Clinically Meaningful Reduction in Seizure Frequency in Patients with Tuberous Sclerosis Complex Treated with Cannabidiol

In antiseizure medication clinical trials, a ≥ 50% reduction in seizure frequency is a relatively standard primary efficacy endpoint, but the real-world threshold for response perceived as clinically impactful for patients with tuberous sclerosis complex (TSC) is largely unassessed. We investigated this threshold in patients with TSC from the randomized controlled trial evaluating cannabidiol (CBD; Epidyolex® [EU]/Epidiolex® [USA]; ClinicalTrials.gov ID: NCT02544763). This post hoc analysis used receiver operating characteristics (ROC) to quantify thresholds at which monthly seizure frequency reduction could be deemed clinically important in pooled data from patients receiving 25 or 50 mg/kg/day CBD (n = 132) for 16 weeks. Reductions in seizure frequency were anchored to Caregiver Global Impression of Change (CGIC; caregiver-reported assessment tool) ratings of ‘slightly improved’ or better, or ‘much improved’ or better. Anchor-based methods and distribution-based methods were applied to determine the thresholds for a clinically important response and minimal clinically important difference, respectively. The best-fit ROC-derived threshold for a clinically important response associated with a CGIC of ‘slightly improved’ or better was a 33% reduction in seizure frequency; for ‘much improved’ or better, the threshold was a 52% reduction. Thresholds for the minimal clinically important difference, based on half standard deviation (standard error of the mean), were – 17.8% (– 19.5%) for a CGIC rating of ‘slightly improved’ or better, and – 17.2% (– 18.9%) for CGIC rating of ‘much improved’ or better. Spearman’s correlation was 0.54 (P < 0.001). When anchored to a CGIC rating of ‘slightly improved’ or better, the threshold for a clinically important response in seizure reduction was 33%, suggesting that a cut-off of 50% may overlook patients who are achieving meaningful improvements in their overall condition, as perceived by their caregivers. This exploratory analysis may help physicians to ascertain the level of improvement that patients and caregivers perceive as beneficial in TSC, particularly when seizure reductions are < 50%. ClinicalTrials.gov ID: NCT02544763. Tuberous sclerosis complex (TSC) is a rare genetic disorder that often causes treatment-resistant seizures and other health problems. Highly-purified cannabidiol (Epidyolex® in Europe; Epidiolex® in the USA) is a plant-based medicine approved for patients with TSC whose seizures do not respond well to other treatments. Clinical trials usually define treatment success as a 50% or greater reduction in seizures, but it is unclear whether smaller reductions can still make a meaningful difference to patients and their caregivers. This analysis used data from a phase 3 clinical trial of cannabidiol in patients with TSC to understand how much seizure reduction is needed for caregivers to notice an improvement in the patient’s overall condition. Caregivers reported that the patient’s condition was ‘slightly improved’ or better when seizures were reduced by about one-third (33%) and ‘much improved’ or better when seizures were reduced by about half (52%). These results suggest that reductions in seizure frequency that are less than 50% can still positively impact a patient’s overall condition. These data may help physicians to understand the level of seizure reduction and improvement that is meaningful to patients and caregivers, allowing for better assessment of the treatment benefits that patients are experiencing.