treatment modalities may already have been or are simultaneously being used.
Epilepsy affects a diverse set of individuals of varying age, ethnicity and comor-
bidity. Thus, it was important for clinical trials to more thoroughly assess whether
addition of CBD to existing antiepileptic regimens could be done in a safe, tolerated
and effective manner in children and adults with treatment-resistant epilepsy.
Between January 15, 2014 and January 15, 2015, one clinical trial of CBD
enrolled 214 patients (aged 1–30 years) with severe, intractable, childhood-onset,
treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs
before study entry. Oral CBD doses (open label study) of 2–5 mg/kg/day
(Epidiolex®, GW Pharma) were up-titrated until intolerance or to a maximum
dose of 25 mg/kg or 50 mg/kg/day (dependent on study location and protocol). The
adverse events experienced in greater than 10% of the 162 patients in the safety and
tolerability analysis were (in order of decreasing frequency) somnolence, decreased
appetite, diarrhea, fatigue and convulsion. Serious adverse events occurred in 48
patients (30%), including one sudden unexpected death in epilepsy regarded as
unrelated to study drug, and 20 (12%) patients had severe adverse events pos-
sibly related to CBD use, the most common of which was status epilepticus. In the
137 patients included in the efficacy assessment, the median monthly frequency of
motor seizures was 30.0 (interquartile range, or IQR, 11.0–96.0) at baseline and
15.8 (IQR 5.6–57.6) over the 12-week treatment period. The median reduction in
monthly motor seizures was 36.5% (IQR 0-64.7) (Devinsky et al. 2016 ).
Epidiolex® was also tested in a clinical study of 7 children with febrile
infection-related epilepsy syndrome who had not responded to antiepileptic drugs
or other therapies. While this was also an unblinded (open label) study, with
subjects in either the acute or chronic phase of illness, 6 of 7 patients’seizures were
reduced in frequency and duration, and an average of 4 antiepileptic drugs were
weaned. Five of the 7 subjects were titrated to 25 mg/kg/day, the maximum allowed
under the protocol. One subject stopped the dose escalation at 15 mg/kg/day due to
significant reduction in seizures to less than 1 per week, and the other was titrated
to 20 mg/kg/day and kept there due to the therapeutic response (Gofshteyn et al.
2016 ). The results of these unblinded studies provide further support for random-
ized controlled trials to characterize the safety profile and true efficacy of this
compound and suggest that CBD might be safe and reduce seizure in children and
young adults with highly treatment-resistant epilepsy.
Epidiolex®has now demonstrated further therapeutic efficacy in a randomized,
double-blind, placebo-controlled Phase 3 clinical trial for the treatment of
Lennox-Gastaut syndrome, a rare and severe form of childhood-onset epilepsy.
When added as an adjunct to the patient’s current treatment, it achieved the primary
endpoint of a significant reduction in the monthly frequency of drop seizures
assessed over the entire 14-week treatment period compared with placebo
(p = 0.0135) (GW Pharmaceuticals Press Release2016b). In a second randomized,
double-blind, placebo-controlled Phase 3 trial, patients taking Epidiolex®
20 mg/kg/day achieved a median reduction in monthly drop seizures of 42%
compared to a 17% reduction in patients taking placebo (p = 0.0047), while
patients taking 10 mg/kg/day achieved a median reduction of 37% (p = 0.0016)
256 B.F. Thomas