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Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial

Published online by Cambridge University Press:  27 January 2020

Erica V. Stelmaszewski*
Affiliation:
Pediatric Cardiology Department, Hospital de Pediatría Garrahan, Buenos Aires, Argentina
Daniella B. Parente
Affiliation:
Radiology Department, D’Or Institute for Research and Education, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Alberto Farina
Affiliation:
Medical Affairs Department, Mundipharma Pharmaceuticals SRL, Milan, Italy
Anna Stein
Affiliation:
Nephrology Department, Hospital Moinhos de Vento, Porto Alegre, Brazil
Anthony Gutierrez
Affiliation:
Medical Department, Pontificia Universidad Católica Madre y Maestra, Facultad Ciencias de la Salud, Santiago de los Caballeros, Dominican Republic
Antonio F. Raquelo-Menegassio
Affiliation:
Medical Department, Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahía, Brazil
Carla Manterola
Affiliation:
Neurology Department, Clínica Alemana de Santiago/Facultad de Medicina, Universidad de Chile, Santiago, Chile
Carolina F. de Sousa
Affiliation:
Pharmacy Department, Faculdades Oswaldo Cruz, São Paulo, Brazil
Carolina Victor
Affiliation:
Oncology Department, Instituto do Cáncer do Estado de São Paulo (ICESP), São Paulo, Brazil
Dina Maki
Affiliation:
Nephrology Department, Hamad General Hospital, Hamad Medical Corporation (HMC), Doha, Qatar
Elias M. Morón
Affiliation:
Adjunct Faculty, Community and Public Health Sciences Department, Nova Southeastern University College of Dental Medicine, Davie, FL, USA Community Dentistry and Behavioral Science Department, University of Florida College of Dentistry, Gainesville, FL, USA
Fabiano F. de Abrantes
Affiliation:
Neurology Department, Universidade Federal da São Paulo (UNIFESP), São Paulo, Brazil
Fatima Iqbal
Affiliation:
Infectious Diseases Department, Communicable Disease Center, Doha, Qatar
Jazmin Camacho-Vilchez
Affiliation:
Oncology Department, Instituto Nacional del Cancer “Rosa Emilia Sanchez Perez de Tavares” C/Correa y Cidrón, Ciudad Universitaria, Santo Domingo, Dominican Republic
Joanna Jimenez-Pavón
Affiliation:
Mood Disorders Department, National Institute of Psychiatry, México City, México
Juan P. Polania
Affiliation:
Pediatric Neurology Department, Hospital Pediatrico la Misericordia, Bogotá, Colombia
Lorenzo Thompson
Affiliation:
Medical Department, Universidad Iberoamericana Unibe, Santo Domingo, Dominican Republic
Lygia Bonanato
Affiliation:
Medical Department, Eurofarma, São Paulo, Brazil
Matthias Diebold
Affiliation:
Nephrology Department, Cardiovascular Research Institute, Basel, Switzerland
Maria V. C. P. Da Silva
Affiliation:
Ophthalmology Department, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada
Mariam W. J. Nashwan
Affiliation:
Medical Department, University of Jordan, Amman, Jordan Emergency Department, Hamad Medical Corporation, Doha, Qatar
Marianna A. G. Galvani
Affiliation:
Oncology Department, Faculdade de Medicina do ABC, Santo André, Brazil
Osama E. A. Idris
Affiliation:
Geriatric Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar
Pierina Danos
Affiliation:
Genetics and Molecular Biology Department, Centro de Genética y Biología Molecular (CGBM), Instituto de Investigación – Facultad de Medicina Humana, Universidad de San Martín de Porres (USMP), La Molina, Lima, Perú
Rocio Ortiz-Lopez
Affiliation:
Medical Department, Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, Mexico
Rofida A. A. Mahmoud
Affiliation:
Pharmacy Department, Hamad Medical Corporation, Doha, Qatar
Sergio Gresse Jr
Affiliation:
Health Economics and Outcomes Research Department, Baxter Healthcare, São Paulo, Brazil
Karla L. Loss
Affiliation:
Pediatric Cardiology Department, Dr Alzir Bernardino Alves Pediatric Hospital and Maternity, Vila Velha, Espírito Santo, Brazil
*
Author for correspondence: E. V. Stelmaszewski, Department of Pediatric Cardiology, Hospital Garrahan, Combate de los Pozos 1881, Buenos Aires, CP1245, Argentina. Tel: +54 9 11 6586 1655; Fax: +54 11 4941 1123; E-mail: eryvictoria@yahoo.com.ar

Abstract

Introduction:

Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma.

Methods:

ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure.

Conclusions:

ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

Type
Original Article
Copyright
© Cambridge University Press 2020

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Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial
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Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial
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Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial
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