A Double-Blind Trial to Evaluate Efficacy and Safety of Cannabidiol as an add-on Therapy for Treatment in Refractory Epilepsy

A Double-blind, Randomized Placebo-controlled Trial to Evaluate Efficacy and Safety of Cannabidiol as an add-on Therapy for Treatment in Refractory Epileptic Crisis in Children and Adolescents

The purpose of this study is to assess the efficacy of the adjuvant use of cannabidiol administered twice daily in doses of 5-25 mg/kg/day through the proportion of responsive patients; that is, participants with at least 50% decrease in the frequency of epileptic seizures in the last month of the trial relative to baseline (pretreatment with AEDs only).

Primary end point(s): Rate of responsive patients; that is, participants with at least 50% decrease in the frequency of epileptic seizures in the last month of the trial relative to baseline (pretreatment with AEDs only).

Inclusion Criteria:

• Men and women aged 2 years to 18 years.
• Diagnosis of treatment-resistant epilepsy according to the criteria of the International League Against Epilepsy (ILAE) (Kwan et al., 2010).
• Participants with at least 4 epileptic seizures with intervals no longer than 21 days.
• In treatment with up to 3 AEDs concomitantly and at stable doses for at least 1 month before the baseline assessment and expected to remain stable during the period of the trial. Vagus nerve stimulation (VNS) will be considered as an AED.
• Availability of a legal guardian able to follow the protocol (e.g., understand and fill up diaries) and visitation and medication schemes, according to the decision of the investigator.
• Availability of brain neuroimaging exams (magnetic resonance or computed tomography) collected within the last 5 years.
• No significant comorbid conditions, according to medical decision, to other criteria in this Protocol, and to additional assessments: medical records, blood pressure, heart rate, and temperature measures, physical exam, ECG, EEG, and laboratory tests.
• Women in reproductive age may be included as long as they are sexually abstinent or using effective contraceptive methods.
• Participants and their legal guardians, when applicable, must sign an informed consent form approved by the local ethics committee.

Exclusion Criteria:

• Occurrence of simple partial seizures (preserved consciousness) only, with no motor symptomatology.
• History or presence of pseudoseizures.
• History of suicide attempt.
• History of major depression.
• Pregnancy.
• Drug use.
• Hypertension.
• Participants with severe dysphagia and no gastric or nasogastric tubes.
• Current treatment with drugs that may significantly affect the metabolism of CBD, except AEDs if stable for at least 1 month before the screening interview.
• Presence of any clinical or neuroimaging finding suggestive of brain disorders, brain tumors, or metabolic or neurodegenerative diseases of rapid progression.
• Presence of acute and clinically significant diseases as assessed by a medical investigator, such as kidney, liver, urinary, bowel, or respiratory infections.
• Presence of known chronic and clinically significant diseases as assessed by a medical investigator and which may interfere with participation in the trial or pose safety risks for the participant.
• History of liver, kidney, lung, hematological, heart, or psychiatric diseases that may affect the volunteers' health or participation in the trial.
• Hypotension or hypertension with any etiology and requiring pharmacological management.
• History of surgeries that may affect the volunteers' health and/or participation in the trial.
• Regular or intermittent use of marijuana over the 60 days preceding the baseline assessment.
• Regular or intermittent treatment with CBD over the 60 days preceding the baseline assessment.
• History of allergies or idiosyncratic reactions to Cannabis sativa derivatives or components of the pharmaceutical formulation.
• Clinically significant ECG alterations as judged by a medical investigator.
• Participation in other clinical trials within less than 3 months before the baseline assessment.
• Donation or loss of 450 mL or more of blood within 90 days before the baseline assessment.
• Impaired liver function: AST, ALP, alkaline phosphatase and γGT values more than 3 times above the upper limit of the reference value. Results of γGT values 3 times above the upper limit will only be accepted if attributable to liver enzymatic induction caused by concomitant treatment with AEDs and with levels of other liver enzymes lower than 3 times the upper limit of the reference range.
• Participants with clinically significant discrepancies from the reference ranges of the following laboratory tests: creatinine clearance < 50 ml/min, platelets < 100.000/μL, and neutrophils < 1.800/μL.