Cerebral Cavernous MalformationNCT04467489
Biomarkers of CASH
An observational study of Cerebral Cavernous Malformation and Cavernous Angioma, run by University of Chicago at 4 sites in United States.
Trial summary
The project aims to develop prognostic and diagnostic blood tests for symptomatic brain hemorrhage in patients diagnosed with cavernous angiomas, a critical clinical challenge in a disease affecting more than a million Americans. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Cerebral Cavernous Malformation, Cavernous Angioma, Hemorrhagic Microangiopathy
- What is being tested?
- observational
- How many people
- 1,040 participants
- Where
- 4 sitesUnited States
- Study dates
- 22 May 2020to 30 Jun 2026
- How long will I take part?
- 1 Year
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: We propose to recruit human subjects at three sites, with the project approved and coordinated by the University of Chicago Medicine (UCM) central institutional review board (IRB) and endorsed by respective IRBs at the other two enrolling sites. The study involves no more than minimal risks, discussed herein. The enrolling sites include UCM where the project will be led and where the data coordinating center (DCC) is located and all plasma biomarker assays and statistical analyses are planned, the University of California at San Francisco (UCSF), and Mayo Clinic, Rochester, MN (Mayo). UCSF and Mayo are participants in imaging biomarker validations in longitudinal follow-up of cavernous angioma with symptomatic hemorrhage (CASH) subjects in the TR Project. We project enrolling 1,040 cases during 4 years to address hypotheses in 3 Specific Aims (40 cases enrolled in Specific Aim 2 are also included among the 800 subjects addressing hypotheses of Specific Aim 1).
Who may be able to join
- Clinical diagnosis of CA
- age 18 or older
- solitary or multiple
- familial or sporadic
- with or without prior symptoms
- < 30 years of age
Show all 15Show fewer
- one or more seizures (with or without medical therapy) in the prior year
- OR
- > 50 years of age
- having received an MRI of the brain with SWI (susceptibility weighted imaging) sequences for any indication in the year prior to enrollment
- No HMA on brain MRI SWI sequences
- OR
- > 50 years of age
- having received an MRI of the brain with SWI sequences for any indication in the year prior to enrollment
- Two or more microbleeds on SWI brain MRI sequences, adjudicated by neuroradiologist
Who cannot join
- Prior excision of a solitary CA lesion
- prior stereotactic radiosurgery or any brain irradiation
- spinal cavernoma without brain lesion
- other brain pathology unrelated to CA (demyelinating disease, brain tumor)
- seizures or stroke unrelated to CA in the prior year
- current pregnancy or within 6 months postpartum
Show all 32Show fewer
- reluctance to undergo venipuncture or donate blood specimen, or be called for clinical follow-up for up to one year
- homeless or incarcerated persons, or other reason a subject will be unable/unlikely to be reached for follow-up
- Aim 3:
- concurrent brain disease or structural brain pathology
- medical illness requiring hospitalization or surgery, seizure or stroke in the prior 12 months
- active use of prescription medications in the prior 12 months
- current pregnancy or within 6 months postpartum
- reluctance to undergo venipuncture or donate blood specimen
- OR
- concurrent brain disease or structural brain pathology
- medical illness requiring hospitalization or surgery, or stroke in the prior 12 months other than seizure disorder
- active use of prescription medications in the prior 12 months except anticonvulsants
- current pregnancy or within 6 months postpartum
- reluctance to undergo venipuncture or donate blood specimen
- OR
- concurrent brain disease or structural brain pathology
- medical illness requiring hospitalization or surgery within the prior year
- any history of stroke or epileptic seizure within the prior year
- current pregnancy or within 6 months postpartum
- reluctance to undergo venipuncture or donate blood specimen
- OR
- concurrent brain disease or structural brain pathology
- medical illness requiring hospitalization or surgery within the prior year
- any history of stroke or epileptic seizure within the prior year
- current pregnancy or within 6 months postpartum
- reluctance to undergo venipuncture or donate blood specimen
Trial locations and contacts
4 sites in 1 country.
United States4 sites
The University of Chicago Medical Center
Chicago, Illinois, 60637
Barrow Neurological Institute at St. Joseph's Hospital and Medical Center
Phoenix, Arizona, 85013
Mayo Clinic
Rochester, Minnesota, 55905
University of California, San Francisco
San Francisco, California, 94117
About this study
Official title: Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH)
The project aims to develop prognostic and diagnostic blood tests for symptomatic brain hemorrhage in patients diagnosed with cavernous angiomas, a critical clinical challenge in a disease affecting more than a million Americans. We further examine whether blood biomarkers can replace or enhance the accuracy of advanced imaging in association with lesional bleeding. The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease, with a clinically relevant context of use.
Read the detailed description
Cerebral cavernous angioma (CA) is a capillary microangiopathy affecting more than a million Americans, predisposing them to a premature risk of brain hemorrhage. Fewer than 200,000 cases who have suffered a recent symptomatic hemorrhage (SH) are most likely to re-bleed again with serious clinical sequelae, and are the primary focus of therapeutic development. Genetic mechanisms of CA have been extensively studied, and consequent signaling aberrations in the neurovascular unit. These include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammation and immune mediated processes, anticoagulant vascular domain, and gut microbiome-driven mechanisms. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and hemorrhage leak on magnetic resonance imaging (MRI) have been correlated with CA hemorrhage in pilot studies. It would be desirable to optimize these biomarkers to accurately diagnose CASH, to prognosticate the risk of future SH, and to monitor cases after a bleed and in response to therapy. This would influence clinical management, and select higher risk cases for clinical trials. Additional candidate biomarkers are emerging from ongoing mechanistic and differential transcriptome studies, which would be expected to further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Weighed combinations of levels of plasma proteins and characteristic micro-ribonucleic acids (miRNA) may further strengthen biomarker associations. Plasma biomarkers may reflect (and potentially replace) more cumbersome and expensive imaging biomarkers for monitoring CA hemorrhage. We here assemble CA researchers and propose to deploy advanced statistical and computational biology approaches for the integration of novel candidate biomarkers. In Specific Aim 1 we assess these biomarkers in a large CA cohort to discover the best plasma biomarkers and validate them in sex, age and relevant clinical subgroups. In Specific Aim 2 we compare changes in MRI measures of vascular permeability and hemorrhage with plasma biomarkers over time. In Specific Aim 3 we query the biomarkers in non-CA subjects, to identify potential confounders in the clinical context. This project integrates analytic and computational biology expertise to develop blood tests for better CASH diagnosis and prognosis. The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use. This approach is applicable to other neurological diseases with similar pathobiologic features.
- Being tested
- observational
- Keywords
- plasma biomarker, imaging biomarker, machine learning
- Medical subject headings
- Hemangioma, Cavernous, Central Nervous System, Hemangioma, Cavernous
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
observationalOther
There is no intervention for any group in this observational study.
| Study group | Role | What they receive |
|---|---|---|
| CA (non-CASH) | Cavernous Angioma (CA) without symptomatic hemorrhage cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting Receives: Other: observational | |
| CA (CASH) | Cavernous Angioma (CA) with Symptomatic Hemorrhage (SH) cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting Receives: Other: observational | |
| Young with seizure | Young (<30 years old) healthy control cohorts with seizures in the prior year Receives: Other: observational | |
| Young without seizure | Young (<30 years old) healthy control cohorts without seizures in the prior year Receives: Other: observational | |
| Older with HMA | Older (>50 years old) with hemorrhagic microangiopathy (HMA) Receives: Other: observational | |
| Older without HMA | Older (>50 years old) without hemorrhagic microangiopathy (HMA) Receives: Other: observational |
What is being measured
The primary outcome is the main question the study is designed to answer.
Circulating Diagnostic and Prognostic Biomarkers of CASH
To test whether individual and combined levels of candidate plasma proteins and miRNAs can be associated with diagnosis of CASH (cross sectional) and can predict/prognosticate future SH (longitudinal) in CAs
Measured: 5 years
Secondary outcomes (2)
Correlation of Imaging and Plasma Biomarkers of CASH
To assess whether changes in QSM (quantitative susceptibility mapping) and DCEQP (dynamic contrast enhanced quantitative permeability) used as monitoring biomarkers after a SH, are reflected by changes in plasma biomarkers and miRNAs
Measured: 5 years
Confounders of CASH Biomarkers
To assess the plasma biomarkers in non-CA young and older subjects, with and without seizures and hemorrhagic microangiopathy on MRI, to clarify potential confounders in the context of clinical use, and to motivate novel hypotheses for broader applications
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Jul 2020
- Study start22 May 2020
- Primary completion30 Apr 2025
- Study completion30 Jun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Cerebral Cavernous MalformationStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 1,040 participants (estimated)
- Target duration
- 1 Year
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Collaborators
- Mayo Clinic, University of California, San Francisco, National Institute of Neurological Disorders and Stroke (NINDS), Barrow Neurological Institute
- Responsible party
- Sponsor
- Investigators
- Issam Awad, MD, Principal investigator, University of Chicago
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04467489
- Sponsor's protocol ID
- IRB20-0518
- Other IDs
- 5R01NS114552-05
- Status last verified
- Aug 2025
- First submitted
- 8 Jul 2020
- Last updated
- 11 Aug 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Within the first year, we will publish the protocol paper. At the end of the 5 year study, we will publish the data dictionary along with study findings. The expression profile data will be made publicly available no later than the date of initial publication or six months after the receipt of the final sequencing data, whichever comes first.
Publications
Girard R, Li Y, Stadnik A, Shenkar R, Hobson N, Romanos S, Srinath A, Moore T, Lightle R, Shkoukani A, Akers A, Carroll T, Christoforidis GA, Koenig JI, Lee C, Piedad K, Greenberg SM, Kim H, Flemming KD, Ji Y, Awad IA. A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH). Neurosurgery. 2021 Feb 16;88(3):686-697. doi: 10.1093/neuros/nyaa478.
PubMed 33469662
Study at a glance
From the registry record, last updated by the sponsor on 11 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH)
- ClinicalTrials.gov ID
- NCT04467489
- Acronym / sponsor ID
- IRB20-0518
- Keywords
- plasma biomarker, imaging biomarker, machine learning
- Study type
- Observational
- Recruitment status
- Active, not recruiting
- Enrolment
- 1,040 participants (estimated)
- Lead sponsor
- University of ChicagoUniversity, hospital or other
- Collaborators
- Mayo Clinic, University of California, San Francisco, National Institute of Neurological Disorders and Stroke (NINDS), Barrow Neurological Institute
- Study start
- 22 May 2020 (actual)
- Primary completion
- 30 Apr 2025 (actual)
- Study completion
- 30 Jun 2026 (estimated)
- First posted
- 13 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The project aims to develop prognostic and diagnostic blood tests for symptomatic brain hemorrhage in patients diagnosed with cavernous angiomas, a critical clinical challenge in a disease affecting more than a million Americans. We further examine whether blood biomarkers can replace or enhance the accuracy of advanced imaging in association with lesional bleeding. The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease, with a clinically relevant context of use.
Detailed description
Cerebral cavernous angioma (CA) is a capillary microangiopathy affecting more than a million Americans, predisposing them to a premature risk of brain hemorrhage. Fewer than 200,000 cases who have suffered a recent symptomatic hemorrhage (SH) are most likely to re-bleed again with serious clinical sequelae, and are the primary focus of therapeutic development. Genetic mechanisms of CA have been extensively studied, and consequent signaling aberrations in the neurovascular unit. These include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammation and immune mediated processes, anticoagulant vascular domain, and gut microbiome-driven mechanisms. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and hemorrhage leak on magnetic resonance imaging (MRI) have been correlated with CA hemorrhage in pilot studies. It would be desirable to optimize these biomarkers to accurately diagnose CASH, to prognosticate the risk of future SH, and to monitor cases after a bleed and in response to therapy. This would influence clinical management, and select higher risk cases for clinical trials. Additional candidate biomarkers are emerging from ongoing mechanistic and differential transcriptome studies, which would be expected to further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Weighed combinations of levels of plasma proteins and characteristic micro-ribonucleic acids (miRNA) may further strengthen biomarker associations. Plasma biomarkers may reflect (and potentially replace) more cumbersome and expensive imaging biomarkers for monitoring CA hemorrhage. We here assemble CA researchers and propose to deploy advanced statistical and computational biology approaches for the integration of novel candidate biomarkers. In Specific Aim 1 we assess these biomarkers in a large CA cohort to discover the best plasma biomarkers and validate them in sex, age and relevant clinical subgroups. In Specific Aim 2 we compare changes in MRI measures of vascular permeability and hemorrhage with plasma biomarkers over time. In Specific Aim 3 we query the biomarkers in non-CA subjects, to identify potential confounders in the clinical context. This project integrates analytic and computational biology expertise to develop blood tests for better CASH diagnosis and prognosis. The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use. This approach is applicable to other neurological diseases with similar pathobiologic features.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Target follow-up
- 1 Year
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| CA (non-CASH) | – | Other: observationalCavernous Angioma (CA) without symptomatic hemorrhage cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting |
| CA (CASH) | – | Other: observationalCavernous Angioma (CA) with Symptomatic Hemorrhage (SH) cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting |
| Young with seizure | – | Other: observationalYoung (<30 years old) healthy control cohorts with seizures in the prior year |
| Young without seizure | – | Other: observationalYoung (<30 years old) healthy control cohorts without seizures in the prior year |
| Older with HMA | – | Other: observationalOlder (>50 years old) with hemorrhagic microangiopathy (HMA) |
| Older without HMA | – | Other: observationalOlder (>50 years old) without hemorrhagic microangiopathy (HMA) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- We propose to recruit human subjects at three sites, with the project approved and coordinated by the University of Chicago Medicine (UCM) central institutional review board (IRB) and endorsed by respective IRBs at the other two enrolling sites. The study involves no more than minimal risks, discussed herein. The enrolling sites include UCM where the project will be led and where the data coordinating center (DCC) is located and all plasma biomarker assays and statistical analyses are planned, the University of California at San Francisco (UCSF), and Mayo Clinic, Rochester, MN (Mayo). UCSF and Mayo are participants in imaging biomarker validations in longitudinal follow-up of cavernous angioma with symptomatic hemorrhage (CASH) subjects in the TR Project. We project enrolling 1,040 cases during 4 years to address hypotheses in 3 Specific Aims (40 cases enrolled in Specific Aim 2 are also included among the 800 subjects addressing hypotheses of Specific Aim 1).
Key inclusion criteria (15 listed)
- Clinical diagnosis of CA
- age 18 or older
- solitary or multiple
- familial or sporadic
- with or without prior symptoms
Key exclusion criteria (32 listed)
- Prior excision of a solitary CA lesion
- prior stereotactic radiosurgery or any brain irradiation
- spinal cavernoma without brain lesion
- other brain pathology unrelated to CA (demyelinating disease, brain tumor)
- seizures or stroke unrelated to CA in the prior year
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| observationalThere is no intervention for any group in this observational study. | Other | CA (CASH), CA (non-CASH), Older with HMA, Older without HMA, Young with seizure, Young without seizure |
Primary outcome
Circulating Diagnostic and Prognostic Biomarkers of CASH
Time frame: 5 years
To test whether individual and combined levels of candidate plasma proteins and miRNAs can be associated with diagnosis of CASH (cross sectional) and can predict/prognosticate future SH (longitudinal) in CAs
2 secondary outcomes
Correlation of Imaging and Plasma Biomarkers of CASH
Time frame: 5 years
Confounders of CASH Biomarkers
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Aug 2025.
- Derived from this study: PubMed 33469662Girard R, Li Y, Stadnik A, Shenkar R, Hobson N, Romanos S, Srinath A, Moore T, Lightle R, Shkoukani A, Akers A, Carroll T, Christoforidis GA, Koenig JI, Lee C, Piedad K, Greenberg SM, Kim H, Flemming KD, Ji Y, Awad IA. A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH). Neurosurgery. 2021 Feb 16;88(3):686-697. doi: 10.1093/neuros/nyaa478.
- Individual participant dataSharing planned: Yes. Within the first year, we will publish the protocol paper. At the end of the 5 year study, we will publish the data dictionary along with study findings. The expression profile data will be made publicly available no later than the date of initial publication or six months after the receipt of the final sequencing data, whichever comes first.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Issam Awad, MD principal investigator
University of Chicago
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Cerebral Cavernous Malformation and Cavernous Angioma, run by University of Chicago at 4 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 11 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Circulating Diagnostic and Prognostic Biomarkers of CASH (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04467489, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Aug 2025.