Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study

Lancet. 2016 Oct 29;388(10056):2153-2163. doi: 10.1016/S0140-6736(16)31419-2. Epub 2016 Sep 6.


Background: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used for various benign tumours associated with tuberous sclerosis complex. We assessed the efficacy and safety of two trough exposure concentrations of everolimus, 3-7 ng/mL (low exposure) and 9-15 ng/mL (high exposure), compared with placebo as adjunctive therapy for treatment-resistant focal-onset seizures in tuberous sclerosis complex.

Methods: In this phase 3, randomised, double-blind, placebo-controlled study, eligible patients aged 2-65 years with tuberous sclerosis complex and treatment-resistant seizures (≥16 in an 8-week baseline phase) receiving one to three concomitant antiepileptic drugs were recruited from 99 centres across 25 countries. Participants were randomly assigned (1:1:1), via permuted-block randomisation (block size of six) implemented by Interactive Response Technology software, to receive placebo, low-exposure everolimus, or high-exposure everolimus. Randomisation was stratified by age subgroup (<6 years, 6 to <12 years, 12 to <18 years, and ≥18 years). Patients, investigators, site personnel, and the sponsor's study team were masked to treatment allocation. The starting dose of everolimus depended on age, body-surface area, and concomitant use of cytochrome 3A4/P-glycoprotein inducers. Dose adjustments were done to attain target trough ranges during a 6-week titration period, and as needed during a 12-week maintenance period of core phase. Patients or their caregivers recorded events in a seizure diary throughout the study. The primary endpoint was change from baseline in the frequency of seizures during the maintenance period, defined as response rate (the proportion of patients achieving ≥50% reduction in seizure frequency) and median percentage reduction in seizure frequency, in all randomised patients. This study is registered with, number NCT01713946.

Findings: Between July 3, 2013, and May 29, 2015, 366 patients were enrolled and randomly assigned to placebo (n=119), low-exposure everolimus, (n=117), or high-exposure everolimus (n=130). The response rate was 15·1% with placebo (95% CI 9·2-22·8; 18 patients) compared with 28·2% for low-exposure everolimus (95% CI 20·3-37·3; 33 patients; p=0·0077) and 40·0% for high-exposure everolimus (95% CI 31·5-49·0; 52 patients; p<0·0001). The median percentage reduction in seizure frequency was 14·9% (95% CI 0·1-21·7) with placebo versus 29·3% with low-exposure everolimus (95% CI 18·8-41·9; p=0·0028) and 39·6% with high-exposure everolimus (95% CI 35·0-48·7; p<0·0001). Grade 3 or 4 adverse events occurred in 13 (11%) patients in the placebo group, 21 (18%) in the low-exposure group, and 31 (24%) in the high-exposure group. Serious adverse events were reported in three (3%) patients who received placebo, 16 (14%) who received low-exposure everolimus, and 18 (14%) who received high-exposure everolimus. Adverse events led to treatment discontinuation in two (2%) patients in the placebo group versus six (5%) in the low-exposure group and four (3%) in the high-exposure group.

Interpretation: Adjunctive everolimus treatment significantly reduced seizure frequency with a tolerable safety profile compared with placebo in patients with tuberous sclerosis complex and treatment-resistant seizures.

Funding: Novartis Pharmaceuticals Corporation.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anticonvulsants / therapeutic use*
  • Antineoplastic Agents / therapeutic use*
  • Child
  • Child, Preschool
  • Combined Modality Therapy
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Everolimus / adverse effects
  • Everolimus / therapeutic use*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Seizures / drug therapy*
  • Tuberous Sclerosis / complications*


  • Anticonvulsants
  • Antineoplastic Agents
  • Everolimus

Associated data