<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/NCT04400513</url>
  </required_header>
  <id_info>
    <org_study_id>2020.3</org_study_id>
    <nct_id>NCT04400513</nct_id>
  </id_info>
  <brief_title>Development of an Algorithm to Differentiate Heart Murmurs Using Electronic Stethoscopes</brief_title>
  <official_title>Development of an Algorithm to Differentiate Heart Murmurs by Timing, Disease Type, and Severity in Adult Patients Using Electronic Stethoscopes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Eko Devices, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Eko Devices, Inc.</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The Eko CORE and DUO stethoscopes are FDA-approved electronic devices that have the capacity&#xD;
      to record heart sounds. The study seeks to expand murmur detection to include VHD&#xD;
      classification through the development of novel ML algorithms that are able to distinguish&#xD;
      between systolic vs. diastolic vs. continuous murmurs, as well as classify VHD type and&#xD;
      severity, using 4-point auscultation with Eko CORE and DUO electronic stethoscopes to record&#xD;
      heart sounds.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Valvular heart disease (VHD), a subclass of structural heart disease (SHD), is a major cause&#xD;
      of mortality and reduced quality of life for tens of millions of patients worldwide.&#xD;
      Detecting VHD early allows the disease to be carefully monitored so that surgery can be&#xD;
      considered as soon as the stenosis progresses to severe. Unfortunately, it is difficult for&#xD;
      many clinicians to accurately identify VHD in its early stages and assess its severity&#xD;
      through physical examination alone. This difficulty stems from both the subtlety of symptoms&#xD;
      associated with VHD, and from clinicians' inability to reliably detect the heart murmurs&#xD;
      indicative of VHD using a traditional stethoscope, particularly in the noisy and rushed&#xD;
      environments characteristic of many healthcare settings.&#xD;
&#xD;
      AS, mitral regurgitation (MR), and tricuspid regurgitation (TR) all result in reliably&#xD;
      reproducible auscultatory findings. Yet despite this, auscultation as a diagnostic procedure&#xD;
      is notoriously poor: its accuracy to detect AS, MR, and TR ranges only from 5-40%. In&#xD;
      addition, diastolic and continuous murmurs, which are rarer than the systolic murmurs caused&#xD;
      by AS, MR and TR, and almost always pathologic, are usually very difficult to detect by&#xD;
      frontline clinicians. Diastolic murmurs are typically caused by VHD such as aortic&#xD;
      regurgitation (AR), pulmonic regurgitation (PR), mitral stenosis (MS), or tricuspid stenosis&#xD;
      (TS), and continuous murmurs are typically caused by non-valvular forms of SHD, such as&#xD;
      congenital aortopulmonary window, shunts, and patent ductus arteriosus (PDA). Missing one of&#xD;
      these murmurs could lead to significantly delayed diagnosis and care.&#xD;
&#xD;
      Because of how difficult it is for clinicians to reliably screen for SHD through history&#xD;
      taking and physical examination, the diagnosis of SHD relies heavily on echocardiography&#xD;
      (echos), which is accepted as the gold standard for diagnosis of SHD severity by the&#xD;
      cardiology community. The consequence of this is several-fold. First, many patients receive&#xD;
      echos that would not be necessary if better screening and assessment tools existed. Second,&#xD;
      echocardiography makes up a disproportionately large segment of healthcare expenditure.&#xD;
      Third, patients are burdened with the responsibility of getting repeated echos due to the&#xD;
      lack of better screening tools. The emotional, physical, and financial burden that&#xD;
      accompanies such excessive testing, especially for patients living in underserved&#xD;
      communities, cannot be overstated.&#xD;
&#xD;
      Overall, there is a growing need for better preliminary screening tools that would identify&#xD;
      these conditions, even when asymptomatic, early on and more consistently, to a degree of&#xD;
      accuracy comparable to gold standard echocardiography. Such a tool would improve clinicians'&#xD;
      confidence in their assessment during physical exams, which would enable them to help their&#xD;
      patients make informed care decisions, offer disease-altering therapies, and at the same time&#xD;
      reduce the reliance on, and frequency of, unnecessary and expensive auxiliary workups.&#xD;
      Lastly, by facilitating early detection of VHD, morbidity and mortality rates would be&#xD;
      expected to decrease due to earlier intervention.&#xD;
&#xD;
      The FDA-approved Eko CORE and Eko DUO electronic stethoscopes offer clinicians a familiar and&#xD;
      inexpensive tool that is widely accepted by patients, while at the same time offer sensors&#xD;
      and technology that can improve screening and detection of medical conditions such as valve&#xD;
      disease, as compared to auscultation with the traditional stethoscope. Both CORE and DUO&#xD;
      feature sound amplification during auscultation, which improves the ability for the clinician&#xD;
      to detect nuanced changes in heart sounds and patterns. The CORE allows recording of the&#xD;
      audio to produce a phonocardiogram (PCG), while the DUO is able to record audio to produce a&#xD;
      PCG as well as simultaneous recording of a single-lead electrocardiogram (ECG). Both devices&#xD;
      use Bluetooth to wirelessly transmit PCG and ECG data to the Eko mobile application, which&#xD;
      allows clinicians to visualize PCG and ECG as they auscultate, as well as to playback heart&#xD;
      sound recordings, annotate notes on recorded audio, and save and share recordings. These&#xD;
      features uniquely situate Eko electronic stethoscopes to be highly effective as preliminary&#xD;
      screening tools in clinical practice.&#xD;
&#xD;
      Eko Devices has developed and received 510(k) FDA approval for a machine-learning (ML)&#xD;
      algorithm that can detect the presence or absence of heart murmur in adult patients with VHD,&#xD;
      using either the Eko CORE or DUO electronic stethoscopes to record heart sounds. This&#xD;
      algorithm was built using a deep neural network model trained on 5,878 PCG recordings&#xD;
      collected on Eko CORE and Eko DUO from over 5,318 unique patients to classify heart sound&#xD;
      recordings as containing a heart murmur or containing no audible murmur, and to discriminate&#xD;
      good quality heart sound recordings from poor quality heart sound recordings. The trained&#xD;
      model has been independently validated in a multi-site clinical study that enrolled 681 VHD&#xD;
      patients with matched gold-standard echocardiograms. FDA approval was received in January&#xD;
      2020.&#xD;
&#xD;
      The present study seeks to expand murmur detection to include VHD classification through the&#xD;
      development of novel ML algorithms that are able to distinguish between systolic vs.&#xD;
      diastolic vs. continuous murmurs, as well as classify VHD type and severity, using 4-point&#xD;
      auscultation with Eko CORE and DUO electronic stethoscopes to record heart sounds. These new&#xD;
      algorithms will integrate the time-synchronized ECG streams from DUO to improve distinction&#xD;
      between S1 and S2 heart sounds and improve performance of identifying systolic vs. diastolic&#xD;
      time intervals. When combined with the FDA-approved algorithm for signal quality and murmur&#xD;
      detection, these new algorithms will enable clinicians to have a complete VHD decision&#xD;
      support system, as based on ACC/AHA Patient Management Guidelines, when using Eko&#xD;
      stethoscopes in their clinical practice.20 This will arm clinicians with information to help&#xD;
      them detect SHD early, make clinical care decisions with confidence and consistency, and&#xD;
      improve overall patient outcomes while decreasing cost and increasing efficiency.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 25, 2020</start_date>
  <completion_date type="Actual">December 31, 2021</completion_date>
  <primary_completion_date type="Actual">June 30, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Murmur Timing</measure>
    <time_frame>Within two minutes of device use</time_frame>
    <description>Develop a model that can classify murmurs based on the timing of the murmur in the cardiac cycle, allowing the algorithm to distinguish between systolic, diastolic, and continuous murmurs using time-synchronized ECG and PCG data.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Systolic Murmur Type Classification</measure>
    <time_frame>Within two minutes of device use</time_frame>
    <description>Develop a model that can classify systolic murmurs into disease categories including aortic stenosis (AS), mitral regurgitation (MR), tricuspid regurgitation (TR), other (O), and innocent murmurs (I).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systolic Murmur Severity Classification</measure>
    <time_frame>Within two minutes of device use</time_frame>
    <description>Develop a model that can grade the severity of AS, MR, and TR following the American Society of Echocardiography (ASE) guidelines as mild, moderate, or severe.</description>
  </secondary_outcome>
  <number_of_groups>6</number_of_groups>
  <enrollment type="Actual">1145</enrollment>
  <condition>Murmur, Heart</condition>
  <condition>Aortic Valve Stenosis</condition>
  <condition>Tricuspid Regurgitation</condition>
  <condition>Mitral Regurgitation</condition>
  <condition>Innocent Murmurs</condition>
  <condition>Heart Murmurs</condition>
  <arm_group>
    <arm_group_label>Aortic Stenosis</arm_group_label>
    <description>Subjects with echo-confirmed AS graded moderate-to-severe or worse</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Mitral Regurgitation</arm_group_label>
    <description>Subjects with echo-confirmed MR graded moderate-to-severe or worse</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tricuspid Regurgitation</arm_group_label>
    <description>Subjects with echo-confirmed TR graded moderate-to-severe or worse</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Innocent Murmur</arm_group_label>
    <description>Subjects with echo-confirmed trace/trivial valve disease severity</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Diastolic Murmur</arm_group_label>
    <description>Subjects with pathology associated with diastolic murmur (e.g. AR, PR, MS, TS)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Continuous Murmur</arm_group_label>
    <description>Subjects with pathology associated with continuous murmur (e.g. congenital shunts, PDA)</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Use of Eko CORE and Eko DUO electronic stethoscopes</intervention_name>
    <description>Auscultation of heart sounds using electronic stethoscopes</description>
    <arm_group_label>Aortic Stenosis</arm_group_label>
    <arm_group_label>Continuous Murmur</arm_group_label>
    <arm_group_label>Diastolic Murmur</arm_group_label>
    <arm_group_label>Innocent Murmur</arm_group_label>
    <arm_group_label>Mitral Regurgitation</arm_group_label>
    <arm_group_label>Tricuspid Regurgitation</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Potential research subjects will be screened for eligibility from cardiology clinics,&#xD;
        echocardiogram clinics, and inpatient areas. Alternatively, potential subjects will be&#xD;
        identified in the echocardiography clinic the day of their echocardiogram appointment and&#xD;
        approached for participation once eligibility is confirmed.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adults aged 18 years and older&#xD;
&#xD;
          2. Patient or patient's legal healthcare proxy consents to participation&#xD;
&#xD;
          3. Have an audible heart murmur in at least one auscultation position, as heard by a&#xD;
             clinician&#xD;
&#xD;
          4. Undergoing or have undergone a complete (i.e., not limited) echocardiogram&#xD;
&#xD;
          5. Willing to have heart recordings done with two different electronic stethoscopes&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient or proxy is unwilling or unable to give written informed consent&#xD;
&#xD;
          2. Unable to complete a full clinical echocardiogram&#xD;
&#xD;
          3. No audible heart murmur in at least one auscultation position, as heard by a clinician&#xD;
&#xD;
          4. Experiencing a known or suspected acute cardiac event&#xD;
&#xD;
          5. Mechanical ventricular support (such as ECMO, LVAD, RVAD, BiVAD, Impella, intra-aortic&#xD;
             balloon pumps, TAH, VentrAssist, DuraHeart, HVAD, EVAHEART LVAS, HeartMate, Jarvik&#xD;
             2000)&#xD;
&#xD;
          6. Unwilling or unable to follow or complete study procedures&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>CoxHealth</name>
      <address>
        <city>Springfield</city>
        <state>Missouri</state>
        <zip>65807</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>May 18, 2020</study_first_submitted>
  <study_first_submitted_qc>May 21, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 22, 2020</study_first_posted>
  <last_update_submitted>February 13, 2023</last_update_submitted>
  <last_update_submitted_qc>February 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>artificial intelligence</keyword>
  <keyword>machine learning</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aortic Valve Stenosis</mesh_term>
    <mesh_term>Mitral Valve Insufficiency</mesh_term>
    <mesh_term>Tricuspid Valve Insufficiency</mesh_term>
    <mesh_term>Heart Murmurs</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/NCT04400513
org study id: 2020.3
nct id: NCT04400513
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The Eko CORE and DUO stethoscopes are FDA-approved electronic devices that have the capacity
      to record heart sounds. The study seeks to expand murmur detection to include VHD
      classification through the development of novel ML algorithms that are able to distinguish
      between systolic vs. diastolic vs. continuous murmurs, as well as classify VHD type and
      severity, using 4-point auscultation with Eko CORE and DUO electronic stethoscopes to record
      heart sounds.
Valvular heart disease (VHD), a subclass of structural heart disease (SHD), is a major cause
      of mortality and reduced quality of life for tens of millions of patients worldwide.
      Detecting VHD early allows the disease to be carefully monitored so that surgery can be
      considered as soon as the stenosis progresses to severe. Unfortunately, it is difficult for
      many clinicians to accurately identify VHD in its early stages and assess its severity
      through physical examination alone. This difficulty stems from both the subtlety of symptoms
      associated with VHD, and from clinicians' inability to reliably detect the heart murmurs
      indicative of VHD using a traditional stethoscope, particularly in the noisy and rushed
      environments characteristic of many healthcare settings.

      AS, mitral regurgitation (MR), and tricuspid regurgitation (TR) all result in reliably
      reproducible auscultatory findings. Yet despite this, auscultation as a diagnostic procedure
      is notoriously poor: its accuracy to detect AS, MR, and TR ranges only from 5-40%. In
      addition, diastolic and continuous murmurs, which are rarer than the systolic murmurs caused
      by AS, MR and TR, and almost always pathologic, are usually very difficult to detect by
      frontline clinicians. Diastolic murmurs are typically caused by VHD such as aortic
      regurgitation (AR), pulmonic regurgitation (PR), mitral stenosis (MS), or tricuspid stenosis
      (TS), and continuous murmurs are typically caused by non-valvular forms of SHD, such as
      congenital aortopulmonary window, shunts, and patent ductus arteriosus (PDA). Missing one of
      these murmurs could lead to significantly delayed diagnosis and care.

      Because of how difficult it is for clinicians to reliably screen for SHD through history
      taking and physical examination, the diagnosis of SHD relies heavily on echocardiography
      (echos), which is accepted as the gold standard for diagnosis of SHD severity by the
      cardiology community. The consequence of this is several-fold. First, many patients receive
      echos that would not be necessary if better screening and assessment tools existed. Second,
      echocardiography makes up a disproportionately large segment of healthcare expenditure.
      Third, patients are burdened with the responsibility of getting repeated echos due to the
      lack of better screening tools. The emotional, physical, and financial burden that
      accompanies such excessive testing, especially for patients living in underserved
      communities, cannot be overstated.

      Overall, there is a growing need for better preliminary screening tools that would identify
      these conditions, even when asymptomatic, early on and more consistently, to a degree of
      accuracy comparable to gold standard echocardiography. Such a tool would improve clinicians'
      confidence in their assessment during physical exams, which would enable them to help their
      patients make informed care decisions, offer disease-altering therapies, and at the same time
      reduce the reliance on, and frequency of, unnecessary and expensive auxiliary workups.
      Lastly, by facilitating early detection of VHD, morbidity and mortality rates would be
      expected to decrease due to earlier intervention.

      The FDA-approved Eko CORE and Eko DUO electronic stethoscopes offer clinicians a familiar and
      inexpensive tool that is widely accepted by patients, while at the same time offer sensors
      and technology that can improve screening and detection of medical conditions such as valve
      disease, as compared to auscultation with the traditional stethoscope. Both CORE and DUO
      feature sound amplification during auscultation, which improves the ability for the clinician
      to detect nuanced changes in heart sounds and patterns. The CORE allows recording of the
      audio to produce a phonocardiogram (PCG), while the DUO is able to record audio to produce a
      PCG as well as simultaneous recording of a single-lead electrocardiogram (ECG). Both devices
      use Bluetooth to wirelessly transmit PCG and ECG data to the Eko mobile application, which
      allows clinicians to visualize PCG and ECG as they auscultate, as well as to playback heart
      sound recordings, annotate notes on recorded audio, and save and share recordings. These
      features uniquely situate Eko electronic stethoscopes to be highly effective as preliminary
      screening tools in clinical practice.

      Eko Devices has developed and received 510(k) FDA approval for a machine-learning (ML)
      algorithm that can detect the presence or absence of heart murmur in adult patients with VHD,
      using either the Eko CORE or DUO electronic stethoscopes to record heart sounds. This
      algorithm was built using a deep neural network model trained on 5,878 PCG recordings
      collected on Eko CORE and Eko DUO from over 5,318 unique patients to classify heart sound
      recordings as containing a heart murmur or containing no audible murmur, and to discriminate
      good quality heart sound recordings from poor quality heart sound recordings. The trained
      model has been independently validated in a multi-site clinical study that enrolled 681 VHD
      patients with matched gold-standard echocardiograms. FDA approval was received in January
      2020.

      The present study seeks to expand murmur detection to include VHD classification through the
      development of novel ML algorithms that are able to distinguish between systolic vs.
      diastolic vs. continuous murmurs, as well as classify VHD type and severity, using 4-point
      auscultation with Eko CORE and DUO electronic stethoscopes to record heart sounds. These new
      algorithms will integrate the time-synchronized ECG streams from DUO to improve distinction
      between S1 and S2 heart sounds and improve performance of identifying systolic vs. diastolic
      time intervals. When combined with the FDA-approved algorithm for signal quality and murmur
      detection, these new algorithms will enable clinicians to have a complete VHD decision
      support system, as based on ACC/AHA Patient Management Guidelines, when using Eko
      stethoscopes in their clinical practice.20 This will arm clinicians with information to help
      them detect SHD early, make clinical care decisions with confidence and consistency, and
      improve overall patient outcomes while decreasing cost and increasing efficiency.
observational model: Other
time perspective: Cross-Sectional
measure: Murmur Timing
time frame: Within two minutes of device use
description: Develop a model that can classify murmurs based on the timing of the murmur in the cardiac cycle, allowing the algorithm to distinguish between systolic, diastolic, and continuous murmurs using time-synchronized ECG and PCG data.
measure: Systolic Murmur Type Classification
time frame: Within two minutes of device use
description: Develop a model that can classify systolic murmurs into disease categories including aortic stenosis (AS), mitral regurgitation (MR), tricuspid regurgitation (TR), other (O), and innocent murmurs (I).
measure: Systolic Murmur Severity Classification
time frame: Within two minutes of device use
description: Develop a model that can grade the severity of AS, MR, and TR following the American Society of Echocardiography (ASE) guidelines as mild, moderate, or severe.
arm group label: Aortic Stenosis
description: Subjects with echo-confirmed AS graded moderate-to-severe or worse
arm group label: Mitral Regurgitation
description: Subjects with echo-confirmed MR graded moderate-to-severe or worse
arm group label: Tricuspid Regurgitation
description: Subjects with echo-confirmed TR graded moderate-to-severe or worse
arm group label: Innocent Murmur
description: Subjects with echo-confirmed trace/trivial valve disease severity
arm group label: Diastolic Murmur
description: Subjects with pathology associated with diastolic murmur (e.g. AR, PR, MS, TS)
arm group label: Continuous Murmur
description: Subjects with pathology associated with continuous murmur (e.g. congenital shunts, PDA)
intervention type: Device
intervention name: Use of Eko CORE and Eko DUO electronic stethoscopes
description: Auscultation of heart sounds using electronic stethoscopes
arm group label: Aortic Stenosis
arm group label: Continuous Murmur
arm group label: Diastolic Murmur
arm group label: Innocent Murmur
arm group label: Mitral Regurgitation
arm group label: Tricuspid Regurgitation
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor
mesh term: Aortic Valve Stenosis
mesh term: Mitral Valve Insufficiency
mesh term: Tricuspid Valve Insufficiency
mesh term: Heart Murmurs