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

Completed

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

Interventional

Enrollment (Actual)

71

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • FG
      • San Giovanni Rotondo, FG, Italy, 71013
        • IRCCS Casa Sollievo della Sofferenza
    • ME
      • Messina, ME, Italy, 98124
        • IRCCS Centro Neurolesi "Bonino Pulejo"
    • MI
      • Milano, MI, Italy, 20162
        • ASST Grande Ospedale Metropolitano Niguarda
      • Milano, MI, Italy, 20133
        • Fond. IRCCS Ist. Naz. Neurologico Carlo Besta
    • Mi
      • Milano, Mi, Italy, 20122
        • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
    • RM
      • Roma, RM, Italy, 00168
        • Fondazione Policlinico Universitario "A. Gemelli"

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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
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.
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:
  • Inderal

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
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
De novo CCM lesions depiction on MRI.
Time Frame: up to 24 months
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.
up to 24 months
Adverse clinical outcomes, other than ICH and FND.
Time Frame: up to 24 months
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.).
up to 24 months
Location and MRI signal characteristics of CCM lesions at MRI.
Time Frame: up to 24 months
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
up to 24 months
Diameter of CCM lesions at MRI.
Time Frame: up to 24 months
Diameter will be assessed in millimeters.
up to 24 months
Length of CCM lesions at MRI
Time Frame: up to 24 months
Length will be assessed in millimeters.
up to 24 months
Micro-hemorrhages at MRI.
Time Frame: up to 24 months
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.
up to 24 months
Dynamic contrast enhanced permeability (DCEP) at MRI.
Time Frame: up to 24 months
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.
up to 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

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

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 11, 2018

Primary Completion (Actual)

October 31, 2021

Study Completion (Actual)

December 31, 2021

Study Registration Dates

First Submitted

May 17, 2018

First Submitted That Met QC Criteria

July 16, 2018

First Posted (Actual)

July 17, 2018

Study Record Updates

Last Update Posted (Actual)

February 25, 2022

Last Update Submitted That Met QC Criteria

February 24, 2022

Last Verified

February 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

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

By Dec 31st 2021 IPD will be made available.

IPD Sharing 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.

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

No

Studies a U.S. FDA-regulated device product

No

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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