PMID- 27613521
OWN - NLM
STAT- MEDLINE
DCOM- 20170410
LR  - 20220408
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 388
IP  - 10056
DP  - 2016 Oct 29
TI  - Adjunctive everolimus therapy for treatment-resistant focal-onset seizures 
      associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, 
      double-blind, placebo-controlled study.
PG  - 2153-2163
LID - S0140-6736(16)31419-2 [pii]
LID - 10.1016/S0140-6736(16)31419-2 [doi]
AB  - 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 ClinicalTrials.gov, 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.
CI  - Copyright (c) 2016 Elsevier Ltd. All rights reserved.
FAU - French, Jacqueline A
AU  - French JA
AD  - NYU Comprehensive Epilepsy Center, New York, NY, USA. Electronic address: 
      jacqueline.french@nyumc.org.
FAU - Lawson, John A
AU  - Lawson JA
AD  - Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children's 
      Hospital, Randwick, NSW, Australia.
FAU - Yapici, Zuhal
AU  - Yapici Z
AD  - Division of Child Neurology, Department of Neurology, Istanbul Faculty of 
      Medicine, Istanbul University, Istanbul, Turkey.
FAU - Ikeda, Hiroko
AU  - Ikeda H
AD  - NHO Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 
      Shizuoka, Japan.
FAU - Polster, Tilman
AU  - Polster T
AD  - Paediatric Epileptology, Mara Hospital, Bethel Epilepsy Center, Germany.
FAU - Nabbout, Rima
AU  - Nabbout R
AD  - Hospital Necker-Enfants Malades, Paris Descartes University, Paris, France.
FAU - Curatolo, Paolo
AU  - Curatolo P
AD  - Tor Vergata University Hospital, Rome, Italy.
FAU - de Vries, Petrus J
AU  - de Vries PJ
AD  - Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, 
      South Africa.
FAU - Dlugos, Dennis J
AU  - Dlugos DJ
AD  - Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia, 
      Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 
      USA.
FAU - Berkowitz, Noah
AU  - Berkowitz N
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
FAU - Voi, Maurizio
AU  - Voi M
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
FAU - Peyrard, Severine
AU  - Peyrard S
AD  - Novartis Pharmaceuticals SAS, Rueil-Malmaison, France.
FAU - Pelov, Diana
AU  - Pelov D
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
FAU - Franz, David N
AU  - Franz DN
AD  - Departments of Pediatrics and Neurology, Cincinnati Children's Hospital Medical 
      Center, Cincinnati, OH, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01713946
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
DEP - 20160906
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Anticonvulsants)
RN  - 0 (Antineoplastic Agents)
RN  - 9HW64Q8G6G (Everolimus)
SB  - IM
CIN - Lancet. 2016 Oct 29;388(10056):2062-2064. PMID: 27613522
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Anticonvulsants/*therapeutic use
MH  - Antineoplastic Agents/*therapeutic use
MH  - Child
MH  - Child, Preschool
MH  - Combined Modality Therapy
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Everolimus/adverse effects/*therapeutic use
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Seizures/*drug therapy
MH  - Tuberous Sclerosis/*complications
EDAT- 2016/09/11 06:00
MHDA- 2017/04/11 06:00
CRDT- 2016/09/11 06:00
PHST- 2016/07/13 00:00 [received]
PHST- 2016/08/11 00:00 [revised]
PHST- 2016/08/12 00:00 [accepted]
PHST- 2016/09/11 06:00 [pubmed]
PHST- 2017/04/11 06:00 [medline]
PHST- 2016/09/11 06:00 [entrez]
AID - S0140-6736(16)31419-2 [pii]
AID - 10.1016/S0140-6736(16)31419-2 [doi]
PST - ppublish
SO  - Lancet. 2016 Oct 29;388(10056):2153-2163. doi: 10.1016/S0140-6736(16)31419-2. 
      Epub 2016 Sep 6.