Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation

NCT ID: NCT03589014

Last Updated: 2022-02-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 71 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-11
• Study Completion Date: 2021-12-31

Brief Summary

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.

Detailed Description

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.

Conditions

Cerebral Cavernous Malformation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Control

Standard Treatments recommended for CCM

Group Type: NO_INTERVENTION

No interventions assigned to this group

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.

Group Type: EXPERIMENTAL

Propranolol

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Inderal

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

IFOM ETS - The AIRC Institute of Molecular Oncology

OTHER

Sponsor Role: collaborator

Mario Negri Institute for Pharmacological Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elisabetta Dejana, Professor

Role: STUDY_CHAIR

IFOM ETS - The AIRC Institute of Molecular Oncology

Roberto Latini

Role: STUDY_DIRECTOR

Istituto Di Ricerche Farmacologiche Mario Negri

Locations

IRCCS Casa Sollievo della Sofferenza

San Giovanni Rotondo, FG, Italy

IRCCS Centro Neurolesi "Bonino Pulejo"

Messina, ME, Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Mi, Italy

Fond. IRCCS Ist. Naz. Neurologico Carlo Besta

Milan, MI, Italy

ASST Grande Ospedale Metropolitano Niguarda

Milan, MI, Italy

Fondazione Policlinico Universitario "A. Gemelli"

Roma, RM, Italy

Countries

Italy

References

Lampugnani MG, Malinverno M, Dejana E, Rudini N. Endothelial cell disease: emerging knowledge from cerebral cavernous malformations. Curr Opin Hematol. 2017 May;24(3):256-264. doi: 10.1097/MOH.0000000000000338.

Reference Type: BACKGROUND

PMID: 28212190 (View on PubMed)

Bravi L, Malinverno M, Pisati F, Rudini N, Cuttano R, Pallini R, Martini M, Larocca LM, Locatelli M, Levi V, Bertani GA, Dejana E, Lampugnani MG. Endothelial Cells Lining Sporadic Cerebral Cavernous Malformation Cavernomas Undergo Endothelial-to-Mesenchymal Transition. Stroke. 2016 Mar;47(3):886-90. doi: 10.1161/STROKEAHA.115.011867. Epub 2016 Feb 2.

Reference Type: BACKGROUND

PMID: 26839352 (View on PubMed)

Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini MF, Maddaluno L, Baeyens N, Adams RH, Jain MK, Owens GK, Schwartz M, Lampugnani MG, Dejana E. KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO Mol Med. 2016 Jan 1;8(1):6-24. doi: 10.15252/emmm.201505433.

Reference Type: BACKGROUND

PMID: 26612856 (View on PubMed)

Marchi S, Corricelli M, Trapani E, Bravi L, Pittaro A, Delle Monache S, Ferroni L, Patergnani S, Missiroli S, Goitre L, Trabalzini L, Rimessi A, Giorgi C, Zavan B, Cassoni P, Dejana E, Retta SF, Pinton P. Defective autophagy is a key feature of cerebral cavernous malformations. EMBO Mol Med. 2015 Nov;7(11):1403-17. doi: 10.15252/emmm.201505316.

Reference Type: BACKGROUND

PMID: 26417067 (View on PubMed)

Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, Tournier-Lasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E. EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature. 2013 Jun 27;498(7455):492-6. doi: 10.1038/nature12207. Epub 2013 Jun 9.

Reference Type: BACKGROUND

PMID: 23748444 (View on PubMed)

Boulday G, Rudini N, Maddaluno L, Blecon A, Arnould M, Gaudric A, Chapon F, Adams RH, Dejana E, Tournier-Lasserve E. Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice. J Exp Med. 2011 Aug 29;208(9):1835-47. doi: 10.1084/jem.20110571. Epub 2011 Aug 22.

Reference Type: BACKGROUND

PMID: 21859843 (View on PubMed)

Bravi L, Rudini N, Cuttano R, Giampietro C, Maddaluno L, Ferrarini L, Adams RH, Corada M, Boulday G, Tournier-Lasserve E, Dejana E, Lampugnani MG. Sulindac metabolites decrease cerebrovascular malformations in CCM3-knockout mice. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8421-6. doi: 10.1073/pnas.1501352112. Epub 2015 Jun 24.

Reference Type: BACKGROUND

PMID: 26109568 (View on PubMed)

Gore AV, Lampugnani MG, Dye L, Dejana E, Weinstein BM. Combinatorial interaction between CCM pathway genes precipitates hemorrhagic stroke. Dis Model Mech. 2008 Nov-Dec;1(4-5):275-81. doi: 10.1242/dmm.000513. Epub 2008 Oct 28.

Reference Type: BACKGROUND

PMID: 19093037 (View on PubMed)

Meessen JMTA, Abete-Fornara G, Zarino B, Castori M, Tassi L, Carriero MR, D'Alessandris QG, Al-Shahi Salman R, Blanda A, Nicolis EB, Novelli D, Caruana M, Vasami A, Lanfranconi S, Latini R. Patient-reported outcome measures in patients with familial cerebral cavernous malformations: results from the Treat_CCM trial. Front Neurol. 2024 Feb 14;15:1338941. doi: 10.3389/fneur.2024.1338941. eCollection 2024.

Reference Type: DERIVED

PMID: 38419711 (View on PubMed)

Lanfranconi S, Scola E, Meessen JMTA, Pallini R, Bertani GA, Al-Shahi Salman R, Dejana E, Latini R; Treat_CCM Investigators. Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial. Lancet Neurol. 2023 Jan;22(1):35-44. doi: 10.1016/S1474-4422(22)00409-4. Epub 2022 Nov 17.

Reference Type: DERIVED

PMID: 36403580 (View on PubMed)

Lanfranconi S, Scola E, Bertani GA, Zarino B, Pallini R, d'Alessandris G, Mazzon E, Marino S, Carriero MR, Scelzo E, Farago G, Castori M, Fusco C, Petracca A, d'Agruma L, Tassi L, d'Orio P, Lampugnani MG, Nicolis EB, Vasami A, Novelli D, Torri V, Meessen JMTA, Al-Shahi Salman R, Dejana E, Latini R; Treat-CCM Investigators. Propranolol for familial cerebral cavernous malformation (Treat_CCM): study protocol for a randomized controlled pilot trial. Trials. 2020 May 12;21(1):401. doi: 10.1186/s13063-020-4202-x.

Reference Type: DERIVED

PMID: 32398113 (View on PubMed)

Other Identifiers

2017-003595-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

IRFMN-7358

Identifier Type: -

Identifier Source: org_study_id