Research protocol. Natural history of familial cerebral cavernous malformations: the CCM_Italia cohort study

Silvia Lanfranconi¹Elisa Scola¹Deborah Novelli²Anna Poggesi³Francesca Pescini³Marco Pavanello⁴Ferruccio Romano⁴Quintino Giorgio D'Alessandris⁵Walter Marani⁶Francesco Signorelli⁶Giorgio Iaconetta⁷Giovanni Torelli⁷Enrico Fainardi³Mariasavina Severino⁴Luigi Gianmaria Remore¹Giulio Andrea Bertani¹Giorgio Conte¹Valeria Capra⁴Antonella Vasamì⁸Enrico Nicolis⁸Giorgia Contino⁸Dario Ronchi¹Maria Chiara Palmieri¹Alessandra Previtali¹Pier Paolo Mattogno⁵Carmelo Lucio Sturiale⁵Maria Elena Solarino⁶Rita Caliulo⁷Maria Teresa Bozzi⁶Filippo Fratini³Elisa R Zanier⁸Roberto Latini⁸Jennifer Marie Theresia Anna Meessen^2*Marco Locatelli¹

• ¹Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
• ²Mario Negri Institute for Pharmacological Research (IRCCS), Milano, Italy
• ³Azienda Ospedaliero Universitaria Careggi, Florence, Italy
• ⁴Istituto Giannina Gaslini, Genoa, Italy
• ⁵Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
• ⁶Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy
• ⁷Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d'Aragona, Salerno, Italy
• ⁸Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

1) Abstract Background: Familial Cerebral Cavernous Malformation (fCCMs) are a rare genetic autosomal dominant cerebrovascular disease characterized by multiple cerebral and spinal angiomas. The condition is caused by mutations in KRIT1 (CCM1), CCM2 (Malcavernin), or PDCD10 (CCM3) and may lead to intracerebral haemorrhage (ICH) or non-hemorrhagic focal neurological deficits (FND) potentially leading to severe disability and even death. To date little is known about disease progression and tools to identify patients at higher risk are lacking. Methods: Pediatric and adult fCCM patients either symptomatic or asymptomatic will be enrolled and followed annually for a two years period. Participants will undergo clinical assessments, blood sampling and 3T brain MRI at baseline and at 12 and 24 months. The primary outcome will be new occurrence of symptomatic ICH or FND attributable to CCMs over 24 months. Patient characteristics will be assessed for the primary endpoint and secondary endpoints and illustrated with Kaplan Meier curves and Cox proportional hazard regressions. This trial is registered with ClinicalTrials.gov, NCT06983132, and is currently recruiting. Discussion/conclusion: Despite increasing efforts in basic and clinical research and the improved understanding of the pathogenic mechanisms underlying this condition, tools to predict the progression of the disease and to identify at-risk individuals and effective therapeutic targets are currently lacking. This study will create the largest Italian group of fCCM patients which are closely monitored over time to collect data that may help identify risk factors and disease trajectories. Collection of standardized information about clinical and radiological evolution over time as well as results from circulating biomarkers will help to address the complexities of diseases and suggest potential reliable markers of disease progression. Clinical trial registration: ClinicalTrials.gov, identifier NCT06983132