Modifiers of Disease Severity in Cerebral Cavernous Malformations

Cerebral Cavernous Malformations Clinical Trial

Official title:

Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformations

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01764529
• Other study ID #: BVMC 6201
• Secondary ID: U54NS065705
• Status: Recruiting
• Start date: April 27, 2010
• Est. completion date: June 2025

Study information

• Verified date: December 2023
• Source: University of California, San Francisco
• Contact: Helen Kim, PhD
• Phone: 415-476-2677
• Email: helen.kim2[@]ucsf.edu
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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 - Identify blood biomarkers predictive of CCM disease severity and progression for clinical trials.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 800
• Est. completion date: June 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Cavernous Angioma, Familial
• Cerebral Cavernous Hemangioma
• Cerebral Cavernous Malformations
• Congenital Abnormalities
• Hemangioma

Locations

Country	Name	City	State
United States	University of New Mexico Health Sciences Center	Albuquerque	New Mexico
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Alliance to Cure Cavernous Malformation	Charlottesville	Virginia
United States	University of Chicago, Medicine and Biological Sciences	Chicago	Illinois
United States	Cincinnati Children's Hospital, Division of Pediatric Neurosurgery, Cerebrovascular Program	Cincinnati	Ohio
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	University of California, San Francisco	San Francisco	California

Sponsors (8)

Lead Sponsor	Collaborator
University of California, San Francisco	Alliance to Cure Cavernous Malformation, Barrow Neurological Institute, Boston Children's Hospital, Children's Hospital Medical Center, Cincinnati, National Institute of Neurological Disorders and Stroke (NINDS), University of Chicago, University of New Mexico

Country where clinical trial is conducted

United States, 

References & Publications (28)

Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B, Kim H, Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E, Waggoner D, Whitehead K. Synopsis of Guidelines for the Clinical Management of Cerebral — View Citation

Akers AL, Ball KL, Clancy M, Comi AM, Faughnan ME, Gopal-Srivastava R, Jacobs TP, Kim H, Krischer J, Marchuk DA, McCulloch CE, Morrison L, Moses M, Moy CS, Pawlikowska L, Young WL. Brain Vascular Malformation Consortium: Overview, Progress and Future Directions. J Rare Disord. 2013 Apr 1;1(1):5. — View Citation

Campbell R, Petranovich CL, Cheek S, Morrison L, Hart B. Subjective Cognitive Concerns and Attitudes toward Genetic Testing Are Associated with Depressive Symptoms and Quality of Life after Genetic Testing for the Cerebral Cavernous Malformation Common Hi — View Citation

Choksi F, Weinsheimer S, Nelson J, Pawlikowska L, Fox CK, Zafar A, Mabray MC, Zabramski J, Akers A, Hart BL, Morrison L, McCulloch CE, Kim H. Assessing the association of common genetic variants in EPHB4 and RASA1 with phenotype severity in familial cereb — View Citation

Choquet H, Nelson J, Pawlikowska L, McCulloch CE, Akers A, Baca B, Khan Y, Hart B, Morrison L, Kim H. Association of cardiovascular risk factors with disease severity in cerebral cavernous malformation type 1 subjects with the common Hispanic mutation. Ce — View Citation

Choquet H, Pawlikowska L, Lawton MT, Kim H. Genetics of cerebral cavernous malformations: current status and future prospects. J Neurosurg Sci. 2015 Sep;59(3):211-20. Epub 2015 Apr 22. — View Citation

Choquet H, Pawlikowska L, Nelson J, McCulloch CE, Akers A, Baca B, Khan Y, Hart B, Morrison L, Kim H; Brain Vascular Malformation Consortium (BVMC) Study. Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformat — View Citation

Choquet H, Trapani E, Goitre L, Trabalzini L, Akers A, Fontanella M, Hart BL, Morrison LA, Pawlikowska L, Kim H, Retta SF. Cytochrome P450 and matrix metalloproteinase genetic modifiers of disease severity in Cerebral Cavernous Malformation type 1. Free R — View Citation

Flemming KD, Smith E, Marchuk D, Derry WB. Familial Cerebral Cavernous Malformations. 2003 Feb 24 [updated 2023 Jul 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1293/ — View Citation

Fox CK, Nelson J, McCulloch CE, Weinsheimer S, Pawlikowska L, Hart B, Mabray M, Zafar A, Morrison L, Zabramski JM, Akers A, Kim H. Seizure Incidence Rates in Children and Adults With Familial Cerebral Cavernous Malformations. Neurology. 2021 Aug 13;97(12) — View Citation

Golden M, Saeidi S, Liem B, Marchand E, Morrison L, Hart B. Sensitivity of patients with familial cerebral cavernous malformations to therapeutic radiation. J Med Imaging Radiat Oncol. 2015 Feb;59(1):134-6. doi: 10.1111/1754-9485.12269. Epub 2015 Jan 7. — View Citation

Golden MJ, Morrison LA, Kim H, Hart BL. Increased number of white matter lesions in patients with familial cerebral cavernous malformations. AJNR Am J Neuroradiol. 2015 May;36(5):899-903. doi: 10.3174/ajnr.A4200. Epub 2015 Jan 2. — View Citation

Hart BL, Mabray MC, Morrison L, Whitehead KJ, Kim H. Systemic and CNS manifestations of inherited cerebrovascular malformations. Clin Imaging. 2021 Jul;75:55-66. doi: 10.1016/j.clinimag.2021.01.020. Epub 2021 Jan 20. — View Citation

Hart BL, Taheri S, Rosenberg GA, Morrison LA. Dynamic contrast-enhanced MRI evaluation of cerebral cavernous malformations. Transl Stroke Res. 2013 Oct;4(5):500-6. doi: 10.1007/s12975-013-0285-y. Epub 2013 Sep 21. — View Citation

Mabray MC, Caprihan A, Nelson J, McCulloch CE, Zafar A, Kim H, Hart BL, Morrison L. Effect of Simvastatin on Permeability in Cerebral Cavernous Malformation Type 1 Patients: Results from a Pilot Small Randomized Controlled Clinical Trial. Transl Stroke Re — View Citation

Mabray MC, Starcevich J, Hallstrom J, Robinson M, Bartlett M, Nelson J, Zafar A, Kim H, Morrison L, Hart BL. High Prevalence of Spinal Cord Cavernous Malformations in the Familial Cerebral Cavernous Malformations Type 1 Cohort. AJNR Am J Neuroradiol. 2020 — View Citation

Manole AK, Forrester VJ, Zlotoff BJ, Hart BL, Morrison LA. Cutaneous findings of familial cerebral cavernous malformation syndrome due to the common Hispanic mutation. Am J Med Genet A. 2020 May;182(5):1066-1072. doi: 10.1002/ajmg.a.61519. Epub 2020 Feb 2 — View Citation

Morrison MA, Payabvash S, Chen Y, Avadiappan S, Shah M, Zou X, Hess CP, Lupo JM. A user-guided tool for semi-automated cerebral microbleed detection and volume segmentation: Evaluating vascular injury and data labelling for machine learning. Neuroimage Cl — View Citation

Petersen TA, Morrison LA, Schrader RM, Hart BL. Familial versus sporadic cavernous malformations: differences in developmental venous anomaly association and lesion phenotype. AJNR Am J Neuroradiol. 2010 Feb;31(2):377-82. doi: 10.3174/ajnr.A1822. Epub 200 — View Citation

Polster SP, Sharma A, Tanes C, Tang AT, Mericko P, Cao Y, Carrion-Penagos J, Girard R, Koskimaki J, Zhang D, Stadnik A, Romanos SG, Lyne SB, Shenkar R, Yan K, Lee C, Akers A, Morrison L, Robinson M, Zafar A, Bittinger K, Kim H, Gilbert JA, Kahn ML, Shen L — View Citation

Strickland CD, Eberhardt SC, Bartlett MR, Nelson J, Kim H, Morrison LA, Hart BL. Familial Cerebral Cavernous Malformations Are Associated with Adrenal Calcifications on CT Scans: An Imaging Biomarker for a Hereditary Cerebrovascular Condition. Radiology. — View Citation

Tandberg SR, Bocklage T, Bartlett MR, Morrison LA, Nelson J, Hart BL. Vertebral Intraosseous Vascular Malformations in a Familial Cerebral Cavernous Malformation Population: Prevalence, Histologic Features, and Associations With CNS Disease. AJR Am J Roen — View Citation

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Vosa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morris — View Citation

Tang AT, Sullivan KR, Hong CC, Goddard LM, Mahadevan A, Ren A, Pardo H, Peiper A, Griffin E, Tanes C, Mattei LM, Yang J, Li L, Mericko-Ishizuka P, Shen L, Hobson N, Girard R, Lightle R, Moore T, Shenkar R, Polster SP, Rodel CJ, Li N, Zhu Q, Whitehead KJ, — View Citation

Weinsheimer S, Nelson J, Abla AA, Ko NU, Tsang C, Okoye O, Zabramski JM, Akers A, Zafar A, Mabray MC, Hart BL, Morrison L, McCulloch CE, Kim H; Brain Vascular Malformation Consortium Cerebral Cavernous Malformation Investigator Group *. Intracranial Hemor — View Citation

Wetzel-Strong SE, Weinsheimer S, Nelson J, Pawlikowska L, Clark D, Starr MD, Liu Y, Kim H, Faughnan ME, Nixon AB, Marchuk DA. Pilot investigation of circulating angiogenic and inflammatory biomarkers associated with vascular malformations. Orphanet J Rare — View Citation

Zafar A, Quadri SA, Farooqui M, Ikram A, Robinson M, Hart BL, Mabray MC, Vigil C, Tang AT, Kahn ML, Yonas H, Lawton MT, Kim H, Morrison L. Familial Cerebral Cavernous Malformations. Stroke. 2019 May;50(5):1294-1301. doi: 10.1161/STROKEAHA.118.022314. No abstract available. — View Citation

Zou X, Hart BL, Mabray M, Bartlett MR, Bian W, Nelson J, Morrison LA, McCulloch CE, Hess CP, Lupo JM, Kim H. Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations. Neuroradiology. 2017 Jul;59(7):685-690. d — View Citation

* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patient-Reported Quality of Life (QoL) (NIH PROMIS-29)	Standardized patient reported outcome measurement tools to assess pain, fatigue, physical function, emotional distress, and social participation.	Baseline and annual assessment
Primary	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
Primary	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	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
Secondary	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

External Links

•   Angioma Alliance is an organization by and for those affected by cavernous angiomas and their loved ones, health professionals, and researchers.