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Modifiers of Disease Severity in Cerebral Cavernous Malformations

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ClinicalTrials.gov Identifier: NCT01764529
Recruitment Status : Recruiting
First Posted : January 9, 2013
Last Update Posted : December 12, 2019
Sponsor:
Collaborators:
University of New Mexico
University of Chicago
National Institute of Neurological Disorders and Stroke (NINDS)
Boston Children’s Hospital
Children's Hospital Medical Center, Cincinnati
Barrow Neurological Institute
Angioma Alliance
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:

Cerebral cavernous malformations (CCMs) are clusters of abnormal blood vessels in the brain and spine. CCMs can bleed and cause strokes, seizures, and headaches. CCMs are often caused by an inherited gene mutation (alteration) in one of three CCM genes (CCM1, CCM2, or CCM3). There is a wide range of disease severity even among family members with this disease, though the natural history has not been clearly described for this particular population.

This study will continue to enroll and follow participants with familial CCM to identify factors that influence CCM disease severity and progression, focusing on barriers to clinical trial preparedness. Our long-term goal is to identify measurable outcomes and robust biomarkers that will help select high-risk patients and help monitor drug response in future clinical trials. The specific goals of this study are to:

identify factors that influence lesion progression to symptomatic hemorrhage and other outcomes, including quality of life; investigate the role of the gut microbiome and lesion burden in CCM disease, and establish blood biomarkers predictive of CCM disease severity and progression for clinical trials.


Condition or disease
Cavernous Angioma, Familial Cerebral Cavernous Malformations Cerebral Cavernous Hemangioma

Detailed Description:

This study is one of three projects participating in the Brain Vascular Malformation Consortium (BVMC) funded by the Office of Rare Diseases Research, which is part of the National Center for Advancing Translational Sciences (NCATS), and the National Institute of Neurological Disorders and Stroke (NINDS).

The CCM project is a cross-sectional and longitudinal study of familial CCM patients. The study is currently in the third 5-year cycle. During the first 5 year cycle (BVMC1), the CCM project was focused on recruiting CCM1 cases with the common Hispanic mutation (CHM). In the second 5-year cycle (BVMC2), we expanded recruitment to include not only CCM1-CHM cases, but also other CCM familial patients and mutation carriers. In the third 5-year cycle (BVMC3), we will continue to recruit familial CCM cases and expand to additional recruitment sites.

We collect clinical, genetic, imaging, treatment, and outcome data in participants, and follow enrolled participants over time to understand the natural history of this disease.

For new study participants, you will be asked to:

Give permission for study staff to access your medical records to collect clinical information and to obtain copies of MRI scans and reports.

Fill out a questionnaire about your quality of life, family history, and medical/surgical history.

Give a blood and/or saliva sample, and stool sample.

Give permission to store and use your CCM resected tissue for research (if undergoing surgery).

Participate in annual follow-ups to update medical, surgical, and neurological information.

Eligible cases include those with a known genetic mutation in one of the three CCM genes or those that meet 2 of 3 following clinical criteria:

  1. Clinical diagnosis of CCM,
  2. Multi-focal lesions on MRI, and/or
  3. Family history of CCMs.

Exclusion Criteria:

  1. Patients who cannot or are unwilling to sign informed consent and for whom no appropriate surrogate is available.
  2. Prisoners and homeless individuals because of the inability to contact the subject and collect follow-up data using standard procedures.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 800 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 15 Years
Official Title: Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformations
Actual Study Start Date : July 2009
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024


Group/Cohort
The BVMC FCCM cohort

Aim 1: To investigate the relationship between lesion burden and outcomes in FCCM.

Aim 2: To investigate the role of the gut microbiome in FCCM disease severity. Aim 3: To establish blood markers predictive of disease severity and progression for medical treatment of CCM.




Primary Outcome Measures :
  1. Total CCM lesion number per patient [ Time Frame: Baseline ]
    The number of lesions (or cavernous angiomas) located in the brain will be counted by a neuroradiologist and by an automated algorithm developed as part of this project.

  2. Rate of symptomatic hemorrhage [ Time Frame: Baseline and annual assessment ]
    Symptomatic hemorrhage is defined as diagnostic evidence of new lesional bleeding or hemorrhagic growth, in association with directly attributable symptoms. Rate of symptomatic hemorrhage and the factors that influence hemorhrage rates will be assessed.


Secondary Outcome Measures :
  1. Change in lesion number [ Time Frame: Baseline, Follow up MRI ]
    The number of lesions (or cavernous angiomas) counted on the baseline MRI will be compared to the number of lesions observed in follow up MRIs.

  2. Modified Rankin score [ Time Frame: Baseline and annual assessment ]
    The modified Rankin score will be assessed at baseline and at approximately one year intervals while remaining in study


Other Outcome Measures:
  1. Patient-Reported Quality of Life (QoL) (The NIH PROMIS-29) [ Time Frame: Baseline and annual assessment ]
    Standardized patient reported outcome measurement tools to assess pain, fatigue, physical function, emotional distress, and social participation.


Biospecimen Retention:   Samples With DNA
We will collect stool specimens in newly recruited FCCM cases. We store saliva as well as whole blood for DNA, RNA, and plasma or serum samples. Brain cavernous malformation tissue will be collected and banked as available.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The study population includes individuals who carry the diagnosis of familial cerebral cavernous malformation (CCM), both symptomatic and asymptomatic.
Criteria

Inclusion Criteria:

  • Individual has a CCM mutation confirmed through DNA testing, or
  • Individual meets 2 or more of the following clinical criteria:

    1. Clinical diagnosis of CCM
    2. Multi-focal CCMs on MRI
    3. Family history of CCM

Exclusion Criteria:

  1. Individuals who are incarcerated
  2. Individuals who are homeless
  3. Unable or unwilling to sign the informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01764529


Contacts
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Contact: Helen Kim, PhD 415-206-8906 helen.kim2@ucsf.edu
Contact: Andres Alvarez Pinzon, PhD, MD 415-476-2677 andres.alvarezpinzon@ucsf.edu

Locations
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United States, Arizona
Barrow Neurological Institute Recruiting
Phoenix, Arizona, United States, 85013
Contact: Norissa Honea    602-406-6267    Norissa.Honea@DignityHealth.org   
Sub-Investigator: Joseph Zabramski, MD         
Principal Investigator: Michael T. Lawton, MD         
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Avery Lui    415-476-2680    avery.lui@ucsf.edu   
Contact: Helen Kim, PhD    415-206-8906    helen.kim2@ucsf.edu   
Principal Investigator: Helen Kim, PhD         
United States, Illinois
University of Chicago, Medicine and Biological Sciences Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Issam Awad, MD    773-702-8996    iawad@surgery.bsd.uchicago.edu   
Contact: Agnieszka Stadnik, MS, CCRP    (773) 702-8996    astadnik@surgery.bsd.uchicago.edu   
Principal Investigator: Issam Awad, MD         
United States, Massachusetts
Boston Children's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Tina Mounlavongsy, MPH, CDA    617-355-8310    tina.mounlavongsy@childrens.harvard.edu   
Principal Investigator: Edward R. Smith, MD         
United States, New Mexico
University of New Mexico Health Sciences Center Recruiting
Albuquerque, New Mexico, United States, 87131
Contact: Atif Zafar, MD    505-272-3194    azafar@salud.unm.edu   
Contact: Richard Torres    505 272-3194    riatorres@salud.unm.edu   
Principal Investigator: Atif Zafar, MD         
Sub-Investigator: Marc Mabray, MD         
United States, North Carolina
Angioma Alliance Enrolling by invitation
Durham, North Carolina, United States, 27713
United States, Ohio
Cincinnati Children's Hospital, Division of Pediatric Neurosurgery, Cerebrovascular Program Not yet recruiting
Cincinnati, Ohio, United States, 45229
Contact: Ashton Roach, MS    513-803-7621    Ashton.Roach@cchmc.org   
Contact: Sudhakar Vadivelu, DO    513-803-7621    Sudhakar.Vadivelu@cchmc.org   
Principal Investigator: Sudhakar Vadivelu, DO         
Sponsors and Collaborators
University of California, San Francisco
University of New Mexico
University of Chicago
National Institute of Neurological Disorders and Stroke (NINDS)
Boston Children’s Hospital
Children's Hospital Medical Center, Cincinnati
Barrow Neurological Institute
Angioma Alliance
Investigators
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Principal Investigator: Helen Kim, PhD University of California, San Francisco
Principal Investigator: Atif Zafar, MD University of New Mexico
Principal Investigator: Issam Awad, MD University of Chicago
Additional Information:
Publications:

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT01764529    
Other Study ID Numbers: BVMC 6201
U54NS065705 ( U.S. NIH Grant/Contract )
First Posted: January 9, 2013    Key Record Dates
Last Update Posted: December 12, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Available data will be released to the Rare Diseases Clinical Research Network repository and will become available to the scientific community one year after publication of planned analyses, or after a period of 5 years from the date when the data were collected, whichever comes first

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemangioma
Hemangioma, Cavernous, Central Nervous System
Hemangioma, Cavernous
Congenital Abnormalities
Neoplasms, Vascular Tissue
Neoplasms by Histologic Type
Neoplasms
Central Nervous System Vascular Malformations
Nervous System Malformations
Nervous System Diseases
Vascular Malformations
Cardiovascular Abnormalities
Cardiovascular Diseases
Hemostatic Disorders
Vascular Diseases
Hemorrhagic Disorders
Hematologic Diseases