PMID- 33833726
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210410
IS  - 1664-2295 (Print)
IS  - 1664-2295 (Electronic)
IS  - 1664-2295 (Linking)
VI  - 12
DP  - 2021
TI  - TuberOus SClerosis registry to increAse disease awareness (TOSCA) 
      Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis 
      Complex.
PG  - 630378
LID - 10.3389/fneur.2021.630378 [doi]
LID - 630378
AB  - This non-interventional post-authorisation safety study (PASS) assessed the 
      long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) 
      who participated in the TuberOus SClerosis registry to increase disease Awareness 
      (TOSCA) clinical study and received everolimus for the licensed indications in 
      the European Union. The rate of adverse events (AEs), AEs that led to dose 
      adjustments or treatment discontinuation, AEs of potential clinical interest, 
      treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. 
      One hundred seventy-nine patients were included in the first 5 years of 
      observation; 118 of 179 patients had an AE of any grade, with the most common AEs 
      being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 
      patients (31.3%) and treatment discontinuation in nine patients (5%). AEs 
      appeared to be more frequent and severe in children. On Tanner staging, all 
      patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 
      female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs 
      were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 
      patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 
      1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had 
      discontinued everolimus for more than 28 days, and none were thought to be 
      related to everolimus according to the treating physicians. The PASS sub-study 
      reflects the safety and tolerability of everolimus in the management of TSC in 
      real-world routine clinical practice.
CI  - Copyright (c) 2021 Kingswood, Belousova, Benedik, Budde, Carter, Cottin, Curatolo, 
      Dahlin, D'Amato, d'Augeres, de Vries, Ferreira, Feucht, Fladrowski, Hertzberg, 
      Jozwiak, Lawson, Macaya, Marques, Nabbout, O'Callaghan, Qin, Sander, Sauter, 
      Shah, Takahashi, Touraine, Youroukos, Zonnenberg, Jansen and TOSCA Consortium and 
      TOSCA Investigators.
FAU - Kingswood, J Chris
AU  - Kingswood JC
AD  - Genomics Clinical Academic Group, Molecular and Clinical Sciences Research 
      Centre, St George's Hospital, University of London, London, United Kingdom.
FAU - Belousova, Elena
AU  - Belousova E
AD  - Research and Clinical Institute of Paediatrics, Pirogov Russian National Research 
      Medical University, Moscow, Russia.
FAU - Benedik, Mirjana P
AU  - Benedik MP
AD  - SPS Pediatricna Klinika, Ljubljana, Slovenia.
FAU - Budde, Klemens
AU  - Budde K
AD  - Internal Medicine and Nephrology, Hypertensiology DHL, University Medicine 
      Berlin, Berline, Germany.
FAU - Carter, Tom
AU  - Carter T
AD  - Tuberous Sclerosis Association, Nottingham, United Kingdom.
FAU - Cottin, Vincent
AU  - Cottin V
AD  - Hopital Louis Pradel, Claude Bernard University Lyon, Lyon, France.
FAU - Curatolo, Paolo
AU  - Curatolo P
AD  - Tor Vergata University Hospital, Rome, Italy.
FAU - Dahlin, Maria
AU  - Dahlin M
AD  - Karolinska University Hospital, Stockholm, Sweden.
FAU - D'Amato, Lisa
AU  - D'Amato L
AD  - Novartis Farma S.p.A., Origgio, Italy.
FAU - d'Augeres, Guillaume B
AU  - d'Augeres GB
AD  - Association Sclerose Tubereuse de Bourneville, Gradignan, France.
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 - Ferreira, Jose C
AU  - Ferreira JC
AD  - Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.
FAU - Feucht, Martha
AU  - Feucht M
AD  - Universitatsklinik fur Kinder-und Jugendheilkunde, Vienna, Austria.
FAU - Fladrowski, Carla
AU  - Fladrowski C
AD  - Associazione Sclerosi Tuberosa ONLUS, Milan, Italy.
AD  - European Tuberous Sclerosis Complex Association, In den Birken, Dattein, 
      Neuharlingersiel, Germany.
FAU - Hertzberg, Christoph
AU  - Hertzberg C
AD  - Vivantes-Klinikum Neukolln, Berlin, Germany.
FAU - Jozwiak, Sergiusz
AU  - Jozwiak S
AD  - Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.
AD  - Department of Neurology and Epileptology, The Children's Memorial Health 
      Institute, Warsaw, Poland.
FAU - Lawson, John A
AU  - Lawson JA
AD  - The Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children's 
      Hospital, Randwick, NSW, Australia.
FAU - Macaya, Alfons
AU  - Macaya A
AD  - Hospital Universitari Vall d'Hebron, Barcelona, Spain.
FAU - Marques, Ruben
AU  - Marques R
AD  - Novartis Farma S.p.A., Origgio, Italy.
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
FAU - Nabbout, Rima
AU  - Nabbout R
AD  - Department of Paediatric Neurology, Necker Enfants Malades Hospital, Paris 
      Descartes University, Paris, France.
FAU - O'Callaghan, Finbar
AU  - O'Callaghan F
AD  - Institute of Child Health, University College London, London, United Kingdom.
FAU - Qin, Jiong
AU  - Qin J
AD  - Department of Paediatrics, Peking University People's Hospital, Beijing, China.
FAU - Sander, Valentin
AU  - Sander V
AD  - Tallinn Children Hospital, Tallinn, Estonia.
FAU - Sauter, Matthias
AU  - Sauter M
AD  - Klinikverbund Kempten-Oberallgau gGmbH, Kempten, Germany.
FAU - Shah, Seema
AU  - Shah S
AD  - Novartis Healthcare Pvt. Ltd, Hyderabad, India.
FAU - Takahashi, Yukitoshi
AU  - Takahashi Y
AD  - National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological 
      Disorders, NHO, Shizuoka, Japan.
FAU - Touraine, Renaud
AU  - Touraine R
AD  - Department of Genetics, CHU-Hopital Nord, Saint Etienne, France.
FAU - Youroukos, Sotiris
AU  - Youroukos S
AD  - St. Sophia Children's Hospital, Athens, Greece.
FAU - Zonnenberg, Bernard
AU  - Zonnenberg B
AD  - University Medical Center, Utrecht, Netherlands.
FAU - Jansen, Anna C
AU  - Jansen AC
AD  - Pediatric Neurology Unit, Department of Paediatrics, UZ Brussel VUB, Brussels, 
      Belgium.
CN  - TOSCA Consortium and TOSCA Investigators
LA  - eng
PT  - Journal Article
DEP - 20210323
PL  - Switzerland
TA  - Front Neurol
JT  - Frontiers in neurology
JID - 101546899
PMC - PMC8021912
OTO - NOTNLM
OT  - TOSCA
OT  - everolimus
OT  - mammalian target of rapamycin
OT  - post-authorization safety study
OT  - tuberous sclerosis complex
COIS- JK, EB, TC, VC, PC, Gd'A, JF, PV, MF, CF, CH, SJ, RN, FO'C, JQ, MS, RT, MD, JL, 
      AM, SY, MB, BZ, and AJ received honoraria and support for travel from Novartis. 
      VC received personal fees for consulting, lecture, and travel from Actelion, 
      Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, MSD, Novartis, Pfizer, 
      Roche, and Sanofi; grants from Actelion, Boehringer Ingelheim, GSK, Pfizer and 
      Roche and personal fees for developing educational material from Boehringer 
      Ingelheim and Roche. PV has been on the study steering group of the EXIST-1, 2 
      and 3 studies sponsored by Novartis and is a co-PI on two investigator-initiated 
      studies part-funded by Novartis. RN received grant support, paid to her 
      institution, from Eisai and lecture fees from Nutricia, Eisai, Advienne and GW 
      Pharma. YT received personal fees from Novartis for lecture and for copyright of 
      referential figures from the journals and received a grant from the Japanese 
      government for intractable epilepsy research. SJ was partly financed by the EC 
      Seventh Framework Programme (FP7/2007-2013; EPISTOP, grant agreement no. 602391), 
      the Polish Ministerial funds for science (years 2013-2018) for implementation of 
      international co-financed project and the grant EPIMARKER of the Polish National 
      Center for Research and Development No STRATEGMED3/306306/4/2016. JK, PC, CH, JL, 
      and JQ received a research grant from Novartis. KB received grants, personal 
      fees, and non-financial support from Novartis, Alexion, Astellas, BMS, 
      CSL-Henring, Chiesi, Fresenius, Genentech, Hansa, Hexal, MSD, Neovii, Otsuka, 
      Pfizer, Roche, Sandoz, Siemens, Veloxis, Vifor, and Vitaeris, grants from Abbvie, 
      Akebia, Calliditas, CSL Henring, Freseniu, Hookipa, MSD Sharp & Dohme, Quark, 
      Sanofi, Shire, UCB. RM and SS are employees of Novartis, while LD'A was a 
      Novartis employee at the time of manuscript concept approval. This study was 
      funded by Novartis Pharma AG. Novartis has contributed to the study design, data 
      analysis, and the decision to publish. The remaining authors declare that the 
      research was conducted in the absence of any commercial or financial 
      relationships that could be construed as a potential conflict of interest.
EDAT- 2021/04/10 06:00
MHDA- 2021/04/10 06:01
PMCR- 2021/03/23
CRDT- 2021/04/09 06:26
PHST- 2020/11/17 00:00 [received]
PHST- 2021/02/03 00:00 [accepted]
PHST- 2021/04/09 06:26 [entrez]
PHST- 2021/04/10 06:00 [pubmed]
PHST- 2021/04/10 06:01 [medline]
PHST- 2021/03/23 00:00 [pmc-release]
AID - 10.3389/fneur.2021.630378 [doi]
PST - epublish
SO  - Front Neurol. 2021 Mar 23;12:630378. doi: 10.3389/fneur.2021.630378. eCollection 
      2021.