RESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Everolimus/uso terapéutico , Neoplasias Cardíacas/tratamiento farmacológico , Rabdomioma/tratamiento farmacológico , Esclerosis Tuberosa/complicaciones , Antineoplásicos/efectos adversos , Niño , Ensayos Clínicos Fase II como Asunto , Método Doble Ciego , Everolimus/efectos adversos , Neoplasias Cardíacas/complicaciones , Humanos , Estudios Multicéntricos como Asunto , Estudios Prospectivos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Rabdomioma/complicaciones , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
Pediatric heart failure (HF) is an important clinical condition with high morbidity, mortality, and costs. Due to the heterogeneity in clinical presentation and etiologies, the development of therapeutic strategies is more challenging in children than adults. Most guidelines recommending drug therapy for pediatric HF are extrapolated from studies in adults. Unfortunately, even using all available treatment, progression to cardiac transplantation is common. The development of prospective clinical trials in the pediatric population has significant obstacles, including small sample sizes, slow recruitment rates, challenging endpoints, and high costs. However, progress is being made as evidenced by the recent introduction of ivabradine and of sacubitril/valsartan. In the last 5 years, new drugs have also been developed for HF with reduced ejection fraction (HFrEF) in adults. The use of well-designed prospective clinical trials will be fundamental in the evaluation of safety and efficacy of these new drugs on the pediatric population. The aim of this article is to review the clinical presentation and management of acute and chronic pediatric heart failure, focusing on systolic dysfunction in patients with biventricular circulation and a systemic left ventricle. We discuss the drugs recently approved for children and those emerging, or in use for adults with HFrEF.