Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial

Abstract

Objective: Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.

Methods: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d.

Results: By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale.

Significance: This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Keywords: cannabinoid; epileptic encephalopathy; seizures; treatment-resistant epilepsy.

Figure 1

Patient disposition. ^aOngoing trial, number of patients completed as of data cutoff of November 3, 2016. ^bPatients originally enrolled in GWPCARE1 Part A (different enrollment criteria) and GWPCARE2 (ongoing and blinded) were excluded from efficacy analyses. Of the 105 patients from GWPCARE1 Part B, one patient discontinued GWPCARE5 prior to reporting seizure frequency data. ^cWithdrawals are shown by the primary reason reported for each patient and encompass full follow‐up period. ^dBased on additional free‐text information entered by the investigator, most were judged to be efficacy‐related. DS, Dravet syndrome

Figure 2

Reduction in (A) convulsive seizure frequency and (B) total seizure frequency (efficacy population). ^aData previously published25 is provided here for context. CBD, cannabidiol; IQR, interquartile range; n, number of patients with available data during visit window; WD, number of withdrawals during visit window

Figure 3

Responder rates for (A) convulsive and (B) total seizures (efficacy population)

Figure 4

Patient/caregiver ratings of change in overall condition on the S/CGIC scale. S/CGIC, Subject/Caregiver Global Impression of Change