Modifiers of Disease Severity in Cerebral Cavernous Malformations

NCT01764529 | Active Not Recruiting

• 2 other identifiers: BVMC 6201U54NS065705-15
• Study Type: observational
• Target: 800
• Locations: 1 country
• Sites: 7

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
• Identify blood biomarkers predictive of CCM disease severity and progression for clinical trials.

Conditions

Cavernous Angioma, Familial; Cerebral Cavernous Malformations; Cerebral Cavernous Hemangioma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Change in lesion number

  Baseline, Follow up MRI

• Modified Rankin score

  Baseline and annual assessment

Other Outcomes (1)

• Patient-Reported Quality of Life (QoL) (NIH PROMIS-29)

  Baseline and annual assessment

Study Arms (1)

The BVMC FCCM cohort

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.

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• Individuals who are incarcerated
• Individuals who are homeless
• Unable or unwilling to sign the informed consent

Sponsors & Collaborators

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

Study Sites (7)

Barrow Neurological Institute

Phoenix, Arizona, 85013, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

University of Chicago, Medicine and Biological Sciences

Chicago, Illinois, 60637, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, 87131, United States

Location

Cincinnati Children's Hospital, Division of Pediatric Neurosurgery, Cerebrovascular Program

Cincinnati, Ohio, 45229, United States

Location

Alliance to Cure Cavernous Malformation

Charlottesville, Virginia, 22901, United States

Location

Related Publications (28)

• 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.

  PMID: 25221778 BACKGROUND

• Flemming KD, Smith E, Marchuk D, Derry WB. Familial Cerebral Cavernous Malformations. 2003 Feb 24 [updated 2023 Jul 27]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1293/

  PMID: 20301470 BACKGROUND

• 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.

  PMID: 25900426 BACKGROUND

• 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.

  PMID: 30909834 BACKGROUND

• 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.

  PMID: 33493737 BACKGROUND

• 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 malformation type 1 severity. Cerebrovasc Dis. 2014;38(6):433-40. doi: 10.1159/000369200. Epub 2014 Dec 3.

  PMID: 25472749 RESULT

• 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. Cerebrovasc Dis. 2014;37(1):57-63. doi: 10.1159/000356839. Epub 2013 Dec 21.

  PMID: 24401931 RESULT

• 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.

  PMID: 25565562 RESULT

• 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.

  PMID: 24323376 RESULT

• 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 2009 Oct 15.

  PMID: 19833796 RESULT

• 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 Radic Biol Med. 2016 Mar;92:100-109. doi: 10.1016/j.freeradbiomed.2016.01.008. Epub 2016 Jan 19.

  PMID: 26795600 RESULT

• 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.

  PMID: 25556204 RESULT

• 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. doi: 10.1007/s00234-017-1845-8. Epub 2017 May 22.

  PMID: 28534135 RESULT

• 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. 2017 Aug;284(2):443-450. doi: 10.1148/radiol.2017161127. Epub 2017 Mar 20.

  PMID: 28318403 RESULT

• 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 Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel. Neurosurgery. 2017 May 1;80(5):665-680. doi: 10.1093/neuros/nyx091.

  PMID: 28387823 RESULT

• 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, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 18;545(7654):305-310. doi: 10.1038/nature22075. Epub 2017 May 10.

  PMID: 28489816 RESULT

• 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 Clin. 2018 Aug 4;20:498-505. doi: 10.1016/j.nicl.2018.08.002. eCollection 2018.

  PMID: 30140608 RESULT

• 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 Res. 2020 Jun;11(3):319-321. doi: 10.1007/s12975-019-00737-4. Epub 2019 Oct 23. No abstract available.

  PMID: 31643041 RESULT

• 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, Zheng X, Akers A, Morrison L, Kim H, Bittinger K, Lengner CJ, Schwaninger M, Velcich A, Augenlicht L, Abdelilah-Seyfried S, Min W, Marchuk DA, Awad IA, Kahn ML. Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Sci Transl Med. 2019 Nov 27;11(520):eaaw3521. doi: 10.1126/scitranslmed.aaw3521.

  PMID: 31776290 RESULT

• 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 Roentgenol. 2020 Feb;214(2):428-436. doi: 10.2214/AJR.19.21492. Epub 2019 Dec 11.

  PMID: 31825263 RESULT

• 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 26.

  PMID: 32100472 RESULT

• 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 Hispanic Mutation (CCM1). J Behav Brain Sci. 2020 Feb;10(2):118-127. doi: 10.4236/jbbs.2020.102007. Epub 2020 Feb 25.

  PMID: 32467778 RESULT

• 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 Jun;41(6):1126-1130. doi: 10.3174/ajnr.A6584. Epub 2020 May 28.

  PMID: 32467184 RESULT

• 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, Awad IA. Permissive microbiome characterizes human subjects with a neurovascular disease cavernous angioma. Nat Commun. 2020 May 27;11(1):2659. doi: 10.1038/s41467-020-16436-w.

  PMID: 32461638 RESULT

• 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 Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation. J Am Heart Assoc. 2023 Feb 7;12(3):e027572. doi: 10.1161/JAHA.122.027572. Epub 2023 Jan 25.

  PMID: 36695309 RESULT

• Fox CK, Nelson J, McCulloch CE, Weinsheimer S, Pawlikowska L, Hart B, Mabray MC, Zafar A, Morrison L, Zabramski JM, Akers A, Kim H. Seizure Incidence Rates in Children and Adults With Familial Cerebral Cavernous Malformations. Neurology. 2021 Sep 20;97(12):e1210-e1216. doi: 10.1212/WNL.0000000000012569.

  PMID: 34389651 RESULT

• 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 cerebral cavernous malformation. Mol Genet Genomic Med. 2021 Oct;9(10):e1794. doi: 10.1002/mgg3.1794. Epub 2021 Sep 7.

  PMID: 34491620 RESULT

• 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 Dis. 2021 Sep 3;16(1):372. doi: 10.1186/s13023-021-02009-7.

  PMID: 34479577 RESULT

Related Links

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

Biospecimen

Retention: SAMPLES WITH DNA

We will collect stool specimens in newly recruited familial CCM cases. We collect and 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.

MeSH Terms

Conditions

Hemangioma, Cavernous, Central Nervous System

Condition Hierarchy (Ancestors)

Hemangioma, Cavernous; Hemangioma; Neoplasms, Vascular Tissue; Neoplasms by Histologic Type; Neoplasms; Cavernous Sinus Syndromes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Central Nervous System Vascular Malformations; Nervous System Malformations; Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Hemostatic Disorders; Vascular Diseases; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Helen Kim, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Issam Awad, MD

  University of Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 15 Years
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 7, 2013
• First Posted: January 9, 2013
• Study Start: April 27, 2010
• Primary Completion: June 1, 2025
• Study Completion: June 1, 2025
• Last Updated: May 29, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

US (7)