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

French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R, Curatolo P, de Vries PJ, Dlugos DJ, Berkowitz N, Voi M, …, Franz DN · 2016 · Lancet · Atlas ID FRE2016

What this study shows

EXIST-3 was a phase 3, double-blind trial in 366 patients aged 2 to 65 with tuberous sclerosis complex and focal seizures that had not responded to standard drugs. They were randomised 1:1:1 to placebo (n=119), everolimus dosed to a low blood trough of 3-7 ng/mL (n=117) or a high trough of 9-15 ng/mL (n=130), added to their existing antiepileptic drugs. For the primary endpoint, at least a 50% fall in seizure frequency during the 12-week maintenance period, the response rate was 15.1% with placebo, 28.2% with low exposure (p=0.0077) and 40.0% with high exposure (p<0.0001); median seizure reduction was 14.9%, 29.3% and 39.6%. Grade 3-4 adverse events occurred in 11%, 18% and 24%, and serious adverse events in 3%, 14% and 14% of patients, respectively. The result showed a dose-dependent effect of mTOR inhibition on seizures in TSC, beyond its known effect on TSC tumours. Boundary: patients with TSC and treatment-resistant focal-onset seizures already on 1-3 antiepileptic drugs; comparator was placebo add-on; 18-week core phase (6-week titration, 12-week maintenance), so long-term durability is not addressed here.

Abstract

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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.

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At a glance

Evidence type	H Human study Marked H because it is direct evidence from a human clinical trial or human cohort; the code names the kind of study, not its quality -- a small, well-run trial is still H.
Study type	2 - Human Clinical Trial
Model system	Humans: 366 patients aged 2-65 with TSC and treatment-resistant focal-onset seizures on 1-3 antiepileptic drugs; phase 3 RCT, placebo vs low-exposure (trough 3-7 ng/mL) vs high-exposure (9-15 ng/mL) everolimus; 99 centres, 25 countries
Journal	Lancet
Year	2016
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1016/s0140-6736(16)31419-2 · PMID 27613521

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Adjunctive everolimus at trough 3-7 or 9-15 ng/mL vs placebo
Target	mTORC1 (via FKBP12)
Model	Human
Effect	Seizure frequency reduced, dose-dependently (responder rate 15.1% placebo, 28.2% low, 40.0% high exposure)

In the Atlas

Cite this paper

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French, J. A., Lawson, J. A., Yapici, Z., Ikeda, H., Polster, T., Nabbout, R., Curatolo, P., de Vries, P. J., Dlugos, D. J., Berkowitz, N., Voi, M., Peyrard, S., Pelov, D., & Franz, D. N. (2016). 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. https://doi.org/10.1016/s0140-6736(16)31419-2

@article{FRE2016,
  author       = {French, J. A. and Lawson, J. A. and Yapici, Z. and Ikeda, H. and Polster, T. and Nabbout, R. and Curatolo, P. and de Vries, P. J. and Dlugos, D. J. and Berkowitz, N. and Voi, M. and Peyrard, S. and Pelov, D. and Franz, D. N.},
  title        = {{Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study}},
  journal      = {Lancet},
  year         = {2016},
  doi          = {10.1016/s0140-6736(16)31419-2},
  note         = {PMID: 27613521},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record FRE2016) [Data set]. https://mtor-atlas.org/study/FRE2016/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_FRE2016,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record FRE2016},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/FRE2016/},
  doi          = {10.5281/zenodo.22059963}
}

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