<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/NCT04402645</url>
  </required_header>
  <id_info>
    <org_study_id>16-0111-E</org_study_id>
    <nct_id>NCT04402645</nct_id>
  </id_info>
  <brief_title>Novel Echocardiographic Methods for Early Identification of Neonates at Risk for Chronic Pulmonary Hypertension</brief_title>
  <official_title>Early Identification of Preterm Neonates With Evolving Chronic Pulmonary Hypertension: Utility of Functional Echocardiographic Markers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mount Sinai Hospital, Canada</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Sunnybrook Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Liverpool Women's NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Rotunda Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Iowa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>BC Women's Hospital &amp; Health Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Mount Sinai Hospital, Canada</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>
      Chronic pulmonary hypertension (cPHT) is a serious cardiopulmonary disorder that causes low&#xD;
      oxygen levels in the blood, difficulty in breathing and ultimately heart failure. Newborn&#xD;
      babies born extremely premature frequently suffer from cPHT while receiving treatment in&#xD;
      neonatal intensive care units and are more likely to die than those without cPHT.&#xD;
      Echocardiography is the investigation of choice for the assessment of heart function in&#xD;
      premature infants however however there is a significant lack of standardization,&#xD;
      sensitivity, and reliability for echocardiography parameters and a lack of consensus&#xD;
      regarding optimal detection timing. In adults and older children it is known that early&#xD;
      diagnosis and treatment, particularly before right side of the heart fails, is an important&#xD;
      determinant of treatment success and survival. Diagnosis late in postnatal course for preterm&#xD;
      infants remains a major barrier to timely and effective treatment.&#xD;
&#xD;
      The primary objective of this study is to develop new, sensitive, quantitative&#xD;
      echocardiographic diagnostic criteria which will allow for the identification of extreme&#xD;
      preterm neonates suffering from significantly high pressure in their pulmonary blood vessels,&#xD;
      early in postnatal course, when the disease is likely to be most amenable to&#xD;
      preventative/curative treatment.&#xD;
&#xD;
      This is an international initiative that will leverage expertise about echocardiography&#xD;
      techniques and cardiopulmonary physiology of preterm infants.The results of this study will&#xD;
      have an immediate impact on the day-to-day care of these highly vulnerable infants. The&#xD;
      results will lead to increased awareness among clinicians, inform future surveillance&#xD;
      protocols and diagnostic timing, and provide ideal preparation for future therapeutic trials.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multi-centre prospective observational study to develop new quantitative&#xD;
      echocardiography diagnostic criteria sensitive to identify the presence of chronic pulmonary&#xD;
      hypertension early in postnatal course. The investigators hypothesize that echocardiographic&#xD;
      markers of pulmonary vascular resistance (PVR) and right ventricular (RV) function will allow&#xD;
      early identification of extremely low birth weight (ELBW) preterm neonates who subsequently&#xD;
      develop chronic pulmonary hypertension in association with chronic neonatal lung disease.&#xD;
      More specifically, based on previous work and preliminary data, the investigators hypothesize&#xD;
      that tricuspid annular plane systolic excursion (TAPSE- a routinely used marker of right&#xD;
      heart function) and pulmonary artery acceleration time (PAAT- a routinely used marker of&#xD;
      resistance in the pulmonary blood vessels) either alone or in combination will be the most&#xD;
      sensitive parameters for early identification reducing the time to diagnosis compared to&#xD;
      contemporary clinical practice.&#xD;
&#xD;
      The aim of the study is to recruit a large cohort of extreme premature neonates at two weeks&#xD;
      of age and sequentially perform two &quot;early-diagnostic assessments&quot;. First assessment will be&#xD;
      performed between 14-21 days of life and the second at a corrected gestational age (CGA) of&#xD;
      32 weeks. Assessment will include a focused ultrasound of the heart to measure pre-defined&#xD;
      markers which are under investigation. The investigators will test the diagnostic utility of&#xD;
      these markers separately for each time point. All babies will also have a standard diagnostic&#xD;
      assessment for evaluation of cPHT at 36 weeks CGA, as per routine practice. The study team&#xD;
      will record this data for participants, along with their relevant medical details and&#xD;
      clinical outcomes, including neurodevelopment assessments performed at 18 months of age as a&#xD;
      routine clinical follow-up. At the end of this study, the investigators will divide the&#xD;
      cohort into those who developed cPHT and those who did not as per currently used standard&#xD;
      criteria and will compare the results of new parameters obtained at earlier time points. The&#xD;
      sensitivity of each marker to pick-up early cPHT will be calculated and its correlation with&#xD;
      health outcomes will be established.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 31, 2017</start_date>
  <completion_date type="Anticipated">August 2023</completion_date>
  <primary_completion_date type="Actual">August 31, 2022</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>Diagnostic test characteristics calculated for TAPSE and PAAT against diagnosis of chronic pulmonary hypertension on standard diagnostic assessment</measure>
    <time_frame>Early diagnostic assessments (14-21 days postnatal age; 32+0/7-32+6/7); Standard diagnostic assessment (~36 weeks CGA)</time_frame>
    <description>Sensitivity, specificity, positive and negative likelihood ratios for TAPSE and PAAT at each early diagnostic assessment against diagnosis of chronic pulmonary hypertension on standard diagnostic assessment using echocardiography using current standard criteria</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Composite of Death/ Chronic Neonatal Lung Disease</measure>
    <time_frame>Composite outcome measure will be assessed on the date of discharge for each study participant from the study Neonatal Intensive Care Unit (NICU) or date of death during admission (if applicable) up to 365 days.</time_frame>
    <description>Infant death prior to 36 weeks CGA and chronic neonatal lung disease are competing risks for the primary outcome of chronic pulmonary hypertension. The presence of both will be assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of need for respiratory support</measure>
    <time_frame>Outcome measure will be assessed on the date of discharge for each study participant from the study Neonatal Intensive Care Unit (NICU) or date of death during admission (if applicable) up to 365 days.</time_frame>
    <description>Total duration of need (number of days) for invasive, non-invasive and supplemental (low-flow) oxygen support</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay</measure>
    <time_frame>Outcome measure will be assessed on the date of discharge for each study participant from the study Neonatal Intensive Care Unit (NICU) or date of death during admission (if applicable) up to 365 days.</time_frame>
    <description>Length of NICU admission from birth to discharge (number of days)</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">350</enrollment>
  <condition>Pulmonary Hypertension</condition>
  <condition>Infant, Premature</condition>
  <arm_group>
    <arm_group_label>Chronic pulmonary hypertension</arm_group_label>
    <description>Diagnosis on echocardiography at 36 weeks CGA using standard criteria (flat interventricular septal motion or right ventricular dilatation)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No chronic pulmonary hypertension</arm_group_label>
    <description>Confirmed on echocardiography at 36 weeks CGA</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Preterm infants will be recruited from tertiary neonatal intensive care units (NICUs) in&#xD;
        Toronto (Mount Sinai Hospital and Sunnybrook Health Sciences Centre) and Vancouver (BC&#xD;
        Women's Hospital &amp; Health Centre) Canada, the United States (University of Iowa Health&#xD;
        Care, Iowa), and Europe (Liverpool University Hospitals NHS Foundation Trust and The&#xD;
        Rotunda Hospital)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Gestational age at birth ≤26+6/7 and/or birth weight &lt;1000g&#xD;
&#xD;
          -  Alive at two weeks of postnatal age&#xD;
&#xD;
          -  Infant cleared by the clinical team for approach&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known major congenital and/or genetic anomaly&#xD;
&#xD;
          -  Congenital heart defects (CHD) except patent ductus arteriosus (PDA), patent foramen&#xD;
             ovale (PFO), peripheral pulmonary artery stenosis and small (&lt; 3 mm in diameter)&#xD;
             ventricular septal defects&#xD;
&#xD;
          -  Any condition which, in the opinion of the investigator, would preclude enrollment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>14 Days</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amish Jain, MD, PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Staff Neonatologist, Clinician Scientist</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Iowa Health Care</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>BC Women's Hospital &amp; Health Centre</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V6H 3N1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rotunda Hospital</name>
      <address>
        <city>Dublin</city>
        <zip>1 DO1 P5W9</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Liverpool</name>
      <address>
        <city>Liverpool</city>
        <zip>L8 7SS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>Ireland</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>May 13, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>July 24, 2023</last_update_submitted>
  <last_update_submitted_qc>July 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Premature Infant</keyword>
  <keyword>Pulmonary Hypertension</keyword>
  <keyword>Echocardiography</keyword>
  <keyword>Extremely Low Birth Weight Neonate</keyword>
  <keyword>Pulmonary Vascular Resistance</keyword>
  <keyword>Right Ventricular Function</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension, Pulmonary</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04402645
org study id: 16-0111-E
nct id: NCT04402645
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Chronic pulmonary hypertension (cPHT) is a serious cardiopulmonary disorder that causes low
      oxygen levels in the blood, difficulty in breathing and ultimately heart failure. Newborn
      babies born extremely premature frequently suffer from cPHT while receiving treatment in
      neonatal intensive care units and are more likely to die than those without cPHT.
      Echocardiography is the investigation of choice for the assessment of heart function in
      premature infants however however there is a significant lack of standardization,
      sensitivity, and reliability for echocardiography parameters and a lack of consensus
      regarding optimal detection timing. In adults and older children it is known that early
      diagnosis and treatment, particularly before right side of the heart fails, is an important
      determinant of treatment success and survival. Diagnosis late in postnatal course for preterm
      infants remains a major barrier to timely and effective treatment.

      The primary objective of this study is to develop new, sensitive, quantitative
      echocardiographic diagnostic criteria which will allow for the identification of extreme
      preterm neonates suffering from significantly high pressure in their pulmonary blood vessels,
      early in postnatal course, when the disease is likely to be most amenable to
      preventative/curative treatment.

      This is an international initiative that will leverage expertise about echocardiography
      techniques and cardiopulmonary physiology of preterm infants.The results of this study will
      have an immediate impact on the day-to-day care of these highly vulnerable infants. The
      results will lead to increased awareness among clinicians, inform future surveillance
      protocols and diagnostic timing, and provide ideal preparation for future therapeutic trials.
This is a multi-centre prospective observational study to develop new quantitative
      echocardiography diagnostic criteria sensitive to identify the presence of chronic pulmonary
      hypertension early in postnatal course. The investigators hypothesize that echocardiographic
      markers of pulmonary vascular resistance (PVR) and right ventricular (RV) function will allow
      early identification of extremely low birth weight (ELBW) preterm neonates who subsequently
      develop chronic pulmonary hypertension in association with chronic neonatal lung disease.
      More specifically, based on previous work and preliminary data, the investigators hypothesize
      that tricuspid annular plane systolic excursion (TAPSE- a routinely used marker of right
      heart function) and pulmonary artery acceleration time (PAAT- a routinely used marker of
      resistance in the pulmonary blood vessels) either alone or in combination will be the most
      sensitive parameters for early identification reducing the time to diagnosis compared to
      contemporary clinical practice.

      The aim of the study is to recruit a large cohort of extreme premature neonates at two weeks
      of age and sequentially perform two "early-diagnostic assessments". First assessment will be
      performed between 14-21 days of life and the second at a corrected gestational age (CGA) of
      32 weeks. Assessment will include a focused ultrasound of the heart to measure pre-defined
      markers which are under investigation. The investigators will test the diagnostic utility of
      these markers separately for each time point. All babies will also have a standard diagnostic
      assessment for evaluation of cPHT at 36 weeks CGA, as per routine practice. The study team
      will record this data for participants, along with their relevant medical details and
      clinical outcomes, including neurodevelopment assessments performed at 18 months of age as a
      routine clinical follow-up. At the end of this study, the investigators will divide the
      cohort into those who developed cPHT and those who did not as per currently used standard
      criteria and will compare the results of new parameters obtained at earlier time points. The
      sensitivity of each marker to pick-up early cPHT will be calculated and its correlation with
      health outcomes will be established.
observational model: Cohort
time perspective: Prospective
measure: Diagnostic test characteristics calculated for TAPSE and PAAT against diagnosis of chronic pulmonary hypertension on standard diagnostic assessment
time frame: Early diagnostic assessments (14-21 days postnatal age; 32+0/7-32+6/7); Standard diagnostic assessment (~36 weeks CGA)
description: Sensitivity, specificity, positive and negative likelihood ratios for TAPSE and PAAT at each early diagnostic assessment against diagnosis of chronic pulmonary hypertension on standard diagnostic assessment using echocardiography using current standard criteria
measure: Composite of Death/ Chronic Neonatal Lung Disease
time frame: Composite outcome measure will be assessed on the date of discharge for each study participant from the study Neonatal Intensive Care Unit (NICU) or date of death during admission (if applicable) up to 365 days.
description: Infant death prior to 36 weeks CGA and chronic neonatal lung disease are competing risks for the primary outcome of chronic pulmonary hypertension. The presence of both will be assessed.
measure: Duration of need for respiratory support
time frame: Outcome measure will be assessed on the date of discharge for each study participant from the study Neonatal Intensive Care Unit (NICU) or date of death during admission (if applicable) up to 365 days.
description: Total duration of need (number of days) for invasive, non-invasive and supplemental (low-flow) oxygen support
measure: Length of hospital stay
time frame: Outcome measure will be assessed on the date of discharge for each study participant from the study Neonatal Intensive Care Unit (NICU) or date of death during admission (if applicable) up to 365 days.
description: Length of NICU admission from birth to discharge (number of days)
arm group label: Chronic pulmonary hypertension
description: Diagnosis on echocardiography at 36 weeks CGA using standard criteria (flat interventricular septal motion or right ventricular dilatation)
arm group label: No chronic pulmonary hypertension
description: Confirmed on echocardiography at 36 weeks CGA
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 14 Days
maximum age: N/A
healthy volunteers: No
last name: Amish Jain, MD, PHD
role: Principal Investigator
affiliation: Staff Neonatologist, Clinician Scientist
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: Ireland
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Hypertension, Pulmonary
mesh term: Hypertension
sharing ipd: No