Cannabidiol in Children and Young Adults With Rare Disease-associated Severe Epilepsy

Study Overview
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Brief Summary
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This is a pilot, open-label, phase II study. The main objective of the study is to demonstrate that Cannabidiol (CBD), used in addition to current anti-seizure medications (ASMs) reduces the number and/or severity of motor (generalized, focal, or both) seizures in children and young adults with rare disease-associated severe epilepsy. Secondary objectives include assessment of safety and tolerability, changes in behaviour, cognition and sleep, pharmacokinetic interaction with concurrent ASMs.

Official Title
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Open-label Pilot Study to Assess the Efficacy and Safety of Cannabidiol Oral Solution as an Adjunctive Treatment for Children and Young Adults With Rare Disease-associated Severe Epilepsy

Conditions
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Epilepsy, Rare Diseases

Intervention / Treatment
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* Drug: Cannabidiol oral solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female; Children (age 2-18 years) and young adults (18-25 years), as of the day of the Screening Visit; Subject with rare disease-associated severe epilepsy. Subject has been certified by the National Health System as affected by a rare disease listed in https://www.malattierare.gov.it Patient has severe epilepsy, with at least 4 motor (generalized, focal, or both) seizures per month during baseline period, despite 2 or more current or prior ASMs; Previous treatment with at least 2 ASMs; Currently taking at least 1 other ASMs or between one and four ASMs, with a stable antiseizure treatment for the previous 4 weeks (including ketogenic diet and vagal nerve stimulation); Subject's parent/caregiver has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian; Subject's parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability in the opinion of the investigator Exclusion Criteria: Age <2 years; Known hypersensitivity to CBD or any of the excipients in the study formulation; Progressive neurological disease; Clinically significant unstable medical conditions other than epilepsy that may place patient's safety at risk; Any other significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, may influence the result of the study, or affect the patient's ability to participate in the study; Impaired hepatic function at screening defined as any of the following: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of normal (ULN) and total bilirubin (TBL) greater than 2 times the ULN; Subject taking more than four concurrent ASMs; Subject has taken corticotropins in the six months prior to screening; Subjects taking felbamate, and they have been taking it for less than one year prior to screening; Inadequate supervision by parents and/or caregivers as judged by the investigator; Subject has been part of a clinical trial involving another investigational medicinal product in the previous six months; Current or past use of recreational or medicinal cannabis, or cannabinoid-based medications, within the three months prior to screening and is unwilling to abstain for the duration for the study; Female patients who are pregnant; Female patients of childbearing potential or male patient whose partner is of childbearing potential, unless willing to ensure that they or their partner use a highly effective method of birth control during the study and for three months thereafter.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 25 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabidiol treatment<br> | Drug: Cannabidiol oral solution<br>* Cannabidiol will be administered orally twice daily into equally divided doses. The starting dose is 2.5 mg/kg twice daily. The dose can be gradually increased to 5 mg/kg twice daily, which is the recommended maintenance dose, up to a maximum dose of 10 mg/kg twice daily, according to tolerability and clinical response. Following titration, subjects will continue treatment over a 20-week maintenance period. The total treatment duration from the beginning of the titration period till the end of the maintenance period will be 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in number of generalized and/or focal motor-onset seizure frequency | percentage change per 28 days from the 4-week baseline period in generalized and/or focal motor-onset seizure frequency during the 24-week treatment period | 24 weeks | 
| Change in severity of generalized and/or focal motor-onset seizure frequency | a score will be established for each patient, based on review and comparison of all baseline-EEG/7-weeks control-EEG and baseline-EEG/15-weeks control-EEG, with values ranging from 0 (= worsened EEG), to a maximum of 2 (= improved); 1 will be assigned if the EEG trace is unmodified | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Adverse events reporting according to Common Terminology Criteria for Adverse Events (CTCAE) from 1 (mild) to 5 (death) | 24 weeks | 
| Body weight | Measurement of body weight for tolerability monitoring | 24 weeks | 
| Maximum Plasma Concentraion [Cmax] of concurrent ASMs | blood levels of concurrent ASMs will be taken at baseline and every 4 weeks | 24 weeks | 
| Number of subjects considered treatment responders | Number of subjects with a ≥25%, ≥50% ≥75% reduction in motor (generalized, focal, or both) seizures from baseline | 24 weeks | 
| Number of subjects who are free of motor (generalized, focal, or both) seizures | Number of subjects who are free of motor (generalized, focal, or both) seizures | 24 weeks | 
| Longest period of seizure freedom | Longest period of seizure freedom | 24 weeks | 
| Number of patients experiencing a >25% worsening, -25 to +25% no change, 25-50% improvement, 50-75% improvement or >75% improvement in total seizures from baseline | Number of patients experiencing a >25% worsening, -25 to +25% no change, 25-50% improvement, 50-75% improvement or >75% improvement in total seizures from baseline | 24 weeks | 
| Changes from baseline in number of inpatient hospitalizations due to epilepsy | Changes from baseline in number of inpatient hospitalizations due to epilepsy | 24 weeks | 
| Change in severity of seizures will be assessed using a pediatric adaptation of the Chalfont Seizure Severity Scale | Change in severity of seizures will be assessed using a pediatric adaptation of the Chalfont Seizure Severity Scale (from 1 minimum severity to >100 max severity) | 24 weeks | 
| Change from baseline to 6-months after treatment initiation in number of seizure-free days | Change from baseline to 6-months after treatment initiation in number of seizure-free days | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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drug resistant epilepsy, rare epilepsy, cannabidiol