<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/NCT02189148</url>
  </required_header>
  <id_info>
    <org_study_id>CIHR-MOP-133672</org_study_id>
    <secondary_id>B14-05-2024</secondary_id>
    <nct_id>NCT02189148</nct_id>
  </id_info>
  <brief_title>First-trimester Prediction of Preeclampsia</brief_title>
  <acronym>PREDICTION</acronym>
  <official_title>First-trimester Prediction of Preeclampsia and Other Placenta-mediated Pregnancy Complications</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CHU de Quebec-Universite Laval</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Canadian Institutes of Health Research (CIHR)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Laval University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>CHU de Quebec-Universite Laval</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Preeclampsia is a complication of pregnancy related to adverse maternal and neonatal&#xD;
      outcomes, including fetal growth restriction and perinatal death. Several measures are used&#xD;
      or under investigation (low-dose aspirin, low-molecular weight heparin, calcium, folic acid,&#xD;
      among others) for the prevention of preeclampsia. Unfortunately, most high-risk women who&#xD;
      could benefit from those preventive measures are not identified until late in pregnancy.&#xD;
      Recent evidences suggest that the investigators could identify women at risk of developing&#xD;
      preeclampsia using a combination of serum and ultrasound biomarkers in the first-trimester of&#xD;
      pregnancy. This screening test needs external validation. A first-trimester screening&#xD;
      strategy will strengthen clinical research on preeclampsia and will contribute to the&#xD;
      development of strategy combining the prediction and prevention of the disease and its&#xD;
      related complications.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Preeclampsia (PE) is a placenta-mediated pregnancy complication related to&#xD;
      adverse maternal and neonatal outcomes, including intra-uterine growth restriction (IUGR) and&#xD;
      perinatal death. A growing body of evidence suggests that the preterm and severe forms of PE&#xD;
      are associated with deep placentation disorders that occur early in gestation. Over the last&#xD;
      decade, maternal characteristic and first-trimester biomarkers, including some that are&#xD;
      already used for aneuploidy screening (PAPP-A) have been strongly related to the preterm and&#xD;
      early forms of PE, suggesting that early prediction is possible. Preventive measures are&#xD;
      actually recommended (low-dose aspirin; calcium) or under investigation (folic acid;&#xD;
      low-molecular weight heparin; anti-oxidant) in high-risk women. However, only women with&#xD;
      chronic disease or prior adverse pregnancy outcomes are eligible for these measures while&#xD;
      most cases of PE occur in nulliparous women. Moreover, there are actually no clear guidelines&#xD;
      for clinicians in Canada whose pregnant patients have one or several risk factors for&#xD;
      preeclampsia (obesity, chronic hypertension, low PAPP-A, etc.). On the other hand, it has&#xD;
      been suggested that prediction of PE, and particularly the most severe cases, is possible&#xD;
      with high sensitivity and specificity by using a combination of anamnestic, biophysical,&#xD;
      biochemical and ultrasonographic biomarkers using the web-based Fetal-Medicine Foundation&#xD;
      (FMF) screening test. This suggests that a strategy of prediction and prevention of PE and&#xD;
      other placenta-mediated complications is becoming possible for nulliparous women as well.&#xD;
      However, certain major concerns must be addressed: 1) The FMF screening test has not been&#xD;
      validated prospectively; 2) a controversy exists about the need and feasibility of Doppler&#xD;
      ultrasound in the general population.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
        1. To validate the 11-13 week FMF screening test for early-onset PE and a composite of&#xD;
           placenta-mediated outcomes (preterm PE, IUGR &lt;3rd percentile, stillbirth); and&#xD;
&#xD;
        2. To compare the screening test with and without uterine artery (UtA) Doppler;&#xD;
&#xD;
        3. To explore the efficiency of new potential biomarkers (ADAM-12; Placental protein (PP)&#xD;
           -13; placental and subplacental volume; placental vascularization) for prediction of PE&#xD;
           in our population.&#xD;
&#xD;
      Methods: A multicenter prospective observational study of nulliparous women recruited between&#xD;
      11 3/7 - 13 6/7 weeks (maternal characteristics; BMI; Mean arterial pressure (MAP); PAPP-A;&#xD;
      placental growth factor (PIGF); UtA Doppler…) and followed until delivery. Delivery and&#xD;
      neonatal data will be collected through chart reviews. Detection rates for early-onset PE&#xD;
      (primary outcome) and other adverse pregnancy outcomes will be measured using the 11-13 weeks&#xD;
      FMF screening test with and without UtA Doppler results. A case-cohort study will be&#xD;
      performed using stored serum samples and three-dimensional ultrasound volume acquired at the&#xD;
      11-13 weeks visit.&#xD;
&#xD;
      Feasibility and power calculation: We estimate a minimum incidence of early-onset PE of 0.7%.&#xD;
      A minimum of 7,600 women will be necessary to demonstrate that the FMF screening test is at&#xD;
      least 80% sensitive and 90% specific where it is expected that it will be 95% sensitive and&#xD;
      92% specific. We will have the power to detect an absolute difference of 15% in the detection&#xD;
      rate between the different screening strategies (± Doppler). Recruitment will take 3.0 years.&#xD;
      The overall study will take 5.0 years.&#xD;
&#xD;
      Expectations: First, our research will potentially provide a validated, highly sensitive and&#xD;
      specific, and cheap tool to help clinicians' decision in the care of nulliparous women with&#xD;
      risk factors for PE. In case of negative results, the clinician will have good evidence to&#xD;
      reassure the patients facing abnormal maternal serum screening values. The validation of a&#xD;
      first-trimester screening strategy will strengthen clinical research on PE providing new&#xD;
      information on the natural evolution of the disease. Finally, this study will contribute to&#xD;
      develop the optimal design for randomized trials aiming at the prevention of early-onset PE&#xD;
      and other placenta-mediated complications of pregnancy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2014</start_date>
  <completion_date type="Actual">March 2018</completion_date>
  <primary_completion_date type="Actual">December 2017</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>early onset preeclampsia</measure>
    <time_frame>diagnosed between 20 and 34 weeks of gestation</time_frame>
    <description>Preeclampsia will be defined according to the Canadian Guidelines for Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy guidelines, as de novo hypertension with diastolic blood pressure &gt;90 mmHg on two occasions at least four hours apart, after 20 weeks of pregnancy, associated with proteinuria ≥300 mg/24 h or at least '2 +' protein on urine dipstick or an adverse conditions</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Severe preeclampsia</measure>
    <time_frame>between 20 and 42 weeks of gestation</time_frame>
    <description>Severe Preeclampsia will be defined by the presence of at least one of the following adverse condition: 1) systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥ 110 mmHg after 4 h of bed rest, 2) proteinuria ≥ 5 g/24 h or at least '3 +' protein on urine dipstick, or 3) oliguria &lt; 400 ml/24 h; 4) cerebral or visual disturbances; epigastric pain; pulmonary edema or cyanosis; thrombocytopenia &lt;100,000mm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fetal growth restriction</measure>
    <time_frame>between 20 and 42 weeks of gestation</time_frame>
    <description>Fetal growth restriction will be defined as a birth weight below the 10th centile (or below the 3rd centile for severe FGR) of Canadian reference growth charts.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">7554</enrollment>
  <condition>Preeclampsia</condition>
  <condition>Severe Preeclampsia</condition>
  <condition>Fetal Growth Restriction</condition>
  <condition>Preterm Birth</condition>
  <arm_group>
    <arm_group_label>Cohort</arm_group_label>
    <description>Each participant will :&#xD;
give consent&#xD;
provide a blood sample (10 ml)&#xD;
be measured (weight and height for BMI calculation)&#xD;
undergo a blood pressure measurement&#xD;
have an ultrasound exam (uterine arteries Doppler, placental volume, thickness of the placenta)&#xD;
answer to a short questionnaire (5 pages)</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Maternal serum&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Nulliparous women who will deliver in one of the participating center:&#xD;
&#xD;
        CHUL Hospital, Quebec city, QC Hôpital Saint-François-d'Assise, Quebec city, QC CHU&#xD;
        Ste-Justine, Montreal, QC Southern Alberta Maternal Fetal Medicine Centre, Calgary, Alberta&#xD;
        Sinai Health System, Mount Sinai Hospital, Toronto, Ontario&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  gestational age between 11 3/7 and 13 6/7 weeks;&#xD;
&#xD;
          -  nulliparous women (no previous delivery ≥ 20 weeks).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  pregnant women &lt;18 years old at recruitment;&#xD;
&#xD;
          -  multiple pregnancies;&#xD;
&#xD;
          -  fetal congenital malformation;&#xD;
&#xD;
          -  positive for HIV or hepatitis C or hepatitis B;&#xD;
&#xD;
          -  negative fetal heart at recruitment;&#xD;
&#xD;
          -  women planning a delivery outside the participating hospitals;&#xD;
&#xD;
          -  women not able to provide an informed consent to the study.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Emmanuel Bujold, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>CHU de Québec</affiliation>
  </overall_official>
  <overall_official>
    <last_name>François Audibert, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>St. Justine's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>South Alberta Maternal Fetal Medicine Centre, University of Calgary</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sinai Health System, Mount Sinai Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 1X5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Ste-Justine</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T 1C5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Québec</name>
      <address>
        <city>Quebec city</city>
        <state>Quebec</state>
        <zip>G1V 4G2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <link>
    <url>http://www.crchudequebec.ulaval.ca/etudes/B14-05-2024.pdf</url>
    <description>Prediction study at Centre de recherche du Centre Hospitalier Universitaire de Québec</description>
  </link>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>July 10, 2014</study_first_submitted>
  <study_first_submitted_qc>July 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 14, 2014</study_first_posted>
  <last_update_submitted>July 22, 2019</last_update_submitted>
  <last_update_submitted_qc>July 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 23, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>CHU de Quebec-Universite Laval</investigator_affiliation>
    <investigator_full_name>Emmanuel Bujold</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Prediction</keyword>
  <keyword>Preeclampsia</keyword>
  <keyword>Preterm birth</keyword>
  <keyword>Pregnancy</keyword>
  <keyword>Placenta</keyword>
  <keyword>Intra-uterine growth restriction</keyword>
  <keyword>fetal growth restriction</keyword>
  <keyword>Ultrasound</keyword>
  <keyword>Doppler</keyword>
  <keyword>Biomarkers</keyword>
  <keyword>PAPP-A</keyword>
  <keyword>Placental growth factor (PlGF)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Premature Birth</mesh_term>
    <mesh_term>Pre-Eclampsia</mesh_term>
    <mesh_term>Fetal Growth Retardation</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/NCT02189148
org study id: CIHR-MOP-133672
secondary id: B14-05-2024
nct id: NCT02189148
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Preeclampsia is a complication of pregnancy related to adverse maternal and neonatal
      outcomes, including fetal growth restriction and perinatal death. Several measures are used
      or under investigation (low-dose aspirin, low-molecular weight heparin, calcium, folic acid,
      among others) for the prevention of preeclampsia. Unfortunately, most high-risk women who
      could benefit from those preventive measures are not identified until late in pregnancy.
      Recent evidences suggest that the investigators could identify women at risk of developing
      preeclampsia using a combination of serum and ultrasound biomarkers in the first-trimester of
      pregnancy. This screening test needs external validation. A first-trimester screening
      strategy will strengthen clinical research on preeclampsia and will contribute to the
      development of strategy combining the prediction and prevention of the disease and its
      related complications.
Background: Preeclampsia (PE) is a placenta-mediated pregnancy complication related to
      adverse maternal and neonatal outcomes, including intra-uterine growth restriction (IUGR) and
      perinatal death. A growing body of evidence suggests that the preterm and severe forms of PE
      are associated with deep placentation disorders that occur early in gestation. Over the last
      decade, maternal characteristic and first-trimester biomarkers, including some that are
      already used for aneuploidy screening (PAPP-A) have been strongly related to the preterm and
      early forms of PE, suggesting that early prediction is possible. Preventive measures are
      actually recommended (low-dose aspirin; calcium) or under investigation (folic acid;
      low-molecular weight heparin; anti-oxidant) in high-risk women. However, only women with
      chronic disease or prior adverse pregnancy outcomes are eligible for these measures while
      most cases of PE occur in nulliparous women. Moreover, there are actually no clear guidelines
      for clinicians in Canada whose pregnant patients have one or several risk factors for
      preeclampsia (obesity, chronic hypertension, low PAPP-A, etc.). On the other hand, it has
      been suggested that prediction of PE, and particularly the most severe cases, is possible
      with high sensitivity and specificity by using a combination of anamnestic, biophysical,
      biochemical and ultrasonographic biomarkers using the web-based Fetal-Medicine Foundation
      (FMF) screening test. This suggests that a strategy of prediction and prevention of PE and
      other placenta-mediated complications is becoming possible for nulliparous women as well.
      However, certain major concerns must be addressed: 1) The FMF screening test has not been
      validated prospectively; 2) a controversy exists about the need and feasibility of Doppler
      ultrasound in the general population.

      Objectives:

        1. To validate the 11-13 week FMF screening test for early-onset PE and a composite of
           placenta-mediated outcomes (preterm PE, IUGR <3rd percentile, stillbirth); and

        2. To compare the screening test with and without uterine artery (UtA) Doppler;

        3. To explore the efficiency of new potential biomarkers (ADAM-12; Placental protein (PP)
           -13; placental and subplacental volume; placental vascularization) for prediction of PE
           in our population.

      Methods: A multicenter prospective observational study of nulliparous women recruited between
      11 3/7 - 13 6/7 weeks (maternal characteristics; BMI; Mean arterial pressure (MAP); PAPP-A;
      placental growth factor (PIGF); UtA Doppler…) and followed until delivery. Delivery and
      neonatal data will be collected through chart reviews. Detection rates for early-onset PE
      (primary outcome) and other adverse pregnancy outcomes will be measured using the 11-13 weeks
      FMF screening test with and without UtA Doppler results. A case-cohort study will be
      performed using stored serum samples and three-dimensional ultrasound volume acquired at the
      11-13 weeks visit.

      Feasibility and power calculation: We estimate a minimum incidence of early-onset PE of 0.7%.
      A minimum of 7,600 women will be necessary to demonstrate that the FMF screening test is at
      least 80% sensitive and 90% specific where it is expected that it will be 95% sensitive and
      92% specific. We will have the power to detect an absolute difference of 15% in the detection
      rate between the different screening strategies (± Doppler). Recruitment will take 3.0 years.
      The overall study will take 5.0 years.

      Expectations: First, our research will potentially provide a validated, highly sensitive and
      specific, and cheap tool to help clinicians' decision in the care of nulliparous women with
      risk factors for PE. In case of negative results, the clinician will have good evidence to
      reassure the patients facing abnormal maternal serum screening values. The validation of a
      first-trimester screening strategy will strengthen clinical research on PE providing new
      information on the natural evolution of the disease. Finally, this study will contribute to
      develop the optimal design for randomized trials aiming at the prevention of early-onset PE
      and other placenta-mediated complications of pregnancy.
observational model: Cohort
time perspective: Prospective
measure: early onset preeclampsia
time frame: diagnosed between 20 and 34 weeks of gestation
description: Preeclampsia will be defined according to the Canadian Guidelines for Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy guidelines, as de novo hypertension with diastolic blood pressure >90 mmHg on two occasions at least four hours apart, after 20 weeks of pregnancy, associated with proteinuria ≥300 mg/24 h or at least '2 +' protein on urine dipstick or an adverse conditions
measure: Severe preeclampsia
time frame: between 20 and 42 weeks of gestation
description: Severe Preeclampsia will be defined by the presence of at least one of the following adverse condition: 1) systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥ 110 mmHg after 4 h of bed rest, 2) proteinuria ≥ 5 g/24 h or at least '3 +' protein on urine dipstick, or 3) oliguria < 400 ml/24 h; 4) cerebral or visual disturbances; epigastric pain; pulmonary edema or cyanosis; thrombocytopenia <100,000mm
measure: Fetal growth restriction
time frame: between 20 and 42 weeks of gestation
description: Fetal growth restriction will be defined as a birth weight below the 10th centile (or below the 3rd centile for severe FGR) of Canadian reference growth charts.
arm group label: Cohort
description: Each participant will :
give consent
provide a blood sample (10 ml)
be measured (weight and height for BMI calculation)
undergo a blood pressure measurement
have an ultrasound exam (uterine arteries Doppler, placental volume, thickness of the placenta)
answer to a short questionnaire (5 pages)
Maternal serum
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Emmanuel Bujold, MD, MSc
role: Principal Investigator
affiliation: CHU de Québec
last name: François Audibert, MD, MSc
role: Principal Investigator
affiliation: St. Justine's Hospital
facility: 
facility: 
facility: 
facility: 
country: Canada
url: http://www.crchudequebec.ulaval.ca/etudes/B14-05-2024.pdf
description: Prediction study at Centre de recherche du Centre Hospitalier Universitaire de Québec
responsible party type: Principal Investigator
investigator affiliation: CHU de Quebec-Universite Laval
investigator full name: Emmanuel Bujold
investigator title: Principal Investigator
mesh term: Premature Birth
mesh term: Pre-Eclampsia
mesh term: Fetal Growth Retardation
sharing ipd: No