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

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

Research output: Contribution to journalArticlepeer-review


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:, NCT03589014. Retrospectively registered on 17 July 2018.

Original languageEnglish
Article number401
Issue number1
Publication statusPublished - May 12 2020


  • Cerebral cavernous malformation
  • Magnetic resonance imaging
  • Propranolol

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology (medical)


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