Cerebral Cavernous MalformationPhase 2Treat_CCMNCT03589014
Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation
A Phase 2 study testing Propranolol in people with Cerebral Cavernous Malformation, run by Mario Negri Institute for Pharmacological Research at 6 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cerebral Cavernous Malformation
- What is being tested?
- Propranolol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 71 participants
- Where
- 6 sitesItaly
- Study dates
- 11 Apr 2018to 31 Dec 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
Show all 11Show fewer
- 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.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
Italy6 sites
IRCCS Centro Neurolesi "Bonino Pulejo"
Messina, ME, 98124
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan, Mi, 20122
Fond. IRCCS Ist. Naz. Neurologico Carlo Besta
Milan, MI, 20133
ASST Grande Ospedale Metropolitano Niguarda
Milan, MI, 20162
Fondazione Policlinico Universitario "A. Gemelli"
Roma, RM, 00168
IRCCS Casa Sollievo della Sofferenza
San Giovanni Rotondo, FG, 71013
About this study
Official title: 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.
Read the 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
- Being tested
- Propranolol
- Keywords
- Cerebral Cavernous Malformation, Propranolol, Magnetic Resonance Imaging
- Medical subject headings
- Hemangioma, Cavernous, Central Nervous System
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PropranololDrug
Also called Inderal
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Propranolol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: up to 24 months
Secondary outcomes (7)
De novo CCM lesions depiction on MRI.
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.
Measured: up to 24 months
Adverse clinical outcomes, other than ICH and FND.
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.).
Measured: up to 24 months
Location and MRI signal characteristics of CCM lesions at MRI.
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
Measured: up to 24 months
Diameter of CCM lesions at MRI.
Diameter will be assessed in millimeters.
Measured: up to 24 months
Length of CCM lesions at MRI
Length will be assessed in millimeters.
Measured: up to 24 months
Micro-hemorrhages at MRI.
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.
Measured: up to 24 months
Dynamic contrast enhanced permeability (DCEP) at MRI.
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.
Measured: up to 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jul 2018
- Study start11 Apr 2018
- Primary completion31 Oct 2021
- Study completion31 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Cerebral Cavernous MalformationStudies of the same condition, open and under way.
- More trials run by Mario Negri Institute for Pharmacological ResearchThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 71 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Collaborators
- IFOM ETS - The AIRC Institute of Molecular Oncology
- Responsible party
- Sponsor
- Investigators
- Elisabetta Dejana, Professor, Study chair, IFOM ETS - The AIRC Institute of Molecular OncologyRoberto Latini, Study director, Istituto Di Ricerche Farmacologiche Mario Negri
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03589014
- Sponsor's protocol ID
- IRFMN-7358
- Other IDs
- 2017-003595-30, 2017
- Acronym
- Treat_CCM
- Status last verified
- Feb 2022
- First submitted
- 17 May 2018
- Last updated
- 25 Feb 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
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.
PubMed 28212190Bravi 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.
PubMed 26839352Cuttano 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.
PubMed 26612856Marchi 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.
PubMed 26417067Maddaluno 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.
PubMed 23748444Boulday 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.
PubMed 21859843Bravi 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.
PubMed 26109568Gore 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.
PubMed 19093037Yan C, Ye Y, Liu N, Zhang D, Du W, Li Y, Li G, Li C, Li J, Ma S, Dai Z, Xiong Z, Wang Y, Men C, Bi R, Duan Q, Xu W, Husilengtu, Cao Y, Du J, Shi C. Metformin limits cerebral cavernous malformation development by targeting KLF4-mediated mitochondrial damage. Biochem Biophys Res Commun. 2025 Sep 1;777:152241. doi: 10.1016/j.bbrc.2025.152241. Epub 2025 Jun 24.
PubMed 40570636Meessen 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.
PubMed 38419711Lanfranconi 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.
PubMed 36403580Lanfranconi 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.
PubMed 32398113
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treat_CCM Clinical Trial A Multicenter Randomized Clinical Trial on Propranolol in Familial Cerebral Cavernous Malformation
- ClinicalTrials.gov ID
- NCT03589014
- Acronym / sponsor ID
- Treat_CCM / IRFMN-7358
- Conditions
- Cerebral Cavernous Malformation
- Keywords
- Cerebral Cavernous Malformation, Propranolol, Magnetic Resonance Imaging
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 71 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Collaborators
- IFOM ETS - The AIRC Institute of Molecular Oncology
- Study start
- 11 Apr 2018 (actual)
- Primary completion
- 31 Oct 2021 (actual)
- Study completion
- 31 Dec 2021 (actual)
- First posted
- 17 Jul 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control | No intervention | –Standard Treatments recommended for CCM |
| Propranolol | Experimental | Drug: PropranololInitial 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (11 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PropranololAlso: InderalPatients 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. | Drug | Propranolol |
Primary outcome
Adverse clinical events CCM-related.
Time frame: up to 24 months
New occurrence of clinical events CCM-related, that is intra-cerebral hemorrhage (ICH) and focal neurological deficits (FND) excluding seizures.
7 secondary outcomes
De novo CCM lesions depiction on MRI.
Time frame: up to 24 months
Adverse clinical outcomes, other than ICH and FND.
Time frame: up to 24 months
Location and MRI signal characteristics of CCM lesions at MRI.
Time frame: up to 24 months
Diameter of CCM lesions at MRI.
Time frame: up to 24 months
Length of CCM lesions at MRI
Time frame: up to 24 months
Micro-hemorrhages at MRI.
Time frame: up to 24 months
Dynamic contrast enhanced permeability (DCEP) at MRI.
Time frame: up to 24 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2022.
- Background: PubMed 28212190Lampugnani 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.
- Background: PubMed 26839352Bravi 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.
- Background: PubMed 26612856Cuttano 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.
- Background: PubMed 26417067Marchi 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.
- Background: PubMed 23748444Maddaluno 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.
- Background: PubMed 21859843Boulday 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.
- Background: PubMed 26109568Bravi 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.
- Background: PubMed 19093037Gore 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.
- Derived from this study: PubMed 40570636Yan C, Ye Y, Liu N, Zhang D, Du W, Li Y, Li G, Li C, Li J, Ma S, Dai Z, Xiong Z, Wang Y, Men C, Bi R, Duan Q, Xu W, Husilengtu, Cao Y, Du J, Shi C. Metformin limits cerebral cavernous malformation development by targeting KLF4-mediated mitochondrial damage. Biochem Biophys Res Commun. 2025 Sep 1;777:152241. doi: 10.1016/j.bbrc.2025.152241. Epub 2025 Jun 24.
- Derived from this study: PubMed 38419711Meessen 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.
- Derived from this study: PubMed 36403580Lanfranconi 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.
- Derived from this study: PubMed 32398113Lanfranconi 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.
- Individual participant dataSharing planned: Yes. 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.
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Cerebral Cavernous Malformation
Not yet recruiting
Biological Collection of the Rare Diseases of the Brain and Eye Vessels Cohort - 2
CADASIL, Cavernous Angioma
Active, not recruitingObservational study
Biomarkers of CASH
Cerebral Cavernous Malformation, Cavernous Angioma
RecruitingObservational study
Study on Treatment Decision-Making and Prognostic Follow-Up for Untreated Cerebral Cavernous Malformations
Hemangioma, Cavernous, Central Nervous System
Not yet recruitingEarly Phase 1
Daratumumab for Familial Cerebral Cavernous Malformations: A Single-Arm Safety and Efficacy Study
Cavernous Malformation, Cerebral
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Elisabetta Dejana, Professor study chair
IFOM ETS - The AIRC Institute of Molecular Oncology
Roberto Latini study director
Istituto Di Ricerche Farmacologiche Mario Negri
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Propranolol in people with Cerebral Cavernous Malformation, run by Mario Negri Institute for Pharmacological Research at 6 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Adverse clinical events CCM-related. (time frame: up to 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03589014, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Feb 2022.