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. 2018 Oct;8(5):412-420.
doi: 10.1212/CPJ.0000000000000514.

Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial

David N Franz  1 , John A Lawson  1 , Zuhal Yapici  1 , Hiroko Ikeda  1 , Tilman Polster  1 , Rima Nabbout  1 , Paolo Curatolo  1 , Petrus J de Vries  1 , Dennis J Dlugos  1 , Maurizio Voi  1 , Jenna Fan  1 , Alexandra Vaury  1 , Diana Pelov  1 , Jacqueline A French  1
Affiliations

Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial

David N Franz et al. Neurol Clin Pract. 2018 Oct.

Abstract

Background: EXamining everolimus In a Study of Tuberous sclerosis 3 (EXIST-3) demonstrated significantly reduced seizure frequency (SF) with everolimus vs placebo. In this study, we evaluate the long-term efficacy and safety of everolimus for tuberous sclerosis complex (TSC)-associated treatment-refractory seizures.

Methods: After completion of the core phase, patients could enter an open-label extension phase and receive everolimus (target exposure, 3-15 ng/mL) for ≥48 weeks. Efficacy end points included change from baseline in average weekly SF expressed as response rate (RR, ≥50% reduction) and median percentage reduction (PR).

Results: Of 366 patients, 361 received everolimus in core/extension phases. The RR was 31% (95% CI, 26.2-36.1; N = 352) at week 18, 46.6% (95% CI, 40.9-52.5; N = 298) at 1 year, and 57.7% (95% CI, 49.7-65.4; N = 163) at 2 years. Median PR in SF was 31.7% (95% CI, 28.5-36.1) at week 18, 46.7% (95% CI, 40.2-54) at 1 year, and 56.9% (95% CI, 50-68.4) at 2 years. Ninety-five patients (26.3%) discontinued everolimus before 2 years; 103 (28.5%) had <2 years of follow-up at study cutoff, and 40% were exposed to everolimus for ≥2 years. An analysis classifying discontinued patients as nonresponders showed an RR of 30.2% (95% CI, 25.5-35.2; N = 361) at week 18, 38.8% (95% CI, 33.7-44.1; N = 358) at 1 year, and 41% (95% CI, 34.6-47.7; N = 229) at 2 years, suggesting sustained benefit over time. The incidence of grade 3/4 adverse events (AEs) (any cause) was 40.2%, and 13% discontinued because of AEs (pneumonia [1.7%] and stomatitis [1.4%]). Two deaths were suspected to be treatment-related (pneumonia and septic shock).

Conclusions: Sustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile was consistent with the core phase with no new safety concerns.

Classification of evidence: This study provides Class IV evidence that long-term everolimus therapy reduces SF in patients with TSC-associated treatment-refractory seizures.

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Figures

Figure 1
Figure 1. Trial profile
AED = antiepileptic drug; IRT = investigator/research team.
Figure 2
Figure 2. Seizure outcomes
(A) Response rate over time from the start of everolimus. Bars represent 95% confidence intervals obtained using Clopper-Pearson method. (B) Median percentage reduction in seizure frequency over time from the start of everolimus. Bars represent 95% confidence intervals based on bootstrap percentiles.
See this image and copyright information in PMC

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