PMID- 35462939
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Real-World Evidence Study on the Long-Term Safety of Everolimus in Patients With 
      Tuberous Sclerosis Complex: Final Analysis Results.
PG  - 802334
LID - 10.3389/fphar.2022.802334 [doi]
LID - 802334
AB  - The TuberOus SClerosis registry to increase disease Awareness (TOSCA) 
      Post-Authorization Safety Study (PASS) was a non-interventional, multicenter, 
      safety substudy that assessed the long-term safety of everolimus in patients with 
      tuberous sclerosis complex (TSC) receiving everolimus for its licensed 
      indications in the European Union (EU). This substudy also aimed to address 
      TSC-associated neuropsychiatric disorders (TAND), sexual development, and male 
      infertility. Eligible patients were enrolled from 39 sites across 11 countries in 
      the EU. Outcomes of interest included the incidence of adverse events (AEs), 
      serious adverse events (SAEs), treatment-related AEs (TRAEs), AEs leading to 
      everolimus discontinuation, AEs of special interest (AESIs), the observed 
      relationship between everolimus blood levels and incidence of AESIs, TAND, and 
      reproductive clinical features. Herein, we present the final analysis results 
      from this substudy (data cutoff date: 22 January 2020). At data cutoff, 179 
      patients were enrolled (female, 59.2%; age >/=18 years, 65.9%), of which the 
      majority completed the study (76%). Overall, 121 patients (67.6%) had AEs 
      regardless of causality. The most frequent TRAEs (>/=5%) were stomatitis (7.8%), 
      aphthous ulcer (6.7%), and hypercholesterolemia (6.1%). The most common 
      treatment-related SAEs (>1%) were pneumonia (3.4%), influenza, pyelonephritis, 
      aphthous ulcer, stomatitis, dyslipidemia, and hypercholesterolemia (1.1% each). 
      Ten patients (5.6%) reported AEs leading to everolimus discontinuation. The 
      common psychiatric disorders (N = 179) were autism spectrum disorder (21.8%), 
      anxiety disorder (12.8%), "other" psychiatric disorders (8.9%), attention-deficit 
      hyperactivity disorder, and depressive disorder (7.8% each). Of 179 patients, 88 
      (49.2%) had >/=1 behavioral problem. Of these (n = 88), the most common (>20%) were 
      sleep difficulties (47.7%), anxiety (43.2%), mood swings (37.5%), depression mood 
      (35.2%), impulsivity (30.7%), severe aggression (23.9%), and overactivity 
      (22.7%). Of 179 patients, four (2.2%) reported abnormal puberty onset, and three 
      (1.7%) reported other reproductive disorders. Of 106 females, 23 (21.7%) reported 
      menstrual cycle disorders and 10 (9.4%) reported amenorrhea. Available data did 
      not show delays in sexual maturation or an association between sexual development 
      and infertility. The results demonstrate that everolimus has a manageable 
      long-term safety profile in the TSC treatment setting. No new safety signals 
      emerged. This substudy also contributed to the mapping of TAND and reproductive 
      clinical features in patients with TSC.
CI  - Copyright (c) 2022 Ruiz-Falco Rojas, Feucht, Macaya, Wilken, Hahn, Maamari, 
      Hirschberg, Ridolfi and Kingswood.
FAU - Ruiz-Falco Rojas, Maria Luz
AU  - Ruiz-Falco Rojas ML
AD  - Hospital Infantil Universitario Nino Jesus, Madrid, Spain.
FAU - Feucht, Martha
AU  - Feucht M
AD  - Universitats-Klinik fur Kinder-und Jugendheilkunde Wien, Vienna, Austria.
FAU - Macaya, Alfons
AU  - Macaya A
AD  - Hospital Universitari Vall d' Hebron, Barcelona, Spain.
FAU - Wilken, Bernd
AU  - Wilken B
AD  - Klinikum Kassel GmbH, Kassel, Germany.
FAU - Hahn, Andreas
AU  - Hahn A
AD  - Abteilung Kinderneurologie, Universitatsklinikum Giessen und Marburg GmbH, 
      Giessen, Germany.
FAU - Maamari, Ricardo
AU  - Maamari R
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States.
FAU - Hirschberg, Yulia
AU  - Hirschberg Y
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States.
FAU - Ridolfi, Antonia
AU  - Ridolfi A
AD  - Novartis Pharma S.A.S, Rueil-Malmaison, France.
FAU - Kingswood, John Chris
AU  - Kingswood JC
AD  - Royal Sussex County Hospital, Brighton, United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20220408
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9023743
OTO - NOTNLM
OT  - TOSCA
OT  - everolimus
OT  - post-authorization safety study (PASS)
OT  - real-world evidence (RWE)
OT  - tuberous sclerosis complex (TSC)
COIS- Authors RM and YH are employees at Novartis and report stock ownership at 
      Novartis. Author AR is an employee at Novartis. MF reports consulting fees for 
      being part of the scientific advisory board and TOSCA working committee; received 
      speaker honoraria, support for travel, and payment for expert testimony from 
      Novartis; and reports leadership or fiduciary role in the following: ILAE task 
      force epilepsy surgery, ERN EpiCARE, OGKN, and OGfE. AM received honoraria and 
      support for travel from Novartis. BW reports honoraria for a lecture from Takeda. 
      JK received honoraria, support for travel, and research grant from Novartis. 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- 2022/04/26 06:00
MHDA- 2022/04/26 06:01
PMCR- 2022/04/08
CRDT- 2022/04/25 05:14
PHST- 2021/11/01 00:00 [received]
PHST- 2022/03/07 00:00 [accepted]
PHST- 2022/04/25 05:14 [entrez]
PHST- 2022/04/26 06:00 [pubmed]
PHST- 2022/04/26 06:01 [medline]
PHST- 2022/04/08 00:00 [pmc-release]
AID - 802334 [pii]
AID - 10.3389/fphar.2022.802334 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Apr 8;13:802334. doi: 10.3389/fphar.2022.802334. 
      eCollection 2022.