<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/NCT03830983</url>
  </required_header>
  <id_info>
    <org_study_id>18055313</org_study_id>
    <nct_id>NCT03830983</nct_id>
  </id_info>
  <brief_title>Atrial Cardiomyopathy in Patients With Stroke of Undetected Mechanism</brief_title>
  <official_title>Atrial Cardiomyopathy in Patients With Stroke of Undetected Mechanism</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Bispebjerg and Frederiksberg</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lundbeck Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Bispebjerg and Frederiksberg</source>
  <oversight_info>
    <has_dmc>Yes</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 goal of this study is to evaluate left atrial structural and functional abnormalities in&#xD;
      stroke of undetected mechanism and atherosclerotic stroke with cardiac MRI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aims and objectives:&#xD;
&#xD;
      The goal of this study is to evaluate left atrial structural and functional abnormalities in&#xD;
      patients with stroke of likely cardio-embolic origin compared with healthy age and sex&#xD;
      matches controls and patients with atherosclerotic stroke using cardiac MRI.&#xD;
&#xD;
      Background:&#xD;
&#xD;
      Despite standard work up for the etiology of ischemic stroke, about 30% of the cases remain&#xD;
      unexplained. It is increasingly accepted that these unexplained cases arise from disease&#xD;
      outside of the brain. Paroxysmal AF (Atrial fibrillation) may often be suspected as the&#xD;
      source but fewer than one third of patients with stroke of undetermined source manifest AF in&#xD;
      any form even after 3 years of continuous heart rhythm monitoring. Emerging evidence suggest&#xD;
      that atrial functional and structural abnormalities may convey a comparable risk of stroke in&#xD;
      which AF is only one of several features. These abnormalities have been termed &quot;atrial&#xD;
      cardiomyopathy&quot; and may be an efficient and practical approach to identify patients at high&#xD;
      risk of AF and ischemic stroke.&#xD;
&#xD;
      Methods and materials:&#xD;
&#xD;
      Cross sectional and prospective cohort study with 3 different groups: 50 patients with stroke&#xD;
      of undetected mechanism, 50 patients with atherosclerotic stroke (large or small vessel&#xD;
      disease) admitted to the University Hospital of Bispebjerg and Frederiksberg and 50 sex and&#xD;
      age matched controls with no history of stroke or AF from the Copenhagen City Heart Study&#xD;
      (ØBUS) will be included during a 2 year-period. The study will measure atrial structural&#xD;
      abnormalities using cardiac magnetic resonance imaging (MRI) and atrial functional&#xD;
      abnormalities by cardiac MRI and echocardiography. A 1 year follow up will examine the&#xD;
      incidence of silent brain infarction with MRI and incidence of stroke, atrial fibrillation,&#xD;
      acute myocardial infarction and cardiovascular death. Secondary endpoints are to examine the&#xD;
      association of functional and structural changes found by MRI with echocardiography, rhythm&#xD;
      abnormalities and biomarkers with the purpose of finding clinical easily applicable methods&#xD;
      to diagnose atrial cardiomyopathy.&#xD;
&#xD;
      Expected outcome and perspectives:&#xD;
&#xD;
      The investigators hypothesize that patients with stroke of likely cardio-embolic origin have&#xD;
      significantly more atrial fibrotic degeneration and reduced atrial emptying function than&#xD;
      patients with atherosclerotic stroke and the control subjects. The investigators expect a&#xD;
      higher incidence of silent brain infarction in the group with stroke of likely cardio-embolic&#xD;
      origin. With atrial cardiomyopathy investigated thoroughly in patients with stroke of likely&#xD;
      cardio-embolic origin the future work-up and treatment strategies could be more efficient and&#xD;
      may thus improve the prognosis in terms of mortality and disability for a considerable number&#xD;
      of patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 8, 2019</start_date>
  <completion_date type="Actual">January 31, 2023</completion_date>
  <primary_completion_date type="Actual">September 6, 2021</primary_completion_date>
  <study_type>Observational</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>
  <primary_outcome>
    <measure>Extent of the fibrosis in the Left Atrium (LA)</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Measured with gadolinium enhanced cardiac MRI</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Left Atrial Emptying Function (LAEF)</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Measured with gadolinium enhanced cardiac MRI</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Observational study: Incidence of silent brain infarctions</measure>
    <time_frame>Between 1-2 years from index event</time_frame>
    <description>Incidence of silent brain infarctions assessed by follow-up MR-cerebrum (Only in patients)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left atrial volume</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Assessed by cardiac MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left atrial appendage morphology</measure>
    <time_frame>Within 8 weeks from index event</time_frame>
    <description>Assessed by cardiac MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left atrium volume</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>2D and 3D left atrial volume assessed by transthoracic echocardiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Left atrium ejection fraction (LAEF)</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Assessed by transthoracic echocardiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Speckle tracking of LA</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Assessed by transthoracic echocardiography</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Atrial rhythm abnormalities: Number of premature atrial contractions (PAC) per hour. Number and length of runs of PAC</measure>
    <time_frame>Within 4 weeks from index event</time_frame>
    <description>Assessed by 48-hours Holter monitoring</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate variability (HRV)</measure>
    <time_frame>Within 4 weeks from index event</time_frame>
    <description>Time domain variables (meanNN, SDNN, SDANN, SDNNidx, RMSSD, pNN50)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Thrombophilia biomarkers</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Assessment of hypercoagulability</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac specific biomarkers</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Atrial Natriuretic Peptide, pro NT-Brain Natriuretic Peptide, High Sensitive Troponins.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory biomarkers</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>High Sensitive CRP, Interleukins: IL1, IL1b, IL6, IL18</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fibrosis related markers</measure>
    <time_frame>Within 12 weeks from index event</time_frame>
    <description>Collagen type I and III</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Observational study: Assessing incidence of stroke, acute myocardial infarction, atrial fibrillation and cardiovascular-death</measure>
    <time_frame>1 year from last included patient</time_frame>
    <description>Follow up in patient records</description>
  </other_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">150</enrollment>
  <condition>Stroke</condition>
  <arm_group>
    <arm_group_label>Stroke of likely cardioembolic cause or undetected mechanism</arm_group_label>
    <description>Lesions in at least one territory on MRI &amp; absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels &gt;50% in arteries supplying the ischemic area(s) &amp; absence of severe small vessel disease including micro-bleeds on Patients with central retinal artery occlusion documented by perimeter and absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels &gt;50% &amp; absence of severe small vessel disease including micro-bleeds on MRI are included independent of acute MRI findings.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atherosclerotic stroke</arm_group_label>
    <description>Large vessel stroke: Acute lesions in one vascular territory on MRI, significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels &gt;50% leading to the infarcted territory &amp; absence of severe small vessel disease including micro-bleeds on MRI Small Vessel stroke: MRI documenting lacunar infarction, absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels &gt;50% and presence of severe small vessel disease possibly including micro bleeds.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls</arm_group_label>
    <description>Age and sex matched healthy controls with no history of stroke or AF.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      For use in future studies of biomarkers and genes we will collect 2 samples of plasma and 1&#xD;
      sample of full blood. Only patient who give informed consent will have these samples&#xD;
      collected.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients are selected amongst individuals admitted with acute stroke to Bispebjerg&#xD;
        University Hospital. Healthy controls will be invited from the the Copenhagen City Heart&#xD;
        Study (ØBUS).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria (Patients):&#xD;
&#xD;
          1. Stroke of likely cardioembolic cause or of undetected mechanism:&#xD;
&#xD;
             Lesions in at least one territory on MRI &amp; absence of significant large vessel disease&#xD;
             defined as stenosis of cerebral or pre-cerebral vessels &gt;50% in arteries supplying the&#xD;
             ischemic area(s) &amp; absence of severe small vessel disease including micro-bleeds on&#xD;
             MRI.&#xD;
&#xD;
             Patients with central retinal artery occlusion documented by perimeter and absence of&#xD;
             significant large vessel disease defined as stenosis of cerebral or pre-cerebral&#xD;
             vessels &gt;50% &amp; absence of severe small vessel disease including micro-bleeds on MRI&#xD;
             are included independent of acute MRI findings.&#xD;
&#xD;
          2. Large or small vessel stroke (atherosclerotic stroke):&#xD;
&#xD;
             Large vessel stroke: Acute lesions in one vascular territory on MRI, significant large&#xD;
             vessel disease defined as stenosis of cerebral or pre-cerebral vessels &gt;50% leading to&#xD;
             the infarcted territory &amp; absence of severe small vessel disease including&#xD;
             micro-bleeds on MRI Small Vessel stroke: MRI documenting lacunar infarction, absence&#xD;
             of significant large vessel disease defined as stenosis of cerebral or pre-cerebral&#xD;
             vessels &gt;50% and presence of severe small vessel disease possibly including micro&#xD;
             bleeds.&#xD;
&#xD;
          3. Ischemic stroke within 30 days prior to inclusion&#xD;
&#xD;
          4. Age &gt; 18 years&#xD;
&#xD;
          5. Life expectancy of at least one year&#xD;
&#xD;
          6. Informed consent&#xD;
&#xD;
               -  Stenosis: % defined by Ultrasound&#xD;
&#xD;
               -  Small vessel disease: defined according to STRIVE criteria&#xD;
&#xD;
        Inclusion Criteria (Controls)&#xD;
&#xD;
        1. Age and sex matched healthy controls. Matched with the group with stroke of likely&#xD;
        cardioembolic stroke.&#xD;
&#xD;
        Exclusion Criteria (Patients):&#xD;
&#xD;
          1. Prior AF or AF &gt;30 sec on at least 6 hours of monitoring during hospitalization.&#xD;
&#xD;
          2. Other major cardio-embolic risk sources assumed as cause of stroke (e.g. endocarditis,&#xD;
             myocardial infarction within last 4 weeks, prosthetic cardiac valve)&#xD;
&#xD;
          3. Contraindications to MRI (Including eGFR&lt;30 or other contraindications for the&#xD;
             contrast agent used during Cardiac MRI)&#xD;
&#xD;
          4. Assumed unable to participate in the study by investigator (including but not&#xD;
             restricted to psychiatric condition, dementia)&#xD;
&#xD;
        Exclusion Criteria (Controls):&#xD;
&#xD;
          1. History of stroke or AF&#xD;
&#xD;
          2. Contraindications to MRI (Including eGFR&lt;30 mL/min/1.73 m2 or other contraindications&#xD;
             for the contrast agent used during Cardiac MRI)&#xD;
&#xD;
          3. Assumed unable to participate in the study by the investigator (For the same reasons&#xD;
             listed above)&#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>Ahmad Sajadieh, MD, DMSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital Bispebjerg and Frederiksberg</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bispebjerg Hospital</name>
      <address>
        <city>Copenhagen NV</city>
        <state>Copenhagen</state>
        <zip>2400</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 29, 2019</study_first_submitted>
  <study_first_submitted_qc>February 2, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 5, 2019</study_first_posted>
  <last_update_submitted>March 30, 2023</last_update_submitted>
  <last_update_submitted_qc>March 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Bispebjerg and Frederiksberg</investigator_affiliation>
    <investigator_full_name>Ahmad Sajadieh</investigator_full_name>
    <investigator_title>MD, DMSc</investigator_title>
  </responsible_party>
  <keyword>Cardioembolic stroke</keyword>
  <keyword>Cardiac MRI</keyword>
  <keyword>Heart disease</keyword>
  <keyword>Vascular disease</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
    <mesh_term>Cardiomyopathies</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>De-identified data will be made available to other research groups upon reasonable request.</ipd_description>
  </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/NCT03830983
org study id: 18055313
nct id: NCT03830983
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The goal of this study is to evaluate left atrial structural and functional abnormalities in
      stroke of undetected mechanism and atherosclerotic stroke with cardiac MRI.
Aims and objectives:

      The goal of this study is to evaluate left atrial structural and functional abnormalities in
      patients with stroke of likely cardio-embolic origin compared with healthy age and sex
      matches controls and patients with atherosclerotic stroke using cardiac MRI.

      Background:

      Despite standard work up for the etiology of ischemic stroke, about 30% of the cases remain
      unexplained. It is increasingly accepted that these unexplained cases arise from disease
      outside of the brain. Paroxysmal AF (Atrial fibrillation) may often be suspected as the
      source but fewer than one third of patients with stroke of undetermined source manifest AF in
      any form even after 3 years of continuous heart rhythm monitoring. Emerging evidence suggest
      that atrial functional and structural abnormalities may convey a comparable risk of stroke in
      which AF is only one of several features. These abnormalities have been termed "atrial
      cardiomyopathy" and may be an efficient and practical approach to identify patients at high
      risk of AF and ischemic stroke.

      Methods and materials:

      Cross sectional and prospective cohort study with 3 different groups: 50 patients with stroke
      of undetected mechanism, 50 patients with atherosclerotic stroke (large or small vessel
      disease) admitted to the University Hospital of Bispebjerg and Frederiksberg and 50 sex and
      age matched controls with no history of stroke or AF from the Copenhagen City Heart Study
      (ØBUS) will be included during a 2 year-period. The study will measure atrial structural
      abnormalities using cardiac magnetic resonance imaging (MRI) and atrial functional
      abnormalities by cardiac MRI and echocardiography. A 1 year follow up will examine the
      incidence of silent brain infarction with MRI and incidence of stroke, atrial fibrillation,
      acute myocardial infarction and cardiovascular death. Secondary endpoints are to examine the
      association of functional and structural changes found by MRI with echocardiography, rhythm
      abnormalities and biomarkers with the purpose of finding clinical easily applicable methods
      to diagnose atrial cardiomyopathy.

      Expected outcome and perspectives:

      The investigators hypothesize that patients with stroke of likely cardio-embolic origin have
      significantly more atrial fibrotic degeneration and reduced atrial emptying function than
      patients with atherosclerotic stroke and the control subjects. The investigators expect a
      higher incidence of silent brain infarction in the group with stroke of likely cardio-embolic
      origin. With atrial cardiomyopathy investigated thoroughly in patients with stroke of likely
      cardio-embolic origin the future work-up and treatment strategies could be more efficient and
      may thus improve the prognosis in terms of mortality and disability for a considerable number
      of patients.
observational model: Case-Control
time perspective: Prospective
measure: Extent of the fibrosis in the Left Atrium (LA)
time frame: Within 12 weeks from index event
description: Measured with gadolinium enhanced cardiac MRI
measure: Left Atrial Emptying Function (LAEF)
time frame: Within 12 weeks from index event
description: Measured with gadolinium enhanced cardiac MRI
measure: Observational study: Incidence of silent brain infarctions
time frame: Between 1-2 years from index event
description: Incidence of silent brain infarctions assessed by follow-up MR-cerebrum (Only in patients)
measure: Left atrial volume
time frame: Within 12 weeks from index event
description: Assessed by cardiac MRI
measure: Left atrial appendage morphology
time frame: Within 8 weeks from index event
description: Assessed by cardiac MRI
measure: Left atrium volume
time frame: Within 12 weeks from index event
description: 2D and 3D left atrial volume assessed by transthoracic echocardiography
measure: Left atrium ejection fraction (LAEF)
time frame: Within 12 weeks from index event
description: Assessed by transthoracic echocardiography
measure: Speckle tracking of LA
time frame: Within 12 weeks from index event
description: Assessed by transthoracic echocardiography
measure: Atrial rhythm abnormalities: Number of premature atrial contractions (PAC) per hour. Number and length of runs of PAC
time frame: Within 4 weeks from index event
description: Assessed by 48-hours Holter monitoring
measure: Heart rate variability (HRV)
time frame: Within 4 weeks from index event
description: Time domain variables (meanNN, SDNN, SDANN, SDNNidx, RMSSD, pNN50)
measure: Thrombophilia biomarkers
time frame: Within 12 weeks from index event
description: Assessment of hypercoagulability
measure: Cardiac specific biomarkers
time frame: Within 12 weeks from index event
description: Atrial Natriuretic Peptide, pro NT-Brain Natriuretic Peptide, High Sensitive Troponins.
measure: Inflammatory biomarkers
time frame: Within 12 weeks from index event
description: High Sensitive CRP, Interleukins: IL1, IL1b, IL6, IL18
measure: Fibrosis related markers
time frame: Within 12 weeks from index event
description: Collagen type I and III
measure: Observational study: Assessing incidence of stroke, acute myocardial infarction, atrial fibrillation and cardiovascular-death
time frame: 1 year from last included patient
description: Follow up in patient records
arm group label: Stroke of likely cardioembolic cause or undetected mechanism
description: Lesions in at least one territory on MRI & absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% in arteries supplying the ischemic area(s) & absence of severe small vessel disease including micro-bleeds on Patients with central retinal artery occlusion documented by perimeter and absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% & absence of severe small vessel disease including micro-bleeds on MRI are included independent of acute MRI findings.
arm group label: Atherosclerotic stroke
description: Large vessel stroke: Acute lesions in one vascular territory on MRI, significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% leading to the infarcted territory & absence of severe small vessel disease including micro-bleeds on MRI Small Vessel stroke: MRI documenting lacunar infarction, absence of significant large vessel disease defined as stenosis of cerebral or pre-cerebral vessels >50% and presence of severe small vessel disease possibly including micro bleeds.
arm group label: Controls
description: Age and sex matched healthy controls with no history of stroke or AF.
For use in future studies of biomarkers and genes we will collect 2 samples of plasma and 1
      sample of full blood. Only patient who give informed consent will have these samples
      collected.
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: Ahmad Sajadieh, MD, DMSc
role: Principal Investigator
affiliation: University Hospital Bispebjerg and Frederiksberg
facility: 
country: Denmark
responsible party type: Principal Investigator
investigator affiliation: University Hospital Bispebjerg and Frederiksberg
investigator full name: Ahmad Sajadieh
investigator title: MD, DMSc
mesh term: Stroke
mesh term: Cardiomyopathies
sharing ipd: Undecided
ipd description: De-identified data will be made available to other research groups upon reasonable request.