Everolimus for treatment-refractory seizures in TSC: Extension of a randomized controlled trial
Open accessAbstract
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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In contrast to most RCTs, the clinical response increased over time as measured in the open-label extension study of patients on everolimus for ≥48 weeks, postulated to be due to a disease-modifying effect.
“In contrast to most RCTs, the clinical response increased over time as measured in the open-label extension study of patients on everolimus for ≥48 weeks, postulated to be due to a disease-modifying effect 204 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [204]
The Results report that response rates increased from 31% at week 18 to 46.6% at one year and 57.7% at two years. The introduction says seizure improvement might increase over time because everolimus addresses the underlying pathophysiology of TSC, and states that all patients had completed at least 48 weeks of the extension phase. Our copy does not establish the comparison with most RCTs. (LLM, conf=0.85)
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References 16 · Cited by 108
- Authors
- Franz, D. N., Lawson, J. A., Yapici, Z., Ikeda, H., Polster, T., Nabbout, R., Curatolo, P., de Vries, P. J., Dlugos, D. J., Voi, M., Fan, J., Vaury, A., Pelov, D., French, J. A., Schteinschnaider, A., Sfaello, I., Lawson, J., Nagarajan, L., Harvey, S., Verhelst, H., De Waele, L., Van Bogaert, P., El Tahry, R., Jansen, A., Connolly, M., Major, P., Velez, A., Carreno, O., Gomez, J., Christensen, J., Vallee, L., The Tich, S. N., Milh, M., De Saint Martin, A., Berquin, P., Ville, D., Wiemer-Kruel, A., Hertzberg, C., Wiegand, G., Polster, T., Papavasiliou, A., Tzoufi, M., Fogarasi, A., Gyorsok, Z., Dioszeghy, P., Webb, D. W., Bartalini, G., Gobbi, G., Canevini, M. P., Veggiotti, P., Baglietto, M. G., Giallonardo, A. T., Laforgia, N., Falsaperla, R., Ikeda, H., Nabatame, S., Kawawaki, H., Yoshinaga, H., Kubota, M., Suzuki, Y., Moreno, H. C., Zonnenberg, B., de Wit, M. C. Y., Majoie, M., Bjoernvold, M., Jozwiak, S., Kim, K., Kim, H. D., Lee, M., Ko, T., Belousova, E., Ermolenko, N., Poverennova, I., Kuzenkova, L., Ruiz Falco Rojas, M. L., Lopez de Munain, A., Uranga, J. R., Villanueva, V., Fan, P.-C., Huang, C.-C., Chang, Y.-C., Nabangchang, C., Chomtho, K., Likasitwattanakul, S., Thampratankul, L., Yapici, Z., Serdaroglu, A., Ahlar, B., Aylett, S., Desurkar, A., Johnston, C., Koepp, M., Cock, H., Parker, A., McCorry, D., Appleton, R., Sparagana, S., Taub, K., Frost, M., Roberts, C., Sahin, M., Koh, S., Koenig, M., Bebin, M., Miles, D., Franz, D., Wheless, J., Wilfong, A., Gipson, T., Wu, J., Kuperman, R., Zupanc, M., Kohrman, M., DiMario, F., Wong, M., Trauner, D., Mahalingam, R., & Narayanan, V.
- Affiliations
- Department of Neurology (DNF), Cincinnati Children's Hospital Medical Center, OH; Tuberous Sclerosis Multidisciplinary Management Clinic (JAL), Sydney Children's Hospital, Randwick, New South Wales, Australia; Division of Child Neurology (ZY), Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Turkey; NHO Epilepsy Center (HI), Shizuoka Institute of Epilepsy and Neurological Disorders, Japan; Paediatric Epileptology (TP), Mara Hospital, Bethel Epilepsy Center, Germany;...
- Cincinnati Children's Hospital Medical Center (US)
- ORCID
- Nabbout, Rima
- Curatolo, Paolo
- Dlugos, Dennis J.
- French, Jacqueline A.
- Nagarajan, Lakshmi
- Verhelst, Hélène
- Jansen, Anna
- Connolly, Mary
- Major, Philippe
- Christensen, Jakob
- Milh, Mathieu
- Berquin, Patrick
- Ville, Dorothee
- Hertzberg, Christoph
- Wiegand, Gert
- Papavasiliou, Antigone
- Canevini, Maria Paola
- Veggiotti, Pierangelo
- Giallonardo, Anna Teresa
- Laforgia, Nicola
- Falsaperla, Raffaele
- Nabatame, Shin
- Yoshinaga, Harumi
- Kubota, Masaya
- Suzuki, Yasuhiro
- Zonnenberg, Bernard
- Majoie, M
- Kim, Heung Dong
- Villanueva, Vicente
- Fan, Pi-Chuan
- Huang, Chao-Ching
- Likasitwattanakul, Surachai
- Thampratankul, Lunliya
- Aylett, Sarah
- Desurkar, Archana
- Koepp, Matthias
- Cock, Hannah
- Parker, Alasdair
- Sparagana, Steven
- Frost, Michael
- Koenig, Mary
- Bebin, Martina
- Wheless, James
- Wilfong, Angus
- Gipson, Tanjala
- Wu, Joyce
- Wong, Michael
- Narayanan, Vinodh
- Venue
- Neurology Clinical Practice
- Published
- 2018-10
- Volume
- 8
- Issue
- 5
- Pages
- 412-420
- ISSN
- 2163-0402 (ISSN-L)
- 2163-0933
- PMC
- PMC6276348
- OpenAlex
- W2894432237
- Cited by
- 108
- References
- 16
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8 · 2023: 11 · 2022: 12 · 2021: 32 · 2020: 20 · 2019: 9
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Neurology Clinical Practice (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- everolimus, tuberous sclerosis complex, seizure frequency reduction, long-term efficacy, drug safety, mTOR inhibition, open-label extension
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