<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/NCT02996630</url>
  </required_header>
  <id_info>
    <org_study_id>PR(AMI)317/2012</org_study_id>
    <nct_id>NCT02996630</nct_id>
  </id_info>
  <brief_title>Assessing Neurodevelopment in Congenital Heart Disease.</brief_title>
  <acronym>NEUROHEART</acronym>
  <official_title>Abnormal Neurodevelopment Detection in Congenital Heart Disease: Predictive Methods Based on Prenatal and Postnatal Factors.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Universitari Vall d'Hebron Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital Sant Joan de Deu</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Universitario La Paz</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Universitario 12 de Octubre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital General Universitario Gregorio Marañon</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut Universitari Dexeus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital Universitari Vall d'Hebron Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Congenital heart disease (CHD) is the most prevalent congenital malformation affecting 1 in&#xD;
      100 newborns per year. Children with CHD are a known risk population for brain injury, with&#xD;
      neurodevelopmental alterations shown over time in up to 50% of cases. No adequate description&#xD;
      exists of the type of neurocognitive anomalies or risk factors associated with CHD, and&#xD;
      consequently no prognostic markers that may allow identification of high-risk cases are&#xD;
      available.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main objectives of this study are: 1. to describe the neurodevelopmental outcome of&#xD;
      patients with CHD at 24 months of age; 2. identify the subgroup with poorer outcome; and 3.&#xD;
      evaluate the utility of fetal and postnatal diagnostic techniques for early detection of&#xD;
      patients at risk for altered neurological outcomes.&#xD;
&#xD;
      Seven Spanish referral centers for CHD included in the research network on maternal and child&#xD;
      health currently participating in this prospective multicentric case-control coordinated&#xD;
      study. Fetuses with CHD (transposition of great arteries, tetralogy of Fallot, hypoplastic&#xD;
      left heart syndrome and septal defects) will be studied from 24 weeks of gestation to 2 years&#xD;
      of age. Diagnostic tests will be repeated throughout the study in all patients, from the&#xD;
      fetal period to 24 months of age, and will include: fetal cerebral hemodynamic Doppler&#xD;
      assessment, functional echocardiography, brain MRI, regional cerebral oxymetry,&#xD;
      electroencephalography and serum neurological and cardiac biomarkers analysis.&#xD;
      Neurodevelopmental assessment will be made at 12 months of age using the ages and stages&#xD;
      questionnaire (ASQ) and at 24 months of age with the Bayley-III test. From this data,&#xD;
      statistical analysis will select the most useful as predictors of damage; to be then combined&#xD;
      and create algorithms for predicting brain damage and poor neurodevelopment. Once description&#xD;
      has been made, we will proceed to identify amongst our results, children with the poorest&#xD;
      neurological outcome and remark possible common prenatal and early life markers in them as&#xD;
      well as the CHD severity they present.&#xD;
&#xD;
      While advances in early diagnosis and postnatal management have increased survival in CHD&#xD;
      children, worrying long-term outcomes, particularly neurodevelopmental disability, have&#xD;
      emerged as a key prognostic factor in the counseling of these pregnancies. Evidence available&#xD;
      does not allow clinicians to assess on neurological prognosis although has opened up the&#xD;
      possibility of finding prenatal markers of brain damage. Even though, no prospective studies&#xD;
      have been performed until now. We present a multicentric prospective study able to recruit&#xD;
      enough fetal CHD affected pregnancies to obtain neurological prognostic tools.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>May 2013</start_date>
  <completion_date type="Anticipated">May 2018</completion_date>
  <primary_completion_date type="Anticipated">May 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Bailey-III test punctuation</measure>
    <time_frame>45 minutes</time_frame>
    <description>Results in pediatric Bailey-III test scale</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Biparietal diameter (mm)</measure>
    <time_frame>one day</time_frame>
    <description>Biparietal diameter (mm) measured with MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lateral sulcus depth</measure>
    <time_frame>one day</time_frame>
    <description>Lateral sulcus depth (mm) measured with MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebral insula</measure>
    <time_frame>one day</time_frame>
    <description>Insula (mm) measured with MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain biometries</measure>
    <time_frame>one day</time_frame>
    <description>Calcarine sulcus depth (mm)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebral cingulata sulcus</measure>
    <time_frame>one day</time_frame>
    <description>Cingulata sulcus depth (mm) measured with MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Corpus callosum</measure>
    <time_frame>one day</time_frame>
    <description>Corpus callosum (mm) measured with MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebellum</measure>
    <time_frame>one day</time_frame>
    <description>Cerebellum vermis (mm) measured with MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Umbilical doppler</measure>
    <time_frame>one day</time_frame>
    <description>Umbilical artery pulsatility index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Middle cerebral artery doppler</measure>
    <time_frame>one day</time_frame>
    <description>Middle cerebral artery pulsatility index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Angiogenic PLGF (placental growth factor)</measure>
    <time_frame>Two days</time_frame>
    <description>Placental growth factor in maternal serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Angiogenic s-FLt (soluble fms-like tyrosine kinase)</measure>
    <time_frame>Two days</time_frame>
    <description>Soluble fms-like tyrosine kinase factor in maternal serum</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">250</enrollment>
  <condition>Congenital Heart Disease</condition>
  <arm_group>
    <arm_group_label>Healthy fetuses</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Pregnant patients carrying a healthy fetus. Interventions in this group will be: cord blood sample, sonography, Magnetic Resonance Imaging and bailey test.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Congenital Hearth Disease</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Pregnant patients carrying a fetus with a moderate-severe congenital heart disease Interventions in this group will be: cord blood sample, sonography, Magnetic Resonance Imaging, Surgical intervention, brain monitoring and bailey test.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Sonography</intervention_name>
    <description>Fetal Ultrasound exploration</description>
    <arm_group_label>Congenital Hearth Disease</arm_group_label>
    <arm_group_label>Healthy fetuses</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Magnetic Resonance Imaging</intervention_name>
    <description>Fetal MRI for brain study</description>
    <arm_group_label>Congenital Hearth Disease</arm_group_label>
    <arm_group_label>Healthy fetuses</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Bailey Test</intervention_name>
    <description>Neurodevelopment paediatric assessment test performed at 2 years of age.</description>
    <arm_group_label>Congenital Hearth Disease</arm_group_label>
    <arm_group_label>Healthy fetuses</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Surgical intervention</intervention_name>
    <description>Congenital Heart Disease repair</description>
    <arm_group_label>Congenital Hearth Disease</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Brain monitoring</intervention_name>
    <description>EEG and continuous brain oximetry before surgery.</description>
    <arm_group_label>Congenital Hearth Disease</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>cord blood sample</intervention_name>
    <description>Cord blood samples will be taken after birth in both groups.</description>
    <arm_group_label>Congenital Hearth Disease</arm_group_label>
    <arm_group_label>Healthy fetuses</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Single pregnancies&#xD;
&#xD;
          -  Major Congenital Heart Disease&#xD;
&#xD;
          -  Informed Consent Signed&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Major extra-cardiac malformations&#xD;
&#xD;
          -  Parental Refusal to participate&#xD;
&#xD;
          -  Maternal Chronic Disease&#xD;
&#xD;
          -  Multiple Pregnancies&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elisa Llurba, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Hospital Universitari Vall d'Hebrón</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Irene Ribera, MD</last_name>
    <phone>934893000</phone>
    <phone_ext>3086</phone_ext>
    <email>irene.ribera@vhir.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Aina Ruiz, MD</last_name>
    <phone>934893000</phone>
    <phone_ext>3086</phone_ext>
    <email>aruizrom@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hospital Universitari Vall d'Hebrón</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Irene Ribera, Dr</last_name>
      <phone>934893000</phone>
      <phone_ext>3086</phone_ext>
      <email>irene.ribera@vhir.org</email>
    </contact>
    <contact_backup>
      <last_name>Elisa Llurba, Dr</last_name>
      <phone>934893000</phone>
      <phone_ext>3086</phone_ext>
      <email>irene.ribera@vhir.org</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <results_reference>
    <citation>Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002 Jun 19;39(12):1890-900. doi: 10.1016/s0735-1097(02)01886-7.</citation>
    <PMID>12084585</PMID>
  </results_reference>
  <results_reference>
    <citation>Bellinger DC, Jonas RA, Rappaport LA, Wypij D, Wernovsky G, Kuban KC, Barnes PD, Holmes GL, Hickey PR, Strand RD, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med. 1995 Mar 2;332(9):549-55. doi: 10.1056/NEJM199503023320901.</citation>
    <PMID>7838188</PMID>
  </results_reference>
  <results_reference>
    <citation>Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr. 2000 Nov;137(5):638-45. doi: 10.1067/mpd.2000.109152.</citation>
    <PMID>11060529</PMID>
  </results_reference>
  <results_reference>
    <citation>Masoller N, Martinez JM, Gomez O, Bennasar M, Crispi F, Sanz-Cortes M, Egana-Ugrinovic G, Bartrons J, Puerto B, Gratacos E. Evidence of second-trimester changes in head biometry and brain perfusion in fetuses with congenital heart disease. Ultrasound Obstet Gynecol. 2014 Aug;44(2):182-7. doi: 10.1002/uog.13373. Epub 2014 Jul 8.</citation>
    <PMID>24687311</PMID>
  </results_reference>
  <results_reference>
    <citation>Ruiz A, Cruz-Lemini M, Masoller N, Sanz-Cortes M, Ferrer Q, Ribera I, Martinez JM, Crispi F, Arevalo S, Gomez O, Perez-Hoyos S, Carreras E, Gratacos E, Llurba E. Longitudinal changes in fetal biometry and cerebroplacental hemodynamics in fetuses with congenital heart disease. Ultrasound Obstet Gynecol. 2017 Mar;49(3):379-386. doi: 10.1002/uog.15970.</citation>
    <PMID>27214694</PMID>
  </results_reference>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>October 31, 2016</study_first_submitted>
  <study_first_submitted_qc>December 14, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 19, 2016</study_first_posted>
  <last_update_submitted>December 14, 2016</last_update_submitted>
  <last_update_submitted_qc>December 14, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 19, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>LVOTO</keyword>
  <keyword>Fallot</keyword>
  <keyword>Great Arteries Transposition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Diseases</mesh_term>
    <mesh_term>Heart Defects, Congenital</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/NCT02996630
org study id: PR(AMI)317/2012
nct id: NCT02996630
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
Congenital heart disease (CHD) is the most prevalent congenital malformation affecting 1 in
      100 newborns per year. Children with CHD are a known risk population for brain injury, with
      neurodevelopmental alterations shown over time in up to 50% of cases. No adequate description
      exists of the type of neurocognitive anomalies or risk factors associated with CHD, and
      consequently no prognostic markers that may allow identification of high-risk cases are
      available.
The main objectives of this study are: 1. to describe the neurodevelopmental outcome of
      patients with CHD at 24 months of age; 2. identify the subgroup with poorer outcome; and 3.
      evaluate the utility of fetal and postnatal diagnostic techniques for early detection of
      patients at risk for altered neurological outcomes.

      Seven Spanish referral centers for CHD included in the research network on maternal and child
      health currently participating in this prospective multicentric case-control coordinated
      study. Fetuses with CHD (transposition of great arteries, tetralogy of Fallot, hypoplastic
      left heart syndrome and septal defects) will be studied from 24 weeks of gestation to 2 years
      of age. Diagnostic tests will be repeated throughout the study in all patients, from the
      fetal period to 24 months of age, and will include: fetal cerebral hemodynamic Doppler
      assessment, functional echocardiography, brain MRI, regional cerebral oxymetry,
      electroencephalography and serum neurological and cardiac biomarkers analysis.
      Neurodevelopmental assessment will be made at 12 months of age using the ages and stages
      questionnaire (ASQ) and at 24 months of age with the Bayley-III test. From this data,
      statistical analysis will select the most useful as predictors of damage; to be then combined
      and create algorithms for predicting brain damage and poor neurodevelopment. Once description
      has been made, we will proceed to identify amongst our results, children with the poorest
      neurological outcome and remark possible common prenatal and early life markers in them as
      well as the CHD severity they present.

      While advances in early diagnosis and postnatal management have increased survival in CHD
      children, worrying long-term outcomes, particularly neurodevelopmental disability, have
      emerged as a key prognostic factor in the counseling of these pregnancies. Evidence available
      does not allow clinicians to assess on neurological prognosis although has opened up the
      possibility of finding prenatal markers of brain damage. Even though, no prospective studies
      have been performed until now. We present a multicentric prospective study able to recruit
      enough fetal CHD affected pregnancies to obtain neurological prognostic tools.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Bailey-III test punctuation
time frame: 45 minutes
description: Results in pediatric Bailey-III test scale
measure: Biparietal diameter (mm)
time frame: one day
description: Biparietal diameter (mm) measured with MRI
measure: Lateral sulcus depth
time frame: one day
description: Lateral sulcus depth (mm) measured with MRI
measure: Cerebral insula
time frame: one day
description: Insula (mm) measured with MRI
measure: Brain biometries
time frame: one day
description: Calcarine sulcus depth (mm)
measure: Cerebral cingulata sulcus
time frame: one day
description: Cingulata sulcus depth (mm) measured with MRI
measure: Corpus callosum
time frame: one day
description: Corpus callosum (mm) measured with MRI
measure: Cerebellum
time frame: one day
description: Cerebellum vermis (mm) measured with MRI
measure: Umbilical doppler
time frame: one day
description: Umbilical artery pulsatility index
measure: Middle cerebral artery doppler
time frame: one day
description: Middle cerebral artery pulsatility index
measure: Angiogenic PLGF (placental growth factor)
time frame: Two days
description: Placental growth factor in maternal serum
measure: Angiogenic s-FLt (soluble fms-like tyrosine kinase)
time frame: Two days
description: Soluble fms-like tyrosine kinase factor in maternal serum
arm group label: Healthy fetuses
arm group type: Other
description: Pregnant patients carrying a healthy fetus. Interventions in this group will be: cord blood sample, sonography, Magnetic Resonance Imaging and bailey test.
arm group label: Congenital Hearth Disease
arm group type: Other
description: Pregnant patients carrying a fetus with a moderate-severe congenital heart disease Interventions in this group will be: cord blood sample, sonography, Magnetic Resonance Imaging, Surgical intervention, brain monitoring and bailey test.
intervention type: Procedure
intervention name: Sonography
description: Fetal Ultrasound exploration
arm group label: Congenital Hearth Disease
arm group label: Healthy fetuses
intervention type: Device
intervention name: Magnetic Resonance Imaging
description: Fetal MRI for brain study
arm group label: Congenital Hearth Disease
arm group label: Healthy fetuses
intervention type: Other
intervention name: Bailey Test
description: Neurodevelopment paediatric assessment test performed at 2 years of age.
arm group label: Congenital Hearth Disease
arm group label: Healthy fetuses
intervention type: Procedure
intervention name: Surgical intervention
description: Congenital Heart Disease repair
arm group label: Congenital Hearth Disease
intervention type: Procedure
intervention name: Brain monitoring
description: EEG and continuous brain oximetry before surgery.
arm group label: Congenital Hearth Disease
intervention type: Procedure
intervention name: cord blood sample
description: Cord blood samples will be taken after birth in both groups.
arm group label: Congenital Hearth Disease
arm group label: Healthy fetuses
criteria: 
gender: Female
minimum age: N/A
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Elisa Llurba, MD, PhD
role: Study Director
affiliation: Hospital Universitari Vall d'Hebrón
last name: Irene Ribera, MD
phone: 934893000
phone ext: 3086
email: irene.ribera@vhir.org
last name: Aina Ruiz, MD
phone: 934893000
phone ext: 3086
email: aruizrom@gmail.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Spain
citation: Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002 Jun 19;39(12):1890-900. doi: 10.1016/s0735-1097(02)01886-7.
PMID: 12084585
citation: Bellinger DC, Jonas RA, Rappaport LA, Wypij D, Wernovsky G, Kuban KC, Barnes PD, Holmes GL, Hickey PR, Strand RD, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med. 1995 Mar 2;332(9):549-55. doi: 10.1056/NEJM199503023320901.
PMID: 7838188
citation: Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr. 2000 Nov;137(5):638-45. doi: 10.1067/mpd.2000.109152.
PMID: 11060529
citation: Masoller N, Martinez JM, Gomez O, Bennasar M, Crispi F, Sanz-Cortes M, Egana-Ugrinovic G, Bartrons J, Puerto B, Gratacos E. Evidence of second-trimester changes in head biometry and brain perfusion in fetuses with congenital heart disease. Ultrasound Obstet Gynecol. 2014 Aug;44(2):182-7. doi: 10.1002/uog.13373. Epub 2014 Jul 8.
PMID: 24687311
citation: Ruiz A, Cruz-Lemini M, Masoller N, Sanz-Cortes M, Ferrer Q, Ribera I, Martinez JM, Crispi F, Arevalo S, Gomez O, Perez-Hoyos S, Carreras E, Gratacos E, Llurba E. Longitudinal changes in fetal biometry and cerebroplacental hemodynamics in fetuses with congenital heart disease. Ultrasound Obstet Gynecol. 2017 Mar;49(3):379-386. doi: 10.1002/uog.15970.
PMID: 27214694
responsible party type: Sponsor
mesh term: Heart Diseases
mesh term: Heart Defects, Congenital
sharing ipd: No