Long-term Safety and Efficacy of Add-on Cannabidiol (CBD) for Seizures Associated with Tuberous Sclerosis Complex (TSC): 3-year Results from GWPCARE6 Open-label Extension (OLE)
Abstract number :
2.237
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2022
Submission ID :
2204724
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:26 AM
Authors :
Elizabeth Thiele, MD, PhD – Massachusetts General Hospital; E. Martina Bebin, MD – University of Alabama School of Medicine; Francis Filloux, MD – University of Utah School of Medicine; Floor Jansen, MD, PhD – Brain Center University Medical Center; Patrick Kwan, PhD – Monash University and the University of Melbourne; John Lawson, PhD – Sydney Children’s Hospital; Rachael Loftus, MSc – Jazz Pharmaceuticals, Inc.; Farhad Sahebkar, MD – Jazz Pharmaceuticals, Inc.; Steven Sparagana, MD – Scottish Rite for Children and the University of Texas Southwestern Medical Center; James Wheless, MD – Le Bonheur Children’s Hospital and the University of Tennessee Health Science Center
Rationale: Add-on CBD demonstrated efficacy with an acceptable safety profile in patients with TSC in the phase 3 randomized controlled trial (RCT) GWPCARE6 (NCT02544763). To evaluate long-term safety and efficacy of CBD, patients who completed the RCT were enrolled in an OLE, for which we report safety for the full follow-up and efficacy through 156 wks of treatment.
Methods: Patients in OLE received 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 across 12-wk treatment windows. Changes in patients’ overall condition on Subject/Caregiver Global Impression of Change (S/CGIC) scale from baseline to 52 and 104 wks were assessed.
Results: Of 201 patients who completed the RCT, 199 (99%) entered OLE. Median (range) age at RCT baseline was 10.7 yrs (1.1–56.8). Median (range) number of antiseizure medications (ASMs) at baseline was 3 (0–5). Most common concomitant ASMs during OLE were valproate (43%), vigabatrin (37%), and clobazam (35%). Median (Q1, Q3) monthly TSC-associated seizure frequency at baseline was 57 (28, 109). Thirty-four patients (17%) completed treatment in OLE and 165 (83%) withdrew. The most common reason for withdrawal was patients (93 [56%]) transitioning to commercial product. Median (range) treatment time during OLE was 631 d (18–1462). The mean (SD) of patients’ modal CBD dose was 28 mg/kg/d (9); 140 (70%) were treated with modal dose ≤25 mg/kg/d. Adverse events (AEs) were reported in 96% of patients, serious AEs in 28%, and 9% discontinued treatment due to an AE. Most frequently reported AEs (>20% of all patients) were diarrhea, seizures, pyrexia, and decreased appetite (Table). Overall, 7% of patients had elevation in ALT levels and 5% in AST levels. There was 1 death due to cardiopulmonary failure, deemed not treatment related by the investigator. Median reduction from baseline in TSC-associated seizures ranged from 53%-90% across 12-wk windows through 156 wks (Figure). Results for last observation carried forward analysis ranged from 52%-62%. Seizure reductions ranged from 53%-93% for patients with a modal dose ≤25 mg/kg/d. Reductions in TSC-associated seizures ≥50%, ≥75%, and 100% were maintained up to 156 wks, ranging from 52%-78%, 29%-69%, and 6%-31%, respectively. Improvement on S/CGIC was reported by 105/118 patients/caregivers (89%) at 52 wks and 68/73 (93%) at 104 wks.
Conclusions: Add-on CBD treatment was well tolerated and produced sustained reductions in TSC-associated seizures for up to 156 wks in patients treated in OLE, supporting long-term use of CBD for treatment of seizures associated with TSC.
Funding: Jazz Pharmaceuticals, Inc.
Anti-seizure Medications