blood samples will be collected pre-dose and 2 (before meal), 4, 6 hours after the morning dose (but before next dose).

6. Trough Plasma Concentration (Ctrough) and Dose normalized Ctrough (Ctrough/Dose) for Cannabidiol Under Fed, Fasted and Normal Conditions [ Time Frame: Visit 3 (Week 1, Day 1 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose), Visit 5 (Week 4, Day 6 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose), and Visit 6 (Week 4, Day 7 of Treatment Period; Pre-dose, 2, 4, 6 Hours Post-dose) ]

   Fed: Patient will arrive at the site on Day 1 of Week 4 of the Treatment Period without food and the morning dose. Site will provide a high fat/high calorie food then doses patient. Blood samples will be collected pre-dose (before meal/morning dose) and 2, 4, 6 hours after the morning dose (but before next dose).

   Fasted (2 hours before dose until 2 hours after dose): Patients will arrive at the site on Day 2 of Week 4 of the Treatment Period without food and the morning dose. Site will provide a standard meal 2 hours after dose. Blood samples will be collected pre-dose and 2 (before meal), 4, 6 hours after the morning dose (but before next dose).

   Under normal condition blood samples will be collected pre-dose.

Eligibility Criteria

• Ages Eligible for Study: 3 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patient and/or parent(s)/caregiver(s) fully comprehend the informed consent form (ICF) and assent form, understand all study procedures, and can communicate satisfactorily with the investigator and study coordinator, in accordance with applicable laws, regulations, and local requirements.
2. Male or female between 3 and 12 years (inclusive) at the time of onset and between 3 and 17 years of age (inclusive) at the time of consent.
3. Body weight ≥ 10 kg.
4. Diagnosed with childhood absence epilepsy (CAE), confirmed by electroencephalogram (EEG), with ≥ 5 absence seizures during the 4-hour EEG with treatment-resistant absence seizures, and has had an adequate trial of at least 2 anti-epileptic drugs (AED)s and are treatment-resistant to at least one AED.
5. Willingness to not start a ketogenic diet during the Baseline or Treatment Period.
6. Have on average ≥ 5 absence seizures per day.
7. A female patient is eligible to participate in the study if she is premenarchal, or of childbearing potential with a negative urine pregnancy test at the Screening Visit. If sexually active, she must agree to either complete abstinence from intercourse or use acceptable methods of contraception throughout the study and for 4 weeks after completion of study participation or discontinuation from investigational product.
8. A sexually active male patient must be willing to use acceptable methods of contraception throughout the study and for 4 weeks after completion of study participation or discontinuation from investigational product.
9. In the opinion of the investigator, the parent(s)/caregiver(s) is willing and able to comply with the study procedures and visit schedules and the Follow-up Visits.
10. General good health based on physical and neurological examinations, medical history, and clinical laboratory values completed during the Screening Visit that would prohibit the patient from safely participating in the trial as judged by the investigator.

Exclusion Criteria:

1. Patient or parent(s)/caregiver(s) have daily commitments during the study duration that would interfere with attending all study visits.
2. Has a history of nonfebrile seizures other than absence seizures.
3. Has a history of febrile seizures after 3 years of age.
4. Has a history consistent with juvenile absence epilepsy or juvenile myoclonic epilepsy.
5. Currently taking felbamate.
6. Currently taking phenytoin, fluvoxamine, carbamazepine, or St. John's Wort.
7. Currently taking concomitant medications that are strong inhibitors/inducers/sensitive substrates with a narrow therapeutic index for cytochrome P450 3A4 (CYP3A4), CYP2C9, or CYP2C19. (Stable doses of Valproic Acid during the screening, titration, treatment, and follow-up periods are permitted).
8. Currently on a ketogenic diet.
9. In the opinion of the investigator, any clinically significant, unstable medical abnormality, chronic disease, or a history of a clinically significant abnormality of the cardiovascular, gastrointestinal, respiratory, hepatic, or renal systems.
10. Clinically significant abnormal liver function test (LFT) values, including albumin, direct bilirubin, total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≥3 times the upper limit of normal (ULN).
11. History or presence of abnormal electrocardiograms (ECGs) that are clinically significant in the opinion of the investigator.
12. Has a current or history of clinically significant intellectual disability or major psychiatric disease, including autism spectrum disorder, which would interfere with compliance.
13. For patients aged 7 to 17 years of age and for whom the Columbia Suicide Severity Rating Scale (C-SSRS) is developmentally appropriate, an affirmative answer to queries regarding active suicidal ideation with some intent to act but without a specific plan or active suicidal ideation with a specific plan and intent on the C-SSRS assessment at the Screening Visit.
14. Any history of attempted suicide.
15. Previously received any investigational drug or device or investigational therapy within 30 days before Screening.
16. Taken any cannabinoids in the 30 days prior to the Screening Visit.
17. History of an allergic reaction or a known or suspected sensitivity to any substance that is contained in the investigational product formulation.
18. Known infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
19. In the opinion of the investigator, the patient is unsuitable in any other way to participate in this study.
20. Body weight < 10 kg or > 80 kg.
21. Patients who do not have at least 5 absence seizures on 4-hour video-EEG will be considered screen failures.

Contacts and Locations

Locations

United States, Florida

Nicklaus Children's Hospital

Miami, Florida, United States, 33155

Pediatric Epilepsy and Neurology Specialists

Tampa, Florida, United States, 33609

United States, Georgia

Clinical Integrative Research Center of Atlanta

Atlanta, Georgia, United States, 30328

United States, Nevada

Clinical Research Center of Nevada

Henderson, Nevada, United States, 89052

United States, New Jersey

Northeast Regional Epilepsy Group

Hackensack, New Jersey, United States, 07601

United States, Ohio

Akron Children's Hospital

Akron, Ohio, United States, 44308

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, Utah

Primary Children's Hospital

Salt Lake City, Utah, United States, 84113

United States, Virginia

Children's Specialty Group, Division of Child & Adolescent Neurology

Norfolk, Virginia, United States, 23510

United States, Washington

Research and Innovation/MultiCare Health System

Tacoma, Washington, United States, 98405

Sponsors and Collaborators

Benuvia Therapeutics Inc.

Investigators

• Study Director: Ahmed Elkashef, MD; INSYS Therapeutics Inc

More Information

• Responsible Party: Benuvia Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT03336242
• Other Study ID Numbers: INS011-17-103
• First Posted: November 8, 2017
• Last Update Posted: November 13, 2020
• Last Verified: November 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Seizures; Epilepsy, Absence; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Epilepsy, Generalized; Epileptic Syndromes; Cannabidiol; Anticonvulsants