Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation

NCT03589014 | Completed Phase 2 DMC

• 2 other identifiers: IRFMN-73582017-003595-30
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 6

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.

Conditions

Cerebral Cavernous Malformation

Keywords

Cerebral Cavernous Malformation; Propranolol; Magnetic Resonance Imaging

Outcome Measures

Primary Outcomes (1)

• Adverse clinical events CCM-related.

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

  up to 24 months

Secondary Outcomes (7)

• De novo CCM lesions depiction on MRI.

  up to 24 months

• Adverse clinical outcomes, other than ICH and FND.

  up to 24 months

• Location and MRI signal characteristics of CCM lesions at MRI.

  up to 24 months

• Diameter of CCM lesions at MRI.

  up to 24 months

• Length of CCM lesions at MRI

  up to 24 months

Study Arms (2)

Control

NO INTERVENTION

Standard Treatments recommended for CCM

Propranolol

EXPERIMENTAL

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

Interventions

Propranolol 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.

Also known as: Inderal

Propranolol

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research: lead
• IFOM ETS - The AIRC Institute of Molecular Oncology: collaborator

Study Sites (6)

IRCCS Casa Sollievo della Sofferenza

San Giovanni Rotondo, FG, 71013, Italy

Location

IRCCS Centro Neurolesi "Bonino Pulejo"

Messina, ME, 98124, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Mi, 20122, Italy

Location

Fond. IRCCS Ist. Naz. Neurologico Carlo Besta

Milan, MI, 20133, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, MI, 20162, Italy

Location

Fondazione Policlinico Universitario "A. Gemelli"

Roma, RM, 00168, Italy

Location

Related Publications (11)

• 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.

  PMID: 28212190 BACKGROUND

• 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.

  PMID: 26839352 BACKGROUND

• 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.

  PMID: 26612856 BACKGROUND

• 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.

  PMID: 26417067 BACKGROUND

• 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.

  PMID: 23748444 BACKGROUND

• 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.

  PMID: 21859843 BACKGROUND

• 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.

  PMID: 26109568 BACKGROUND

• 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.

  PMID: 19093037 BACKGROUND

• 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.

  PMID: 38419711 DERIVED

• 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.

  PMID: 36403580 DERIVED

• 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.

  PMID: 32398113 DERIVED

MeSH Terms

Conditions

Hemangioma, Cavernous, Central Nervous System

Interventions

Propranolol

Condition Hierarchy (Ancestors)

Hemangioma, Cavernous; Hemangioma; Neoplasms, Vascular Tissue; Neoplasms by Histologic Type; Neoplasms; Cavernous Sinus Syndromes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Central Nervous System Vascular Malformations; Nervous System Malformations; Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Hemostatic Disorders; Vascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Study Officials

• Elisabetta Dejana, Professor

  IFOM ETS - The AIRC Institute of Molecular Oncology

  STUDY CHAIR

• Roberto Latini

  Istituto Di Ricerche Farmacologiche Mario Negri

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 17, 2018
• First Posted: July 17, 2018
• Study Start: April 11, 2018
• Primary Completion: October 31, 2021
• Study Completion: December 31, 2021
• Last Updated: February 25, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: By Dec 31st 2021 IPD will be made available.
• Access Criteria: 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.

Locations

IT (6)