Treat_CCM: Propranolol in Cerebral Cavernous Malformation
Ključne riječi
Sažetak
Opis
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.
Datumi
| Posljednja provjera: | 03/31/2019 |
| Prvo podneseno: | 05/16/2018 |
| Predviđena prijava predata: | 07/15/2018 |
| Prvo objavljeno: | 07/16/2018 |
| Zadnje ažuriranje poslato: | 01/21/2020 |
| Posljednje ažuriranje objavljeno: | 01/22/2020 |
| Stvarni datum početka studija: | 04/10/2018 |
| Procijenjeni datum primarnog završetka: | 10/30/2020 |
| Predviđeni datum završetka studije: | 12/30/2020 |
Stanje ili bolest
Intervencija / liječenje
Drug: Propranolol
Faza
Grupe ruku
| Arm | Intervencija / liječenje |
|---|---|
| No Intervention: Control Standard Treatments recommended for CCM | |
| Experimental: Propranolol 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. | Drug: Propranolol 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. |
Kriteriji prihvatljivosti
| Uzrast podoban za studiranje | 18 Years To 18 Years |
| Polovi podobni za studiranje | All |
| Prihvaća zdrave volontere | Da |
| Kriterijumi | 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. |
Ishod
Primarne mjere ishoda
1. Adverse clinical events CCM-related. [up to 24 months]
Sekundarne mjere ishoda
1. De novo CCM lesions depiction on MRI. [up to 24 months]
2. Adverse clinical outcomes, other than ICH and FND. [up to 24 months]
3. Location and MRI signal characteristics of CCM lesions at MRI. [up to 24 months]
4. Diameter of CCM lesions at MRI. [up to 24 months]
5. Length of CCM lesions at MRI [up to 24 months]
6. Micro-hemorrhages at MRI. [up to 24 months]
7. Dynamic contrast enhanced permeability (DCEP) at MRI. [up to 24 months]
