<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/NCT04449523</url>
  </required_header>
  <id_info>
    <org_study_id>2020-00227</org_study_id>
    <nct_id>NCT04449523</nct_id>
  </id_info>
  <brief_title>Incidence of Silent Atrial Fibrillation in Patients With Clinically Silent Brain Ischemic Lesions</brief_title>
  <acronym>SILENT2</acronym>
  <official_title>Incidence of Silent Atrial Fibrillation in Patients With Clinically Silent Brain Ischemic Lesions (SILENT2)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</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>
      Arterial Fibrillation (AF) is well-recognized as a cause for cryptogenic Acute Ischemic&#xD;
      Stroke (AIS) and is associated with Silent Brain Infarction (SBI). However, the role of AF in&#xD;
      the formation of lesions (SBIs) is less well established than its role in AIS and needs&#xD;
      clarification.&#xD;
&#xD;
      The investigators hypothesize that continuous rhythm monitoring will yield a similar&#xD;
      incidence of AF diagnosis in patients with SBI as compared to patients with cryptogenic AIS.&#xD;
&#xD;
      The primary objective is to assess the cumulative incidence of AF diagnosis at 24 months in&#xD;
      patients with SBI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Arterial Fibrillation (AF) is well-recognized as a cause for cryptogenic Acute Ischemic&#xD;
      Stroke (AIS) and searched for in clinical practice. However, although AF is associated with&#xD;
      Silent Brain Infarction (SBI), its role in the formation of these lesions is less well&#xD;
      established and needs clarification. A multitude of clinical, laboratory, echocardiographic&#xD;
      and electrocardiographic parameters are associated with AF. Although no single one of these&#xD;
      parameters has sufficient specificity to rule-in AF, their combined use may nevertheless help&#xD;
      to identify patients with SBI at highest risk for AF. The study is expected to provide&#xD;
      evidence that long term monitoring in subjects with SBI yields similar rates of AF as in AIS&#xD;
      patients.&#xD;
&#xD;
      Patients aged ≥65 years with a presumably silent brain lesion in a brain magnetic resonance&#xD;
      imaging fulfilling inclusion criteria and consenting get a subcutaneous implantation of a&#xD;
      cardiac monitor (Reveal LINQ). Data will be directly transferred to the treating physician by&#xD;
      the Medtronic MyCareLink Patient Monitor. In case of a relevant arrhythmia, the respective&#xD;
      study site will be informed by the staff of Inselspital. Relevant arrhythmias are defined as&#xD;
      follows:&#xD;
&#xD;
        -  First episode of atrial fibrillation (≥30 seconds)&#xD;
&#xD;
        -  Sustained ventricular tachycardia (≥30 seconds)&#xD;
&#xD;
        -  Sustained supraventricular tachycardia (≥30 seconds)&#xD;
&#xD;
        -  Asystoly of ≥6 seconds duration&#xD;
&#xD;
        -  Atrial fibrillation with pause of ≥6 seconds duration&#xD;
&#xD;
        -  Higher degree atrioventricular (AV) block (3° AV bloc; 2:1 AV conduction; 2° AV block&#xD;
           type Mobitz)&#xD;
&#xD;
        -  Sustained bradycardia &lt;30 beats per minute (≥30 seconds) It is the responsibility of the&#xD;
           respective study sites to take appropriate actions and inform the patients and treating&#xD;
           physicians about relevant findings. The maximal timeframe from data transmission to data&#xD;
           analysis is one week and from data transmission to patient notification two weeks.&#xD;
&#xD;
      The expected results of the study would be supportive in introducing long term monitoring to&#xD;
      the care pathway in subjects with SBI. Since SBI are more prevalent than AIS and current&#xD;
      recommendations very restrictive, this would have a relevant impact on SBI management.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 8, 2020</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Cumulative incidence of Arterial Fibrillation (AF) diagnosis over a median of 24 months</measure>
    <time_frame>From day 0 to 24 months after inclusion</time_frame>
    <description>Only adjudicated events will be used for the analysis. An AF episode is defined as lasting more than 30 seconds. A diagnosis of atrial flutter will also be considered as a primary endpoint.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to first diagnosis of AF (lasting ≥30 seconds; ≥6 minutes; ≥1 hour; ≥ 24 hour)</measure>
    <time_frame>From day 0 to 24 months after inclusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Burden of AF</measure>
    <time_frame>From day 0 to 24 months after inclusion</time_frame>
    <description>The burden of AF is defined as the amount of time (percentage) in AF during rhythm monitoring. AF burden will be calculated on a monthly basis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to composite of first diagnosis of AF, stroke and death.</measure>
    <time_frame>From day 0 to 24 months after inclusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of AF diagnosis according to Silent Brain Infarction (SBI) neuroradiological appearance (subcortical small vessel versus embolic pattern involving grey matter) and SBI fulfilling ESUS criteria versus lacunar type.</measure>
    <time_frame>From day 0 to 24 months after inclusion</time_frame>
    <description>Embolic stroke of undetermined source (ESUS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Start of oral anticoagulation therapy at 24 months.</measure>
    <time_frame>At 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stroke at 24 months</measure>
    <time_frame>At 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality at 24 months</measure>
    <time_frame>At 24 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence of other possible etiologies for SBI according to a modified TOAST-classification (large artery disease, small artery disease, other specific etiologies, unknown etiology, incomplete workup)</measure>
    <time_frame>From day 0 to 24 months after inclusion</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of new SBI at 24 months (only if sufficient funding can be obtained for repeat brain MRI at 24 months without contrast agent)</measure>
    <time_frame>At 24 months</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Time to first diagnosis of AF (lasting ≥30 seconds; ≥6 minutes; ≥1 hour; ≥ 24 hours) until battery depletion of Implantable Cardiac Monitor (ICM) (36-42 month).</measure>
    <time_frame>From day 0 until battery depletion, expected to be 36 to 42 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Cumulative incidence of AF diagnosis until battery depletion of ICM</measure>
    <time_frame>From day 0 to until battery depletion, expected to be 36 to 42 months</time_frame>
  </other_outcome>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Silent Stroke</condition>
  <condition>Silent Cerebral Infarct</condition>
  <condition>Fibrillation</condition>
  <eligibility>
    <study_pop>
      <textblock>
        ≥ 50 years&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age&#xD;
&#xD;
               -  ≥ 65 years&#xD;
&#xD;
               -  ≥ 50 years AND one the following:&#xD;
&#xD;
                    -  NT-proBNP &gt;400 pg/mL&#xD;
&#xD;
                    -  Left atrial ventricular index &gt;42 ml/m2 or left atrial diameter &gt;46 mm&#xD;
&#xD;
                    -  Covert infarctions with cortical involvement in more than one vascular&#xD;
                       territory (left carotid territory, right carotid territory, vertebrobasilar&#xD;
                       territory)&#xD;
&#xD;
          -  Written informed Consent&#xD;
&#xD;
          -  Any clinically silent ischemic lesions of the brain parenchyma detected on&#xD;
             neuroimaging defined according to established criteria as either:&#xD;
&#xD;
               -  Diffusion weighted imaging (DWI) positive lesions: Focus of restricted diffusion&#xD;
                  (high DWI signal and low apparent diffusion coefficient value) occurring in&#xD;
                  either white or gray matter, located in the cerebrum, cerebellum, or brain stem&#xD;
                  AND not satisfying the diagnostic criteria for multiple sclerosis OR&#xD;
&#xD;
               -  Cavitatory Lesions: ≥ 3 mm in size that follow cerebro-spinal fluid on all&#xD;
                  sequences that are slit or wedge shaped with an irregular margin AND NOT&#xD;
                  longitudinally aligned with perforating vessels or with a multiple, bilateral&#xD;
                  symmetrical distribution OR&#xD;
&#xD;
               -  T2 weighted (T2W) hyperintense/T1 weighted (T1W) hypointense lesions:&#xD;
&#xD;
                    -  Focal lesion with high T2W signal and low T1W signal that have prior&#xD;
                       evidence of restricted diffusion; OR&#xD;
&#xD;
                    -  Present within cortical gray matter or deep gray matter nuclei OR&#xD;
&#xD;
                    -  A lesion that is new, compared with an MRI performed within 3 months OR&#xD;
&#xD;
                    -  T2W hyper/T1W hypointense lesions in the white matter, which are&#xD;
                       discontinuous but associated with the classic confluent periventricular T2&#xD;
                       intense change of leukoaraiosis (Fazekas ≥2) AND NOT satisfying the&#xD;
                       diagnostic criteria for multiple sclerosis or with a significant patient&#xD;
                       history of severe trauma, radiation, drug toxicity, or carbon monoxide&#xD;
                       poisoning&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of AF or atrial flutter&#xD;
&#xD;
          -  Patients with a history of symptoms compatible with an AIS, covert neurological&#xD;
             deficits are allowed.&#xD;
&#xD;
          -  Cardiac implantable electronic devices (pacemaker, implantable cardiac defibrillator&#xD;
             (ICD), implantable cardiac monitor (ICM))&#xD;
&#xD;
          -  Indication for cardiac implantable electronic device implantation (pacemaker, ICD,&#xD;
             ICM)&#xD;
&#xD;
          -  History of or indication for major cardiac surgery or transcutaneous aortic valve&#xD;
             implantation&#xD;
&#xD;
          -  Indication for permanent oral anticoagulation&#xD;
&#xD;
          -  Contraindication for permanent oral anticoagulation&#xD;
&#xD;
          -  Projected life expectancy of less than 2 years&#xD;
&#xD;
          -  Active intra- or extracranial high-grade malignancy&#xD;
&#xD;
          -  Patient is already included in another clinical trial that will affect the objectives&#xD;
             of this study&#xD;
&#xD;
          -  Patient's lack of accountability, inability to appreciate the nature, meaning and&#xD;
             consequences of the study and to formulate his/her own wishes correspondingly&#xD;
&#xD;
          -  Inability to follow the procedures of the study, e.g. due to language problems,&#xD;
             psychological disorders, dementia, etc.&#xD;
&#xD;
          -  Known or suspected non-compliance, drug or alcohol abuse&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Laurent Roten, PD Dr. med.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Inselgruppe AG</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Laurent Roten, PD Dr. med.</last_name>
    <phone>+41 31 632 52 63</phone>
    <email>laurent.roten@insel.ch</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Thomas Meinel, Dr. med.</last_name>
    <phone>+41 76 49 28 545</phone>
    <email>thomas.meinel@insel.ch</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Universitätsspital Graz</name>
      <address>
        <city>Graz</city>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Markus Kneihsl, MD PhD</last_name>
      <email>markus.kneihsl@medunigraz.at</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Charite Berlin</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Christian Nolte, Prof</last_name>
      <email>christian.nolte@charite.de</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre hospitalier universitaire vaudois (CHUV)</name>
      <address>
        <city>Lausanne</city>
        <state>Vaud</state>
        <zip>1011</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Patrizio Pascale, PD Dr. med.</last_name>
      <email>patrizio.pascale@chuv.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kantonsspital Aarau</name>
      <address>
        <city>Aarau</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>University Hospital Basel</name>
      <address>
        <city>Basel</city>
        <zip>4031</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Kühne, Prof.</last_name>
      <email>michael.kuehne@usb.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Inselspital Bern</name>
      <address>
        <city>Bern</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laurent Roten, PD Dr. med.</last_name>
      <email>laurent.roten@insel.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Kantonsspital St.Gallen</name>
      <address>
        <city>Saint Gallen</city>
        <zip>9007</zip>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Peter Ammann, Prof.</last_name>
      <email>peter.ammann@kssg.ch</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Universitätsspital Zurich</name>
      <address>
        <city>Zurich</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Susanne Wegener, Prof</last_name>
      <email>Susanne.Wegener@usz.ch</email>
    </contact>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Germany</country>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 17, 2020</study_first_submitted>
  <study_first_submitted_qc>June 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 29, 2020</study_first_posted>
  <last_update_submitted>June 19, 2023</last_update_submitted>
  <last_update_submitted_qc>June 19, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cerebral Infarction</mesh_term>
    <mesh_term>Atrial Fibrillation</mesh_term>
  </condition_browse>
  <!-- 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/NCT04449523
org study id: 2020-00227
nct id: NCT04449523
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Arterial Fibrillation (AF) is well-recognized as a cause for cryptogenic Acute Ischemic
      Stroke (AIS) and is associated with Silent Brain Infarction (SBI). However, the role of AF in
      the formation of lesions (SBIs) is less well established than its role in AIS and needs
      clarification.

      The investigators hypothesize that continuous rhythm monitoring will yield a similar
      incidence of AF diagnosis in patients with SBI as compared to patients with cryptogenic AIS.

      The primary objective is to assess the cumulative incidence of AF diagnosis at 24 months in
      patients with SBI.
Arterial Fibrillation (AF) is well-recognized as a cause for cryptogenic Acute Ischemic
      Stroke (AIS) and searched for in clinical practice. However, although AF is associated with
      Silent Brain Infarction (SBI), its role in the formation of these lesions is less well
      established and needs clarification. A multitude of clinical, laboratory, echocardiographic
      and electrocardiographic parameters are associated with AF. Although no single one of these
      parameters has sufficient specificity to rule-in AF, their combined use may nevertheless help
      to identify patients with SBI at highest risk for AF. The study is expected to provide
      evidence that long term monitoring in subjects with SBI yields similar rates of AF as in AIS
      patients.

      Patients aged ≥65 years with a presumably silent brain lesion in a brain magnetic resonance
      imaging fulfilling inclusion criteria and consenting get a subcutaneous implantation of a
      cardiac monitor (Reveal LINQ). Data will be directly transferred to the treating physician by
      the Medtronic MyCareLink Patient Monitor. In case of a relevant arrhythmia, the respective
      study site will be informed by the staff of Inselspital. Relevant arrhythmias are defined as
      follows:

        -  First episode of atrial fibrillation (≥30 seconds)

        -  Sustained ventricular tachycardia (≥30 seconds)

        -  Sustained supraventricular tachycardia (≥30 seconds)

        -  Asystoly of ≥6 seconds duration

        -  Atrial fibrillation with pause of ≥6 seconds duration

        -  Higher degree atrioventricular (AV) block (3° AV bloc; 2:1 AV conduction; 2° AV block
           type Mobitz)

        -  Sustained bradycardia <30 beats per minute (≥30 seconds) It is the responsibility of the
           respective study sites to take appropriate actions and inform the patients and treating
           physicians about relevant findings. The maximal timeframe from data transmission to data
           analysis is one week and from data transmission to patient notification two weeks.

      The expected results of the study would be supportive in introducing long term monitoring to
      the care pathway in subjects with SBI. Since SBI are more prevalent than AIS and current
      recommendations very restrictive, this would have a relevant impact on SBI management.
observational model: Cohort
time perspective: Prospective
measure: Cumulative incidence of Arterial Fibrillation (AF) diagnosis over a median of 24 months
time frame: From day 0 to 24 months after inclusion
description: Only adjudicated events will be used for the analysis. An AF episode is defined as lasting more than 30 seconds. A diagnosis of atrial flutter will also be considered as a primary endpoint.
measure: Time to first diagnosis of AF (lasting ≥30 seconds; ≥6 minutes; ≥1 hour; ≥ 24 hour)
time frame: From day 0 to 24 months after inclusion
measure: Burden of AF
time frame: From day 0 to 24 months after inclusion
description: The burden of AF is defined as the amount of time (percentage) in AF during rhythm monitoring. AF burden will be calculated on a monthly basis.
measure: Time to composite of first diagnosis of AF, stroke and death.
time frame: From day 0 to 24 months after inclusion
measure: Incidence of AF diagnosis according to Silent Brain Infarction (SBI) neuroradiological appearance (subcortical small vessel versus embolic pattern involving grey matter) and SBI fulfilling ESUS criteria versus lacunar type.
time frame: From day 0 to 24 months after inclusion
description: Embolic stroke of undetermined source (ESUS)
measure: Start of oral anticoagulation therapy at 24 months.
time frame: At 24 months
measure: Stroke at 24 months
time frame: At 24 months
measure: Mortality at 24 months
time frame: At 24 months
measure: Prevalence of other possible etiologies for SBI according to a modified TOAST-classification (large artery disease, small artery disease, other specific etiologies, unknown etiology, incomplete workup)
time frame: From day 0 to 24 months after inclusion
measure: Incidence of new SBI at 24 months (only if sufficient funding can be obtained for repeat brain MRI at 24 months without contrast agent)
time frame: At 24 months
measure: Time to first diagnosis of AF (lasting ≥30 seconds; ≥6 minutes; ≥1 hour; ≥ 24 hours) until battery depletion of Implantable Cardiac Monitor (ICM) (36-42 month).
time frame: From day 0 until battery depletion, expected to be 36 to 42 months
measure: Cumulative incidence of AF diagnosis until battery depletion of ICM
time frame: From day 0 to until battery depletion, expected to be 36 to 42 months
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: No
last name: Laurent Roten, PD Dr. med.
role: Principal Investigator
affiliation: Inselgruppe AG
last name: Laurent Roten, PD Dr. med.
phone: +41 31 632 52 63
email: laurent.roten@insel.ch
last name: Thomas Meinel, Dr. med.
phone: +41 76 49 28 545
email: thomas.meinel@insel.ch
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Austria
country: Germany
country: Switzerland
responsible party type: Sponsor
mesh term: Cerebral Infarction
mesh term: Atrial Fibrillation