<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04467489</url>
  </required_header>
  <id_info>
    <org_study_id>IRB20-0518</org_study_id>
    <nct_id>NCT04467489</nct_id>
  </id_info>
  <brief_title>Biomarkers of CASH</brief_title>
  <official_title>Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Chicago</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Chicago</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The project aims to develop prognostic and diagnostic blood tests for symptomatic brain&#xD;
      hemorrhage in patients diagnosed with cavernous angiomas, a critical clinical challenge in a&#xD;
      disease affecting more than a million Americans. We further examine whether blood biomarkers&#xD;
      can replace or enhance the accuracy of advanced imaging in association with lesional&#xD;
      bleeding. The project tests a novel integrational approach of biomarker development in a&#xD;
      mechanistically defined cerebrovascular disease, with a clinically relevant context of use.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cerebral cavernous angioma (CA) is a capillary microangiopathy affecting more than a million&#xD;
      Americans, predisposing them to a premature risk of brain hemorrhage. Fewer than 200,000&#xD;
      cases who have suffered a recent symptomatic hemorrhage (SH) are most likely to re-bleed&#xD;
      again with serious clinical sequelae, and are the primary focus of therapeutic development.&#xD;
      Genetic mechanisms of CA have been extensively studied, and consequent signaling aberrations&#xD;
      in the neurovascular unit. These include proliferative dysangiogenesis, blood-brain barrier&#xD;
      hyperpermeability, inflammation and immune mediated processes, anticoagulant vascular domain,&#xD;
      and gut microbiome-driven mechanisms. Plasma levels of molecules reflecting these mechanisms&#xD;
      and measures of vascular permeability and hemorrhage leak on magnetic resonance imaging (MRI)&#xD;
      have been correlated with CA hemorrhage in pilot studies. It would be desirable to optimize&#xD;
      these biomarkers to accurately diagnose CASH, to prognosticate the risk of future SH, and to&#xD;
      monitor cases after a bleed and in response to therapy. This would influence clinical&#xD;
      management, and select higher risk cases for clinical trials. Additional candidate biomarkers&#xD;
      are emerging from ongoing mechanistic and differential transcriptome studies, which would be&#xD;
      expected to further enhance the sensitivity and specificity of diagnosis and prediction of&#xD;
      CASH. Weighed combinations of levels of plasma proteins and characteristic micro-ribonucleic&#xD;
      acids (miRNA) may further strengthen biomarker associations. Plasma biomarkers may reflect&#xD;
      (and potentially replace) more cumbersome and expensive imaging biomarkers for monitoring CA&#xD;
      hemorrhage. We here assemble CA researchers and propose to deploy advanced statistical and&#xD;
      computational biology approaches for the integration of novel candidate biomarkers. In&#xD;
      Specific Aim 1 we assess these biomarkers in a large CA cohort to discover the best plasma&#xD;
      biomarkers and validate them in sex, age and relevant clinical subgroups. In Specific Aim 2&#xD;
      we compare changes in MRI measures of vascular permeability and hemorrhage with plasma&#xD;
      biomarkers over time. In Specific Aim 3 we query the biomarkers in non-CA subjects, to&#xD;
      identify potential confounders in the clinical context. This project integrates analytic and&#xD;
      computational biology expertise to develop blood tests for better CASH diagnosis and&#xD;
      prognosis. The project tests a novel integrational approach of biomarker development in a&#xD;
      mechanistically defined cerebrovascular disease with a relevant context of use. This approach&#xD;
      is applicable to other neurological diseases with similar pathobiologic features.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 22, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>1 Year</target_duration>
  <primary_outcome>
    <measure>Circulating Diagnostic and Prognostic Biomarkers of CASH</measure>
    <time_frame>5 years</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation of Imaging and Plasma Biomarkers of CASH</measure>
    <time_frame>5 years</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Confounders of CASH Biomarkers</measure>
    <time_frame>5 years</time_frame>
    <description>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</description>
  </secondary_outcome>
  <number_of_groups>6</number_of_groups>
  <enrollment type="Anticipated">1040</enrollment>
  <condition>Cerebral Cavernous Malformation</condition>
  <condition>Cavernous Angioma</condition>
  <condition>Hemorrhagic Microangiopathy</condition>
  <arm_group>
    <arm_group_label>CA (non-CASH)</arm_group_label>
    <description>Cavernous Angioma (CA) without symptomatic hemorrhage cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CA (CASH)</arm_group_label>
    <description>Cavernous Angioma (CA) with Symptomatic Hemorrhage (SH) cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Young with seizure</arm_group_label>
    <description>Young (&lt;30 years old) healthy control cohorts with seizures in the prior year</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Young without seizure</arm_group_label>
    <description>Young (&lt;30 years old) healthy control cohorts without seizures in the prior year</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Older with HMA</arm_group_label>
    <description>Older (&gt;50 years old) with hemorrhagic microangiopathy (HMA)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Older without HMA</arm_group_label>
    <description>Older (&gt;50 years old) without hemorrhagic microangiopathy (HMA)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>observational</intervention_name>
    <description>There is no intervention for any group in this observational study.</description>
    <arm_group_label>CA (CASH)</arm_group_label>
    <arm_group_label>CA (non-CASH)</arm_group_label>
    <arm_group_label>Older with HMA</arm_group_label>
    <arm_group_label>Older without HMA</arm_group_label>
    <arm_group_label>Young with seizure</arm_group_label>
    <arm_group_label>Young without seizure</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      plasma samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        We propose to recruit human subjects at three sites, with the project approved and&#xD;
        coordinated by the University of Chicago Medicine (UCM) central institutional review board&#xD;
        (IRB) and endorsed by respective IRBs at the other two enrolling sites. The study involves&#xD;
        no more than minimal risks, discussed herein. The enrolling sites include UCM where the&#xD;
        project will be led and where the data coordinating center (DCC) is located and all plasma&#xD;
        biomarker assays and statistical analyses are planned, the University of California at San&#xD;
        Francisco (UCSF), and Mayo Clinic, Rochester, MN (Mayo). UCSF and Mayo are participants in&#xD;
        imaging biomarker validations in longitudinal follow-up of cavernous angioma with&#xD;
        symptomatic hemorrhage (CASH) subjects in the TR Project. We project enrolling 1,040 cases&#xD;
        during 4 years to address hypotheses in 3 Specific Aims (40 cases enrolled in Specific Aim&#xD;
        2 are also included among the 800 subjects addressing hypotheses of Specific Aim 1).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Aim 1 and 2:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. Clinical diagnosis of CA&#xD;
&#xD;
          2. age 18 or older&#xD;
&#xD;
          3. solitary or multiple&#xD;
&#xD;
          4. familial or sporadic&#xD;
&#xD;
          5. with or without prior symptoms&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior excision of a solitary CA lesion&#xD;
&#xD;
          2. prior stereotactic radiosurgery or any brain irradiation&#xD;
&#xD;
          3. spinal cavernoma without brain lesion&#xD;
&#xD;
          4. other brain pathology unrelated to CA (demyelinating disease, brain tumor)&#xD;
&#xD;
          5. seizures or stroke unrelated to CA in the prior year&#xD;
&#xD;
          6. current pregnancy or within 6 months postpartum&#xD;
&#xD;
          7. reluctance to undergo venipuncture or donate blood specimen, or be called for clinical&#xD;
             follow-up for up to one year&#xD;
&#xD;
          8. homeless or incarcerated persons, or other reason a subject will be unable/unlikely to&#xD;
             be reached for follow-up&#xD;
&#xD;
        Aim 3:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. &lt; 30 years of age&#xD;
&#xD;
          2. one or more seizures (with or without medical therapy) in the prior year&#xD;
&#xD;
        OR&#xD;
&#xD;
          1. &gt; 50 years of age&#xD;
&#xD;
          2. having received an MRI of the brain with SWI (susceptibility weighted imaging)&#xD;
             sequences for any indication in the year prior to enrollment&#xD;
&#xD;
          3. No HMA on brain MRI SWI sequences&#xD;
&#xD;
        OR&#xD;
&#xD;
          1. &gt; 50 years of age&#xD;
&#xD;
          2. having received an MRI of the brain with SWI sequences for any indication in the year&#xD;
             prior to enrollment&#xD;
&#xD;
          3. Two or more microbleeds on SWI brain MRI sequences, adjudicated by neuroradiologist&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. concurrent brain disease or structural brain pathology&#xD;
&#xD;
          2. any medical illness or surgery, seizure or stroke in the prior 12 months&#xD;
&#xD;
          3. active use of prescription medications in the prior 12 months&#xD;
&#xD;
          4. current pregnancy or within 6 months postpartum&#xD;
&#xD;
          5. reluctance to undergo venipuncture or donate blood specimen&#xD;
&#xD;
        OR&#xD;
&#xD;
          1. concurrent brain disease or structural brain pathology&#xD;
&#xD;
          2. any medical illness, surgery, or stroke in the prior 12 months other than seizure&#xD;
             disorder&#xD;
&#xD;
          3. active use of prescription medications in the prior 12 months except anticonvulsants&#xD;
&#xD;
          4. current pregnancy or within 6 months postpartum&#xD;
&#xD;
          5. reluctance to undergo venipuncture or donate blood specimen&#xD;
&#xD;
        OR&#xD;
&#xD;
          1. concurrent brain disease or structural brain pathology&#xD;
&#xD;
          2. medical illness requiring hospitalization or surgery within the prior year&#xD;
&#xD;
          3. any history of stroke or epileptic seizure within the prior year&#xD;
&#xD;
          4. renal dysfunction by history or by impaired renal function on laboratory test&#xD;
&#xD;
          5. current pregnancy or within 6 months postpartum&#xD;
&#xD;
          6. reluctance to undergo venipuncture or donate blood specimen&#xD;
&#xD;
        OR&#xD;
&#xD;
          1. concurrent brain disease or structural brain pathology&#xD;
&#xD;
          2. medical illness requiring hospitalization or surgery within the prior year&#xD;
&#xD;
          3. any history of stroke or epileptic seizure within the prior year&#xD;
&#xD;
          4. renal dysfunction by history or by impaired renal function on laboratory test&#xD;
&#xD;
          5. current pregnancy or within 6 months postpartum&#xD;
&#xD;
          6. reluctance to undergo venipuncture or donate blood specimen&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Issam Awad, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Chicago</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Agnieszka Stadnik, MS</last_name>
    <phone>7737028896</phone>
    <email>astadnik@surgery.bsd.uchicago.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94117</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Helen Kim, PhD</last_name>
      <phone>628-209-8906</phone>
      <email>helen.kim2@ucsf.edu</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>The University of Chicago Medical Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Agnieszka Stadnik, MS</last_name>
      <phone>773-702-8996</phone>
      <email>astadnik@surgery.bsd.uchicago.edu</email>
    </contact>
    <investigator>
      <last_name>Issam A Awad, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Kelly Flemming, MD</last_name>
      <phone>507-266-4143</phone>
      <email>flemming.kelly@mayo.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 8, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 13, 2020</study_first_posted>
  <last_update_submitted>November 16, 2022</last_update_submitted>
  <last_update_submitted_qc>November 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>plasma biomarker</keyword>
  <keyword>imaging biomarker</keyword>
  <keyword>machine learning</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemangioma, Cavernous, Central Nervous System</mesh_term>
    <mesh_term>Hemangioma</mesh_term>
    <mesh_term>Hemangioma, Cavernous</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_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.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_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.</ipd_time_frame>
    <ipd_access_criteria>The expression profile data will be made publicly available.</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04467489
org study id: IRB20-0518
nct id: NCT04467489
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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.
observational model: Case-Control
time perspective: Prospective
measure: Circulating Diagnostic and Prognostic Biomarkers of CASH
time frame: 5 years
description: 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
measure: Correlation of Imaging and Plasma Biomarkers of CASH
time frame: 5 years
description: 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
measure: Confounders of CASH Biomarkers
time frame: 5 years
description: 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
arm group label: CA (non-CASH)
description: Cavernous Angioma (CA) without symptomatic hemorrhage cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting
arm group label: CA (CASH)
description: Cavernous Angioma (CA) with Symptomatic Hemorrhage (SH) cases scheduled for evaluation by their neurology or neurosurgery teams in an inpatient or outpatient setting
arm group label: Young with seizure
description: Young (<30 years old) healthy control cohorts with seizures in the prior year
arm group label: Young without seizure
description: Young (<30 years old) healthy control cohorts without seizures in the prior year
arm group label: Older with HMA
description: Older (>50 years old) with hemorrhagic microangiopathy (HMA)
arm group label: Older without HMA
description: Older (>50 years old) without hemorrhagic microangiopathy (HMA)
intervention type: Other
intervention name: observational
description: There is no intervention for any group in this observational study.
arm group label: CA (CASH)
arm group label: CA (non-CASH)
arm group label: Older with HMA
arm group label: Older without HMA
arm group label: Young with seizure
arm group label: Young without seizure
plasma samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Issam Awad, MD
role: Principal Investigator
affiliation: University of Chicago
last name: Agnieszka Stadnik, MS
phone: 7737028896
email: astadnik@surgery.bsd.uchicago.edu
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
country: United States
responsible party type: Sponsor
mesh term: Hemangioma, Cavernous, Central Nervous System
mesh term: Hemangioma
mesh term: Hemangioma, Cavernous
sharing ipd: Yes
ipd 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.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd 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.
ipd access criteria: The expression profile data will be made publicly available.