Journal Article

Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial

Vasamì, Antonella, d’Orio, Piergiorgio, Nicolis, Enrico Bjorn, Torri, Valter, Dejana, Elisabetta, Latini, Roberto, Castori, Marco, Tassi, Laura, Scola, Elisa, Carriero, Maria Rita, Meessen, Jennifer Marie Theresia Anna, Scelzo, Emma, Mazzon, Emanuela, d’Alessandris, Giorgio, d’Agruma, Leonardo, Marino, Silvia, Novelli, Deborah, Pallini, Roberto, Lanfranconi, Silvia, Zarino, Barbara, Bertani, Giulio Andrea, Lampugnani, Maria Grazia, Faragò, Giuseppe, Fusco, Carmela, Petracca, Antonio, Al-Shahi Salman, Rustam

2020

Overview

Background Cerebral cavernous malformations (CCMs) are vascular malformations characterized by clusters of enlarged leaky capillaries in the central nervous system. They may result in intracranial haemorrhage, epileptic seizure(s), or focal neurological deficits, and potentially lead to severe disability. Globally, CCMs represent the second most common intracranial vascular malformation in humans, and their familial form (FCCMs) accounts for one-fifth of cases. Neurosurgical excision, and perhaps stereotactic radiosurgery, is the only available therapeutic option. Case reports suggest that propranolol might modify disease progression. Methods Treat_CCM is a prospective, randomized, open-label, blinded endpoint (PROBE), parallel-group trial involving six Italian clinical centres with central reading of brain magnetic resonance imaging (MRI) and adverse events. Patients with symptomatic FCCMs are randomized (2:1 ratio) either to propranolol (40–80 mg twice daily) in addition to standard care or to standard care alone (i.e. anti-epileptic drugs or headache treatments). The primary outcome is intracranial haemorrhage or focal neurological deficit attributable to CCMs. The secondary outcomes are MRI changes over time (i.e. de novo CCM lesions, CCM size and signal characteristics, iron deposition, and vascular leakage as assessed by quantitative susceptibility mapping and dynamic contrast enhanced permeability), disability, health-related quality of life, depression severity, and anxiety (SF-36, BDI-II, State-Trait Anxiety Inventory). Discussion Treat_CCM will evaluate the safety and efficacy of propranolol for CCMs following promising case reports in a randomized controlled trial. The direction of effect on the primary outcome and the consistency of effects on the secondary outcomes (even if none of them yield statistically significant differences) of this external pilot study may lead to a larger sample size in a definitive phase 2 trial. Trial registration ClinicalTrails.gov, NCT03589014 . Retrospectively registered on 17 July 2018.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adrenergic beta-Antagonists - administration & dosage / Adrenergic beta-Antagonists - adverse effects / Adrenergic beta-Antagonists - therapeutic use / Adult / Animals / Anxiety - epidemiology / Beta blockers / Biomedicine / Brain / Cardiac arrhythmia / Case-Control Studies / Cerebral cavernous malformation / Convulsions & seizures / Depression - epidemiology / Disease Progression / Female / Genetic aspects / Health aspects / Health Sciences / Hemangioma, Cavernous, Central Nervous System - diagnostic imaging / Hemangioma, Cavernous, Central Nervous System - drug therapy / Hemangioma, Cavernous, Central Nervous System - epidemiology / Hemorrhage / Humans / Hypotension / Intracranial Hemorrhages - epidemiology / Italy - epidemiology / Magnetic resonance imaging / Magnetic Resonance Imaging - methods / Male / Medicine / Medicine & Public Health / Mice / Models, Animal / Mutation / Nervous System Diseases - epidemiology / Patients / Permeability / Propranolol / Propranolol - administration & dosage / Propranolol - adverse effects / Propranolol - therapeutic use / Prospective Studies / Quality of Life / Radiosurgery / Randomized Controlled Trials as Topic / Safety / Seizures (Medicine) / Severity of Illness Index / Statistics for Life Sciences / Study Protocol / Treatment Outcome