- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03589014
Treat_CCM: Propranolol in Familial Cerebral Cavernous Malformation (Treat_CCM)
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.
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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FG
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San Giovanni Rotondo, FG, Italy, 71013
- IRCCS Casa Sollievo della Sofferenza
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ME
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Messina, ME, Italy, 98124
- IRCCS Centro Neurolesi "Bonino Pulejo"
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MI
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Milano, MI, Italy, 20162
- ASST Grande Ospedale Metropolitano Niguarda
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Milano, MI, Italy, 20133
- Fond. IRCCS Ist. Naz. Neurologico Carlo Besta
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Mi
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Milano, Mi, Italy, 20122
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
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RM
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Roma, RM, Italy, 00168
- Fondazione Policlinico Universitario "A. Gemelli"
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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No Intervention: Control
Standard Treatments recommended for CCM
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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.
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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.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Adverse clinical events CCM-related.
Time Frame: up to 24 months
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New occurrence of clinical events CCM-related, that is intra-cerebral hemorrhage (ICH) and focal neurological deficits (FND) excluding seizures.
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up to 24 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
De novo CCM lesions depiction on MRI.
Time Frame: up to 24 months
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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.
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up to 24 months
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Adverse clinical outcomes, other than ICH and FND.
Time Frame: up to 24 months
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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.).
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up to 24 months
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Location and MRI signal characteristics of CCM lesions at MRI.
Time Frame: up to 24 months
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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
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up to 24 months
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Diameter of CCM lesions at MRI.
Time Frame: up to 24 months
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Diameter will be assessed in millimeters.
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up to 24 months
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Length of CCM lesions at MRI
Time Frame: up to 24 months
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Length will be assessed in millimeters.
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up to 24 months
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Micro-hemorrhages at MRI.
Time Frame: up to 24 months
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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.
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up to 24 months
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Dynamic contrast enhanced permeability (DCEP) at MRI.
Time Frame: up to 24 months
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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.
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up to 24 months
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Collaborators and Investigators
Collaborators
Investigators
- Study Chair: Elisabetta Dejana, Professor, IFOM, The FIRC Institute of Molecular Oncology
- Study Director: Roberto Latini, Istituto Di Ricerche Farmacologiche Mario Negri
Publications and helpful links
General 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Hematologic Diseases
- Hemorrhagic Disorders
- Hemostatic Disorders
- Cardiovascular Abnormalities
- Hemangioma
- Neoplasms, Vascular Tissue
- Nervous System Malformations
- Vascular Malformations
- Central Nervous System Vascular Malformations
- Hemangioma, Cavernous
- Congenital Abnormalities
- Hemangioma, Cavernous, Central Nervous System
- Physiological Effects of Drugs
- Adrenergic beta-Antagonists
- Adrenergic Antagonists
- Adrenergic Agents
- Neurotransmitter Agents
- Molecular Mechanisms of Pharmacological Action
- Anti-Arrhythmia Agents
- Antihypertensive Agents
- Vasodilator Agents
- Propranolol
Other Study ID Numbers
- IRFMN-7358
- 2017-003595-30 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
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.
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- Study Protocol
- Statistical Analysis Plan (SAP)
- Informed Consent Form (ICF)
- Clinical Study Report (CSR)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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