Research on Cognitive Effect of Cannabidiol on Dravet Syndrome and Lennox-Gastaut SyndromeGastaut Syndrome

A Prospective Multi-Center Single-Arm Clinical Trial on Cognitive Effect of Cannabidiol (CBD-OS®) on Dravet Syndrome and Lennox-Gastaut Syndrome

The clinical trial "A Prospective Single-Center Single-Arm Clinical Trial on Cognitive Effect of Cannabidiol (CBD-OS®) on Dravet syndrome and Lennox-Gastaut Syndrome" is a single-group phase III study done in single tertiary referral center in Seoul, Korea.

Chief investigator is Dr. Hoon-Chul Kang of Severance Hospital, Yonsei University College of Medicine. Associate investigators are Dr. Heung Dong Kim, Joon Soo Lee, Se Hee Kim, Han Som Choi, Ji Hoon Na, Dong Hwa Yang, and Hee Jung Kang, of Severance Hospital, Yonsei University College of Medicine.

The aim of the study is to evaluate the effect of cannabidiol (CBD-OS®) on cognitive functions in patients aged from 2 to 18 years old diagnosed with Dravet syndrome or Lennox-Gastaut syndrome. The duration of study is planned as one year, after patient recruitment of 6 months. The intervention period in each patient is 24 weeks, with 2 weeks of medication titration, stabilization period of 10 weeks, and maintenance period of 12 weeks. The recruitment goal of patient number is 104, considering the study power of 90 percent.

Primary outcomes are improvement of cognitive and development and improvement of seizure outcome. Secondary outcomes are improvement in behavior and quality of life.

Safety monitoring criteria are adverse event profiles and physician's and caregiver's global assessment.

Statistical analysis of outcomes is subject only to the patients who completed the 24-week medication and 2 times of tests before and after treatment of cannabidiol. Evaluation of seizure outcomes would include all patients who completed the 24-week medication and those who dropped out of the study, either by follow-up loss or discontinuation of medication due to incomplete seizure control or adverse effect of the medication.

To evaluate safety, the investigators would measure adverse events and dropout rates by percentage. The investigators would analyze overall evaluation of the caregivers and investigator. Serious adverse events would be noted after causality evaluation.

Selection criteria of the patients are as below:

1. Age: 2 years old to 18 years old
2. Investigation center: Severance hospital, Yonsei University College of Medicine, Seoul, Korea
3. A) Diagnosed as Dravet syndrome by clinical manifestations and/or genetic test B) Diagnosed as Lennox-Gastaut syndrome by clinical manifestations and electroencephalography
4. The diagnosed patients by criteria 3-(1) or 3-(2) with intractable seizures after using over two antiepileptic medications
5. Patients and caregivers who agreed to participation in this trial

Exclusion criteria of the patients are as below:

1. Patients with possibility of progressive central nervous system disease other systemic disease
2. The patients who started additional antiepileptic medication during the investigation period, with exception of short-term acute treatment of seizures (e.g. benzodiazepine for rescue therapy)
3. Patients with alanine and aspartate aminotransferase and/or total bilirubin levels over 2 times of the normal range, or blood urea nitrogen and creatinine ratio over 3 times of the normal range
4. Patient with hypersensitivity or allergic reactions to cannabidiol
5. patients who are incapable of executing cognitive tests, or cases whom the investigators consider inappropriate to be enrolled in the trial Overall trial schedule for each patient is as follows:

A) Baseline Phase (2 weeks)

• Baseline Phase starts from the screening visit, where the patient and caregiver write permission to the trial and goes through laboratory, electroencephalography, and neuropsychological tests.

B) Treatment Period : Titration(2 weeks) + stabilization period (10 weeks) + maintenance period (12 weeks)

• Titration: cannabidiol titration up to 10mg/kg/day with the caregiver monitoring the patient's tolerability
• Stabilization: caregiver monitoring the patient's tolerability, with no change in medication dosage
• Maintenance: no change in medication dosage
• Statistical analysis of outcomes would be done as follows:

T-test would be done to compare each test before and after cannabidiol treatment. For multiple results along the intervention time period, repeated data analyses would be done. Continuous variables would be evaluated by repeated measures analysis of variance or generalized estimating equations. Nominal variables would be evaluation by chi-squared test or trend test.

Evaluation of seizure outcomes would include all patients who completed the 24-week medication and those who dropped out of the study, either by follow-up loss or discontinuation of medication due to incomplete seizure control or adverse effect of the medication.

Inclusion Criteria:

1. Age: 2 years old to 18 years old
2. Investigation center: Severance hospital, Yonsei University College of Medicine, Seoul, Korea
3. (1) Diagnosed as Dravet syndrome by clinical manifestations and/or genetic test (2) Diagnosed as Lennox-Gastaut syndrome by clinical manifestations and electroencephalography
4. The diagnosed patients by criteria 3-(1) or 3-(2) with intractable seizures after using over two antiepileptic medications
5. Patients and caregivers who agreed to participation in this trial

Exclusion Criteria:

1. Patients with possibility of progressive central nervous system disease other systemic disease
2. The patients who started additional antiepileptic medication during the investigation period, with exception of short-term acute treatment of seizures (e.g. benzodiazepine for rescue therapy)
3. Patients with alanine and aspartate aminotransferase and/or total bilirubin levels over 2 times of the normal range, or blood urea nitrogen and creatinine ratio over 3 times of the normal range
4. Patient with hypersensitivity or allergic reactions to cannabidiol
5. patients who are incapable of executing cognitive tests, or cases whom the investigators consider inappropriate to be enrolled in the trial