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Biomarkers of CASH

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ClinicalTrials.gov Identifier: NCT04467489
Recruitment Status : Recruiting
First Posted : July 13, 2020
Last Update Posted : July 13, 2020
Sponsor:
Collaborators:
Mayo Clinic
University of California, San Francisco
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
University of Chicago

Brief 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. 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.

Condition or disease Intervention/treatment
Cerebral Cavernous Malformation Cavernous Angioma Hemorrhagic Microangiopathy Other: observational

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.

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 1040 participants
Observational Model: Case-Control
Time Perspective: Prospective
Target Follow-Up Duration: 1 Year
Official Title: Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH)
Actual Study Start Date : May 22, 2020
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2025


Group/Cohort Intervention/treatment
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
Other: observational
There is no intervention for any group in this observational study.

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
Other: observational
There is no intervention for any group in this observational study.

Young with seizure
Young (<30 years old) healthy control cohorts with seizures in the prior year
Other: observational
There is no intervention for any group in this observational study.

Young without seizure
Young (<30 years old) healthy control cohorts without seizures in the prior year
Other: observational
There is no intervention for any group in this observational study.

Older with HMA
Older (>50 years old) with hemorrhagic microangiopathy (HMA)
Other: observational
There is no intervention for any group in this observational study.

Older without HMA
Older (>50 years old) without hemorrhagic microangiopathy (HMA)
Other: observational
There is no intervention for any group in this observational study.




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Correlation of Imaging and Plasma Biomarkers of CASH [ Time Frame: 5 years ]
    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

  2. Confounders of CASH Biomarkers [ Time Frame: 5 years ]
    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


Biospecimen Retention:   Samples Without DNA
plasma samples


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
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).
Criteria

Aim 1 and 2:

Inclusion Criteria:

  1. Clinical diagnosis of CA
  2. age 18 or older
  3. solitary or multiple
  4. familial or sporadic
  5. with or without prior symptoms

Exclusion Criteria:

  1. Prior excision of a solitary CA lesion
  2. prior stereotactic radiosurgery or any brain irradiation
  3. spinal cavernoma without brain lesion
  4. other brain pathology unrelated to CA (demyelinating disease, brain tumor)
  5. seizures or stroke unrelated to CA in the prior year
  6. current pregnancy or within 6 months postpartum
  7. reluctance to undergo venipuncture or donate blood specimen, or be called for clinical follow-up for up to one year
  8. homeless or incarcerated persons, or other reason a subject will be unable/unlikely to be reached for follow-up

Aim 3:

Inclusion Criteria:

  1. < 30 years of age
  2. one or more seizures (with or without medical therapy) in the prior year

OR

  1. > 50 years of age
  2. having received an MRI of the brain with SWI (susceptibility weighted imaging) sequences for any indication in the year prior to enrollment
  3. No HMA on brain MRI SWI sequences

OR

  1. > 50 years of age
  2. having received an MRI of the brain with SWI sequences for any indication in the year prior to enrollment
  3. Two or more microbleeds on SWI brain MRI sequences, adjudicated by neuroradiologist

Exclusion Criteria:

  1. concurrent brain disease or structural brain pathology
  2. any medical illness or surgery, seizure or stroke in the prior 12 months
  3. active use of prescription medications in the prior 12 months
  4. current pregnancy or within 6 months postpartum
  5. reluctance to undergo venipuncture or donate blood specimen

OR

  1. concurrent brain disease or structural brain pathology
  2. any medical illness, surgery, or stroke in the prior 12 months other than seizure disorder
  3. active use of prescription medications in the prior 12 months except anticonvulsants
  4. current pregnancy or within 6 months postpartum
  5. reluctance to undergo venipuncture or donate blood specimen

OR

  1. concurrent brain disease or structural brain pathology
  2. medical illness requiring hospitalization or surgery within the prior year
  3. any history of stroke or epileptic seizure within the prior year
  4. renal dysfunction by history or by impaired renal function on laboratory test
  5. current pregnancy or within 6 months postpartum
  6. reluctance to undergo venipuncture or donate blood specimen

OR

  1. concurrent brain disease or structural brain pathology
  2. medical illness requiring hospitalization or surgery within the prior year
  3. any history of stroke or epileptic seizure within the prior year
  4. renal dysfunction by history or by impaired renal function on laboratory test
  5. current pregnancy or within 6 months postpartum
  6. reluctance to undergo venipuncture or donate blood specimen

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): NCT04467489


Contacts
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Contact: Agnieszka Stadnik, MS 7737028896 astadnik@surgery.bsd.uchicago.edu

Locations
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United States, California
University of California, San Francisco Not yet recruiting
San Francisco, California, United States, 94117
Contact: Helen Kim, PhD    628-209-8906    helen.kim2@ucsf.edu   
United States, Illinois
The University of Chicago Medical Center Recruiting
Chicago, Illinois, United States, 60637
Contact: Agnieszka Stadnik, MS    773-702-8996    astadnik@surgery.bsd.uchicago.edu   
Principal Investigator: Issam A Awad, MD         
United States, Minnesota
Mayo Clinic Not yet recruiting
Rochester, Minnesota, United States, 55905
Contact: Kelly Flemming, MD    507-266-4143    flemming.kelly@mayo.edu   
Sponsors and Collaborators
University of Chicago
Mayo Clinic
University of California, San Francisco
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Issam Awad, MD University of Chicago
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Chicago
ClinicalTrials.gov Identifier: NCT04467489    
Other Study ID Numbers: IRB20-0518
First Posted: July 13, 2020    Key Record Dates
Last Update Posted: July 13, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: 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.
Access Criteria: The expression profile data will be made publicly available.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Chicago:
plasma biomarker
imaging biomarker
machine learning
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