Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation (Treat_CCM)

Treat_CCM Clinical Trial A Multicenter Randomized Clinical Trial on Propranolol in Familial Cerebral Cavernous Malformation

Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease which can be either congenital in origin or sporadic and is characterized by the presence of isolated or multiple CCM lesions, causing recurrent headache, seizures, focal neurological deficits and hemorrhages. Inasmuch, to date, the only curative treatment available is limited to surgical lesion eradication or stereotactic radiosurgery. It is therefore necessary to find an effective medical treatment that may limit disease progression and decrease the burden of adverse clinical events. The non-selective betablocker propranolol has been found to be effective in the treatment of infantile cutaneous hemangioma, and anecdotal reports have been published on its efficacy in CCM. The safety profile of propranolol has been documented in millions of patients of all ages. The primary objective of this exploratory trial is to test whether a chronic treatment with propranolol will reduce the burden of cerebrovascular lesions, of clinical events and symptoms in patients with familial CCM.

The project will consist of a multicenter, open-label, randomized study (PROBE design) in patients with CCM to be randomized in a 2:1 ratio (propranolol:control) and will allow comparison of 2 groups: one receiving propranolol (recommended initial dose is 40 mg bid, to be uptitrated to 80 mg bid, however, doses as low as 10 mg bid and up to 160 mg bid are acceptable according to tolerability) on the top of recommended standard care, the other receiving recommended standard care. This investigator-driven study will be open-label with a PROBE design will be applied so that each MRI exam will be centrally read and all adverse clinical events will be centrally adjudicated. It should be pointed out that by no means surgery, whenever indicated, will be delayed and/or avoided because of study treatment allocation. The purpose of this exploratory trial is to test whether a chronic treatment with propranolol will reduce the burden of cerebrovascular lesions, of clinical events and symptoms in patients with familial CCM. Inherited CCM is a rare disease with a prevalence of less than 5/10.000. Thus, since the number of patients to be included in this exploratory trial will be insufficient to prove or disprove a statistically significant beneficial effect of propranolol on clinical events, the extension to more centers and patients is formally included in the present protocol. Special care will be paid to the biologic consistency of the different endpoints, even if none of them will yield statistically significant differences. The assessment of the tolerability of propranolol in normotensive otherwise healthy patients is another clinically relevant endpoint. If the overall evaluation of the safety (no difference in AEs and SAEs between propranolol and control arms), and of the efficacy profile (assessed as consistency between incidence of adverse clinical events and magnetic resonance brain imaging results between propranolol and control arms) at the conclusion of the present study, will be reassuring for propranolol, a protocol for a definitive Phase 2 trial will be submitted for approval to Regulatory Authorities. This second trial may be designed as single-arm as far as adequate data on incidence of endpoint events will be available from Treat_CCM.

Treat_CCM is a Prospective Randomized Open Trial with Blinded Evaluation of outcomes (PROBE). Clinical events CCM-related (i.e. intra-cerebral hemorrhage and focal neurological deficits excluding seizures) will be blindly adjudicated by an independent Event Committee.All MRI exams will be read in a Central Laboratory by experienced neuroradiologists, unaware of patient identification and study treatment.

Initial oral dose 40 mg bid, uptitrated to 80mg bid doses as low as 10 mg bid and up to 160 mg bid, 20 to 320mg daily, are acceptable according to tolerability.

Patients randomized to the experimental arm will receive propranolol on top of standard recommended treatment for CCM. Initial oral dose of 40 mg bid will be uptitrated to 80 mg bid in the absence of excessive bradycardia or hypotension. Doses as low as 10 mg bid and up to 160 mg bid, 20 to 320mg daily, are acceptable according to tolerability.

New occurrence of clinical events CCM-related, that is intra-cerebral hemorrhage (ICH) and focal neurological deficits (FND) excluding seizures.

De novo CCM lesions depiction will be obtained on MRI QSM and Susceptibility Weighted Images (SWI) that is very sensitive to hemoglobin and iron deposition.

Global disability and health related quality of life as assessed by Beck Depression Inventory -BDI- questionnaire. BDI is made of 21 questions scored on a scale from 0 to 3, 0 representing the best condition. Final score will be the sum of all scores and will range from 0 to 63, were 0 is the best condition. SF-36 is made of 36 questions scored on a scale from 0 to 100 representing the highest level of functioning possible. Questions are aggregated in 8 dimensions of health (eg pain, phsical functioning etc.).

Location and MRI signal characteristics of CCM lesions will be assessed by 3 T brain MRI. The encephalic regions evaluated will be: cerebellum, brainstem, right/left hemisphere, right/left basal ganglia. Lesions with previous surgical treatment will be excluded from imaging analysis

Micro-hemorrhages will be assessed by magnetic susceptibility of the brain tissue, a biophysical property proportional to local iron content (quantitative susceptibility mapping, QSM). Unit of Measure of QSM is parts per million (ppm). Changes from baseline will be calculated.

Cerebral vascular permeability will be assessed after injection of gadolinium at MRI by dynamic contrast enhanced permeability (DCEP) method. Changes from baseline will be calculated.

Inclusion Criteria: Patients with Familial cerebral cavernous malformations (FCCM); history of clinical symptoms or events: intracerebral hemorrhage, stroke, permanent or transient focal deficits, seizures, disability or any other neurological symptom supposedly related to CCM; age of at least 18 years. Written informed consent to participate in the study prior to any study procedures. Exclusion Criteria: Implanted pacemaker or any other condition preventing the magnetic resonance imaging (MRI); bradycardia (<50 bpm) or 2nd or 3rd degree AV block, hypotension (symptomatic); unstable diabetes; severe asthma; renal and/or liver failure; current use of verapamil and diltiazem for risk of excessive bradycardia; previous brain surgery (within 6 months); known hypersensitivity to study drug (propranolol or any of the ingredients) pregnant or lactating women or women of childbearing potential who are not protected from pregnancy by an accepted method of contraception participation to another clinical trial; inability to cooperate with the trial procedures.

Locking of the trial data base, completion of main analyses, and submission for publication of the main study result are expected to take at least 14 months after last patient-last-visit date. Only clinical data relative to patients' characteristics and follow-up will be shared for each individual patient. Biohumoral and imaging data will be shared only after approval by the Steering Committee of the trial of a specific request.

Free access for clinical data. Biohumoral and imaging data will be shared only after approval by the Steering Committee of the trial of a specific request.

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