Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation
Treat_CCM: 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.
Inclusion Criteria:

 1. Patients with Familial cerebral cavernous malformations (FCCM);

 2. 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;

 3. age of at least 18 years.

 4. Written informed consent to participate in the study prior to any study procedures.

 Exclusion Criteria:

 1. Implanted pacemaker or any other condition preventing the magnetic resonance imaging
 (MRI);

 2. bradycardia (<50 bpm) or 2nd or 3rd degree AV block, hypotension (symptomatic);

 3. unstable diabetes;

 4. severe asthma;

 5. renal and/or liver failure;

 6. current use of verapamil and diltiazem for risk of excessive bradycardia;

 7. previous brain surgery (within 6 months);

 8. known hypersensitivity to study drug (propranolol or any of the ingredients)

 9. pregnant or lactating women or women of childbearing potential who are not protected
 from pregnancy by an accepted method of contraception

 10. participation to another clinical trial;

 11. inability to cooperate with the trial procedures.