(124) Long-term Safety and Efficacy of Add-on Cannabidiol (CBD) for Treatment of Seizures Associated with Tuberous Sclerosis Complex (TSC) in an Open-Label Extension (OLE) Trial (GWPCARE6)

Rationale: Add-on CBD reduced TSC-associated seizures with an acceptable safety profile in a randomized, placebo-controlled Phase 3 trial (GWPCARE6; NCT02544763). To evaluate long-term safety and efficacy of CBD, patients were enrolled in an OLE. In this 2nd interim analysis, we report safety for the full follow-up and efficacy through 72 wks of treatment in the OLE.

Methods: Patients who completed the randomized controlled trial (RCT) could enroll to receive plant-derived highly purified CBD (Epidiolex^®; 100 mg/mL oral solution). Initially, dose was titrated up to 25 mg/kg/d, which could be decreased or increased up to 50 mg/kg/d based on response and tolerability. The primary endpoint was safety. Secondary endpoints included percentage change from RCT baseline in TSC-associated (countable focal and generalized) seizure frequency per 28 days and responder rates (≥50%, ≥75%, and 100% reduction) evaluated at 12-wk windows throughout treatment. Changes in patients’ overall condition on Subject/Caregiver Global Impression of Change (S/CGIC) scale from baseline to 26 and 52 wks were assessed.

Results: Of 201 patients who completed the RCT, 199 (99%) entered the OLE. Median (range) age at RCT baseline: 10.7 yrs (1.1–56.8). Median (range) number of AEDs at baseline: 3 (0–5). Most common concomitant AEDs during OLE: valproate (42%), vigabatrin (37%), and clobazam (34%). Median (Q1, Q3) monthly TSC-associated seizure frequency at baseline: 57 (28, 109). At the time of this analysis, 12% of patients had completed treatment, 31% had withdrawn, and 57% were ongoing. Median treatment time (range) during OLE: 372 d (18–1127). The mean (SD) of patients’ modal CBD dose was 28 mg/kg/d (9); 145 (73%) were treated with modal dose ≤25 mg/kg/d and 54 (27%) with >25 mg/kg/d. AEs were reported by 94% of patients, serious AEs by 26%, and 8% discontinued treatment due to an AE. Most frequently reported AEs: diarrhea and seizures (Table 1). Seventeen (9%) patients had elevated ALT/AST >3×ULN; 12 of these (71%) were on concomitant valproate. No patient met Hy’s law criteria for severe liver injury. There was one death due to cardiopulmonary failure, deemed not treatment related by the investigator. Median percentage reduction from baseline in TSC-associated seizures ranged from 53%–75% across 12-wk windows through 72 wks. Last observation carried forward analysis showed similar results and ranged from 52%–63%. Seizure reductions ranged from 54%–80% for patients (n=145) with a modal dose ≤25 mg/kg/d. ≥50%, ≥75%, and 100% reductions in TSC-associated seizures were maintained up to 72 wks, ranging from 52%–63%, 29%–51%, and 6%–19%, respectively across 12-wk windows. Improvement on S/CGIC was reported by 141/165 patients/caregivers (85%) at 26 wks and 83/93 (89%) at 52 wks.

Conclusions: Add-on CBD treatment was well tolerated and produced sustained reductions in TSC-associated seizures for up to 72 wks, supporting long-term use of CBD for treatment of seizures associated with TSC.

Funding: Please list any funding that was received in support of this abstract.: GW Research Ltd