Modifiers of Disease Severity in Cerebral Cavernous Malformations

Study Overview
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Brief Summary
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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 Identify blood biomarkers predictive of CCM disease severity and progression for clinical trials.

Detailed Description
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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: Clinical diagnosis of CCM, Multi-focal lesions on MRI, and/or Family history of CCMs. Exclusion Criteria: Patients who cannot or are unwilling to sign informed consent and for whom no appropriate surrogate is available. Prisoners and homeless individuals because of the inability to contact the subject and collect follow-up data using standard procedures.

Official Title
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Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformations

Conditions
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Cavernous Angioma, Familial, Cerebral Cavernous Malformations, Cerebral Cavernous Hemangioma

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individual has a CCM mutation confirmed through DNA testing, or Individual meets 2 or more of the following clinical criteria: Clinical diagnosis of CCM Multi-focal CCMs on MRI Family history of CCM Exclusion Criteria: Individuals who are incarcerated Individuals who are homeless Unable or unwilling to sign the informed consent
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| The BVMC FCCM cohort<br>Aim 1: To investigate the relationship between lesion burden and outcomes in familial CCM. Aim 2: To investigate the role of the gut microbiome in familial CCM disease severity. Aim 3: To establish blood markers predictive of disease severity and progression for medical treatment of CCM. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total CCM lesion number per patient | 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. | Baseline | 
| Rate of symptomatic hemorrhage | 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 hemorrhage rates will be assessed. | Baseline and annual assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in lesion number | 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. | Baseline, Follow up MRI | 
| Modified Rankin score | The modified Rankin score will be assessed at baseline and at approximately one year intervals while remaining in study | Baseline and annual assessment |