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

Abstract

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.

Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations

“…Indeed, we recently reported that propranolol blocks the embryonic CVP malformation by β1 adrenergic receptor antagonism (Li et al, 2021), a result that comports with the beneficial effects of propranolol in murine CCM models (Li et al, 2021;Oldenburg et al, 2021) and in anecdotal reports in humans (Lanfranconi et al, 2020;Reinhard et al, 2016). We have found that blockade or Rho kinase also ameliorates the CVP lesion (Figure 7-figure supplement 2) as it does murine CCM (McDonald et al, 2012).…”

Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models

“…Depending on signal effects in the ongoing pilot propranolol trial (8), and subjects' tolerance to side effects, we propose that propranolol dose escalation might be considered in future human clinical trials to doses which effect physiologic β1 receptor inhibition. β1 adrenergic antagonists ameliorate some of the dose limiting side effects of propranolol such as bronchospasm.…”

“…Several case reports (3)(4)(5)(6)(7) and an ongoing randomized controlled pilot trial, Treat_CCM, clinicaltrials.gov NCT03589014 (8), have proposed treating CCMs with propranolol, a pleiotropic nonselective β adrenergic receptor blocker. It is unclear if the anecdotal observed effects impact lesion growth or bleeding.…”

Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

“…That said, the CVP does lacks CNS accessory cells, such as astrocytes,(Lopez-Ramirez et al, 2021) that that promote CCM development. Indeed, we recently reported that propranolol blocks the embryonic CVP malformation by β1 adrenergic receptor antagonism(Li et al, 2021), a result that comports with the beneficial effects of propranolol in murine CCM models(Li et al, 2021; Oldenburg et al, 2021) and in anecdotal reports in humans(Lanfranconi et al, 2020; Reinhard et al, 2016). We have found that blockade or Rho kinase also ameliorates the CVP lesion (Figure 7-figure supplement 2) as it does murine CCM(McDonald et al, 2012).…”