TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

J Chris Kingswood¹, Elena Belousova², Mirjana P Benedik³, Klemens Budde⁴, Tom Carter⁵, Vincent Cottin⁶, Paolo Curatolo⁷, Maria Dahlin⁸, Lisa D'Amato⁹, Guillaume B d'Augères¹⁰, Petrus J de Vries¹¹, José C Ferreira¹², Martha Feucht¹³, Carla Fladrowski^{14

15}, Christoph Hertzberg¹⁶, Sergiusz Jozwiak^{17

18}, John A Lawson¹⁹, Alfons Macaya²⁰, Ruben Marques^{9

21}, Rima Nabbout²², Finbar O'Callaghan²³, Jiong Qin²⁴, Valentin Sander²⁵, Matthias Sauter²⁶, Seema Shah²⁷, Yukitoshi Takahashi²⁸, Renaud Touraine²⁹, Sotiris Youroukos³⁰, Bernard Zonnenberg³¹, Anna C Jansen³²; TOSCA Consortium and TOSCA Investigators

Affiliations

¹ Genomics Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St George's Hospital, University of London, London, United Kingdom.
² Research and Clinical Institute of Paediatrics, Pirogov Russian National Research Medical University, Moscow, Russia.
³ SPS Pediatrična Klinika, Ljubljana, Slovenia.
⁴ Internal Medicine and Nephrology, Hypertensiology DHL, University Medicine Berlin, Berline, Germany.
⁵ Tuberous Sclerosis Association, Nottingham, United Kingdom.
⁶ Hôpital Louis Pradel, Claude Bernard University Lyon, Lyon, France.
⁷ Tor Vergata University Hospital, Rome, Italy.
⁸ Karolinska University Hospital, Stockholm, Sweden.
⁹ Novartis Farma S.p.A., Origgio, Italy.
¹⁰ Association Sclérose Tubéreuse de Bourneville, Gradignan, France.
¹¹ Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa.
¹² Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.
¹³ Universitätsklinik für Kinder-und Jugendheilkunde, Vienna, Austria.
¹⁴ Associazione Sclerosi Tuberosa ONLUS, Milan, Italy.
¹⁵ European Tuberous Sclerosis Complex Association, In den Birken, Dattein, Neuharlingersiel, Germany.
¹⁶ Vivantes-Klinikum Neukölln, Berlin, Germany.
¹⁷ Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.
¹⁸ Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.
¹⁹ The Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children's Hospital, Randwick, NSW, Australia.
²⁰ Hospital Universitari Vall d'Hebron, Barcelona, Spain.
²¹ Institute of Biomedicine (IBIOMED), University of León, León, Spain.
²² Department of Paediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France.
²³ Institute of Child Health, University College London, London, United Kingdom.
²⁴ Department of Paediatrics, Peking University People's Hospital, Beijing, China.
²⁵ Tallinn Children Hospital, Tallinn, Estonia.
²⁶ Klinikverbund Kempten-Oberallgäu gGmbH, Kempten, Germany.
²⁷ Novartis Healthcare Pvt. Ltd, Hyderabad, India.
²⁸ National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO, Shizuoka, Japan.
²⁹ Department of Genetics, CHU-Hôpital Nord, Saint Etienne, France.
³⁰ St. Sophia Children's Hospital, Athens, Greece.
³¹ University Medical Center, Utrecht, Netherlands.
³² Pediatric Neurology Unit, Department of Paediatrics, UZ Brussel VUB, Brussels, Belgium.

PMID: 33833726
PMCID: PMC8021912
DOI: 10.3389/fneur.2021.630378

TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

J Chris Kingswood et al. Front Neurol. 2021.

. 2021 Mar 23:12:630378.

doi: 10.3389/fneur.2021.630378. eCollection 2021.

Authors

Affiliations

¹ Genomics Clinical Academic Group, Molecular and Clinical Sciences Research Centre, St George's Hospital, University of London, London, United Kingdom.
² Research and Clinical Institute of Paediatrics, Pirogov Russian National Research Medical University, Moscow, Russia.
³ SPS Pediatrična Klinika, Ljubljana, Slovenia.
⁴ Internal Medicine and Nephrology, Hypertensiology DHL, University Medicine Berlin, Berline, Germany.
⁵ Tuberous Sclerosis Association, Nottingham, United Kingdom.
⁶ Hôpital Louis Pradel, Claude Bernard University Lyon, Lyon, France.
⁷ Tor Vergata University Hospital, Rome, Italy.
⁸ Karolinska University Hospital, Stockholm, Sweden.
⁹ Novartis Farma S.p.A., Origgio, Italy.
¹⁰ Association Sclérose Tubéreuse de Bourneville, Gradignan, France.
¹¹ Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa.
¹² Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.
¹³ Universitätsklinik für Kinder-und Jugendheilkunde, Vienna, Austria.
¹⁴ Associazione Sclerosi Tuberosa ONLUS, Milan, Italy.
¹⁵ European Tuberous Sclerosis Complex Association, In den Birken, Dattein, Neuharlingersiel, Germany.
¹⁶ Vivantes-Klinikum Neukölln, Berlin, Germany.
¹⁷ Department of Child Neurology, Medical University of Warsaw, Warsaw, Poland.
¹⁸ Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.
¹⁹ The Tuberous Sclerosis Multidisciplinary Management Clinic, Sydney Children's Hospital, Randwick, NSW, Australia.
²⁰ Hospital Universitari Vall d'Hebron, Barcelona, Spain.
²¹ Institute of Biomedicine (IBIOMED), University of León, León, Spain.
²² Department of Paediatric Neurology, Necker Enfants Malades Hospital, Paris Descartes University, Paris, France.
²³ Institute of Child Health, University College London, London, United Kingdom.
²⁴ Department of Paediatrics, Peking University People's Hospital, Beijing, China.
²⁵ Tallinn Children Hospital, Tallinn, Estonia.
²⁶ Klinikverbund Kempten-Oberallgäu gGmbH, Kempten, Germany.
²⁷ Novartis Healthcare Pvt. Ltd, Hyderabad, India.
²⁸ National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, NHO, Shizuoka, Japan.
²⁹ Department of Genetics, CHU-Hôpital Nord, Saint Etienne, France.
³⁰ St. Sophia Children's Hospital, Athens, Greece.
³¹ University Medical Center, Utrecht, Netherlands.
³² Pediatric Neurology Unit, Department of Paediatrics, UZ Brussel VUB, Brussels, Belgium.

PMID: 33833726
PMCID: PMC8021912
DOI: 10.3389/fneur.2021.630378

Abstract

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.

Keywords: TOSCA; everolimus; mammalian target of rapamycin; post-authorization safety study; tuberous sclerosis complex.

Copyright © 2021 Kingswood, Belousova, Benedik, Budde, Carter, Cottin, Curatolo, Dahlin, D'Amato, d'Augères, 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.

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Conflict of interest statement

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.

Figures

**Figure 1**
Patient disposition in TOSCA PASS sub-study. TOSCA, TuberOus SClerosis registry to increase disease Awareness; PASS, post-authorisation safety study.

See this image and copyright information in PMC

References

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TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

Affiliations

TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

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