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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Childhood Absence Epilepsy

Intervention / Treatment
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* Drug: Cannabidiol Oral Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient and/or parent(s)/caregiver(s) fully comprehend the informed consent form 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. 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. Body weight ≥ 10 kg. Diagnosed with childhood absence epilepsy, confirmed by electroencephalogram (EEG) with at least 3 bursts of general spike wave of 2.7 to 5 hertz lasting ≥3 seconds during the 4-hour EEG, and has had an adequate trial of at least 2 antiepileptic drugs (AEDs) and are treatment-resistant to at least one AED. Willingness to not start a ketogenic diet during the Baseline or Treatment Period. 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. 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. 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. 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: Patient or parent(s)/caregiver(s) have daily commitments during the study duration that would interfere with attending all study visits. Has a history of nonfebrile seizures other than absence seizures. Has a history of febrile seizures after 3 years of age. Has a history consistent with juvenile absence epilepsy or juvenile myoclonic epilepsy. Currently taking felbamate. Currently taking phenytoin, fluvoxamine, carbamazepine, or St. John's Wort. 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). Currently on a ketogenic diet. 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. 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). History or presence of abnormal electrocardiograms (ECGs) that are clinically significant in the opinion of the investigator. Has a current or history of clinically significant intellectual disability or major psychiatric disease, including autism spectrum disorder, which would interfere with compliance. 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. Any history of attempted suicide. Previously received any investigational drug or device or investigational therapy within 30 days before Screening. Taken any cannabinoids in the 30 days prior to the Screening Visit. History of an allergic reaction or a known or suspected sensitivity to any substance that is contained in the investigational product formulation. Known infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). In the opinion of the investigator, the patient is unsuitable in any other way to participate in this study. Body weight <10 kg or >90 kg.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Cannabidiol Oral Solution 20 mg/kg/day<br>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<br>* An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).<br>|
| Experimental: Cohort 2: Cannabidiol Oral Solution 30 mg/kg/day<br>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<br>* An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).<br>|
| Experimental: Cohort 3: Cannabidiol Oral Solution 10 mg/kg/day<br>Treatment Period: Cannabidiol Oral Solution 10 mg/kg/day divided BID for 4 weeks. | Drug: Cannabidiol Oral Solution<br>* An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Absence Seizure Counts Assessed by Video-electroencephalogram (EEG) at Visit 5 | A 4-hour video-EEG was performed for all participants at Baseline, during the Treatment Period, and at the End of the Study/Early Withdrawal Visit. Hyperventilation was conducted during the video-EEG to count the number of absence seizures. A negative change value indicates an improvement in seizure activity. A positive change value indicates a worsening in seizure activity. Percent change from baseline was calculated as (100*(week 4-baseline)/baseline). | Baseline (Visit 2, Day 1 of Titration Period) and Visit 5 (Week 4, Day 6 of Treatment Period) | 
| Percent Change From Baseline in Time to Absence Seizure During Hyperventilation Testing on Video-EEG at Visit 5 | A 4-hour video-EEG was performed for all participants at Baseline, during the Treatment Period, and at the End of the Study/Early Withdrawal Visit. Hyperventilation was conducted during the video-EEG to count the number of absence seizures. Percent change from baseline calculated as (100*(week 4-baseline)/baseline). | Baseline (Visit 2, Day 1 of Titration Period) and Visit 5 (Week 4, Day 6 of Treatment Period) | 
| Number of Participants Seizure-Free at Visit 5 | Daily seizure activity was recorded in a diary. Each day, the participant or parent/caregiver responded to the question: How many absence seizures did the patient have today?. | Visit 5 (Week 4, Day 6 of Treatment Period) | 
| Clinical Global Impression of Improvement (CGI-I) Score at Visit 5 | The CGI-I questionnaire was completed by the parents/caregivers and the investigator and was 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. | Visit 5 (Week 4, Day 6 of Treatment Period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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 treatment-emergent AE 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. A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported AEs module. | Day 1 (after dosing) up to Visit 7 (Week 4 of the Follow-Up Period) | 
| Maximum Plasma Concentration (Cmax) and Dose-normalized Cmax (Cmax/D) for Cannabidiol Under Fed and Fasted Conditions | The Cmax and Cmax/D for cannabidiol were evaluated under fed and fasted conditions. Fed: Participant arrived at the site on Day 1 of Week 4 of the Treatment Period without food and the morning dose. The site provided a high fat/high-calorie food and then dosed the participant. Blood samples were collected pre-dose (before meal/morning dose) and 2, 4, and 6 hours after the morning dose (but before the next dose). Fasted (2 hours before dose until 2 hours after dose): Participants arrived at the site on Day 2 of Week 4 of the Treatment Period without food and the morning dose. The site provided a standard meal 2 hours after the dose. Blood samples were collected pre-dose and 2 (before meal), 4, 6 hours after the morning dose (but before the next dose). | 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) | 
| 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 | The AUC(0-t) and AUC(0-t)/dose for cannabidiol were evaluated under fed and fasted conditions. Fed: Participant arrived at the site on Day 1 of Week 4 of the Treatment Period without food and the morning dose. The site provided a high fat/high-calorie food and then dosed the participant. Blood samples were collected pre-dose (before meal/morning dose) and 2, 4, and 6 hours after the morning dose (but before the next dose). Fasted (2 hours before dose until 2 hours after dose): Participants arrived at the site on Day 2 of Week 4 of the Treatment Period without food and the morning dose. The site provided a standard meal 2 hours after the dose. Blood samples were collected pre-dose and 2 (before meal), 4, 6 hours after the morning dose (but before the next dose). | 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) | 
| Trough Plasma Concentration (Ctrough) and Dose Normalized Ctrough (Ctrough/Dose) for Cannabidiol Under Fed, Fasted, and Normal Conditions | The Ctrough and Ctrough/dose for cannabidiol were evaluated under fed, fasted, and normal conditions. Fed: Participant arrived at the site on Day 1 of Week 4 of the Treatment Period without food and the morning dose. The site provided a high fat/high-calorie food and then dosed the participant. Blood samples were collected pre-dose (before meal/morning dose) and 2, 4, and 6 hours after the morning dose (but before the next dose). Fasted (2 hours before dose until 2 hours after dose): Participants arrived at the site on Day 2 of Week 4 of the Treatment Period without food and the morning dose. The site provided a standard meal 2 hours after the dose. Blood samples were collected pre-dose and 2 (before meal), 4, 6 hours after the morning dose (but before the next dose). | 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) |