<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/NCT03231657</url>
  </required_header>
  <id_info>
    <org_study_id>IIBSP-EUR-2017-20</org_study_id>
    <nct_id>NCT03231657</nct_id>
  </id_info>
  <brief_title>Randomizated Open-label Control Trial to Evaluate if the Incorporation of sFlt1/PlGF Ratio in the Diagnosis and Classification of PE Improves Maternal and Perinatal Outcomes in Women With the Suspicion of the Disease</brief_title>
  <acronym>EuroPE</acronym>
  <official_title>Randomizated Open-label Control Trial to Evaluate if the Incorporation of sFlt1/PlGF Ratio in the Diagnosis and Classification of PE Improves Maternal and Perinatal Outcomes in Women With the Suspicion of the Disease (EuroPE Study)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Carlos III Health Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Spanish Clinical Research Network - SCReN</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau</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>
      Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality worldwide.&#xD;
      The morbidity and mortality of this condition arises from two main causes: 1) the lack of&#xD;
      specific and sensible methods for its diagnosis and prognosis, 2) and the fact that the&#xD;
      course of the disease is often unpredictability at its presentation and speed of progression.&#xD;
      The majority of deaths are undoubtedly avoidable and are due to a substandard care. Nowadays&#xD;
      it's known that preeclampsia is a placental disorder that is characterized by an unbalance of&#xD;
      angiogenic and antiangiogenic factors. It has been recently proven that the ratio of sFlt-1&#xD;
      to PlGF in women who presented with a clinical suspicion of preeclampsia is useful&#xD;
      distinguishing between women in whom preeclampsia would develop and those in whom it would&#xD;
      not. A low ratio also predicted the absence of fetal adverse outcomes in the same time frame.&#xD;
      In addition this ratio demonstrated to be useful to discriminate among patients that would&#xD;
      developed maternal or fetal adverse outcome. Correct identification and diagnosis of women at&#xD;
      risk could potentially prevent all these adverse outcomes thus, clinical experience suggests&#xD;
      that early detection and monitoring are beneficial.&#xD;
&#xD;
      EuroPE aims to provide evidence that the re-definition of pre-eclampsia as an entity caused&#xD;
      by a placental unbalance of angiogenic and anti-angiogenic factors and its incorporation in&#xD;
      the diagnosis and classification of the disease would improve maternal and neonatal health.&#xD;
&#xD;
      This will be an open, multicentre, international, randomised controlled trial with an&#xD;
      intention-to -treat analysis. The study is pragmatic: it will be undertaken to reflect real&#xD;
      clinical practice rather than the very tightly controlled circumstances of explanatory&#xD;
      trials. The main objective of this study is to determine the effects of the use of the ratio&#xD;
      as a diagnostic tool in the definition and classification of PE, as compared with its usual&#xD;
      definition, in triage and delivery decisions and to see whether this new approach is able to&#xD;
      improve maternal and perinatal outcomes.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 6, 2018</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Anticipated">December 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Adverse outcomes</measure>
    <time_frame>Up to 24 weeks</time_frame>
    <description>Composite score for adverse outcomes defined as the presence of any of the following: premature placental abruption, cessation of abnormal CTG, fetal death, need for 2 or more antihypertensive drugs, eclampsia, disseminated intravascular coagulation, maternal mortality, postpartum haemorrhage (need for more than 2 concentrated hematies), acute pulmonary edema, cerebral vascular hemorrhage, pulmonary embolism, sepsis, ICU admission, need for second surgery.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">2536</enrollment>
  <condition>Preeclampsia</condition>
  <arm_group>
    <arm_group_label>Incorporation of the sFlt1/P1GF ratio</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Incorporation of the ratio in the diagnosis and classification of pre-eclampsia:&#xD;
sFlt1/PlGF ratio &gt;38: pre-eclampsia risk&#xD;
sFlt1/PlGF ratio &gt;85: pre-eclampsia&#xD;
ISSHP pre-eclampsia definition + ratio &gt;210: severe PE&#xD;
ISSHP pre-eclampsia definition + ratio sFlt1/PlGF ratio &gt;600: consider deliver</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Routine clinical practice</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Criteria for the definition of PE were those of the International Society for the Study of Hypertension in Pregnancy</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Placental biomarkers</intervention_name>
    <description>sFlt1 and P1GF levels and sFlt1/PlGF ratio</description>
    <arm_group_label>Incorporation of the sFlt1/P1GF ratio</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to read and understand informed consent.&#xD;
&#xD;
          -  Unique pregnancies.&#xD;
&#xD;
          -  &gt; 24 weeks and &lt;41 weeks&#xD;
&#xD;
          -  Suspected preeclampsia:&#xD;
&#xD;
               1. 140/90 or worsening of chronic hypertension&#xD;
&#xD;
               2. Onset of proteinuria (Labstick + or proteinuria&gt; 300mg / 24 hours) or worsening&#xD;
                  of it&#xD;
&#xD;
               3. Preeclampsia prodromal clinic such as epigastric, headache, photopsia, tinnitus&#xD;
                  and increased edema in the face hands or legs or weight gain (&gt; 1 kg per week in&#xD;
                  the third trimester)&#xD;
&#xD;
               4. Analytical alterations: decrease in platelets &lt;100,000. Increased transaminases.&#xD;
&#xD;
               5. Ultrasound alterations: Small fetus for gestational age or restriction of&#xD;
                  interatrial growth, increased resistance of the uterine arteries.&#xD;
&#xD;
          -  Pre-eclampsia (ACOG Practice Bulletin 2013)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Multiple pregnancies&#xD;
&#xD;
          -  &lt;24 weeks of gestation&#xD;
&#xD;
          -  Fetal chromosomal or congenital abnormalities&#xD;
&#xD;
          -  Conditions that require immediate delivery (eclampsia, pulmonary edema, uncontrolled&#xD;
             hypertension, severe visual disturbances, severe headache, fetal demise,&#xD;
             non-reassuring fetal status….)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elisa Llurba, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Elisa Llurba, MD, PhD</last_name>
    <phone>+34935537041</phone>
    <email>ellurba@santpau.cat</email>
  </overall_contact>
  <location>
    <facility>
      <name>Hospital de la Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <zip>08025</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elisa Llurba, MD, PhD</last_name>
      <phone>+34935537041</phone>
      <email>ellurba@santpau.cat</email>
    </contact>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <reference>
    <citation>Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-1131. doi: 10.1097/01.AOG.0000437382.03963.88. No abstract available.</citation>
    <PMID>24150027</PMID>
  </reference>
  <reference>
    <citation>Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 2016 Jan 7;374(1):13-22. doi: 10.1056/NEJMoa1414838.</citation>
    <PMID>26735990</PMID>
  </reference>
  <reference>
    <citation>Verlohren S, Herraiz I, Lapaire O, Schlembach D, Zeisler H, Calda P, Sabria J, Markfeld-Erol F, Galindo A, Schoofs K, Denk B, Stepan H. New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Hypertension. 2014 Feb;63(2):346-52. doi: 10.1161/HYPERTENSIONAHA.113.01787. Epub 2013 Oct 28.</citation>
    <PMID>24166751</PMID>
  </reference>
  <reference>
    <citation>von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F, Cote AM, Douglas MJ, Gruslin A, Hutcheon JA, Joseph KS, Kyle PM, Lee T, Loughna P, Menzies JM, Merialdi M, Millman AL, Moore MP, Moutquin JM, Ouellet AB, Smith GN, Walker JJ, Walley KR, Walters BN, Widmer M, Lee SK, Russell JA, Magee LA; PIERS Study Group. Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet. 2011 Jan 15;377(9761):219-27. doi: 10.1016/S0140-6736(10)61351-7. Epub 2010 Dec 23.</citation>
    <PMID>21185591</PMID>
  </reference>
  <reference>
    <citation>National Institute for Health and Care Excellence guideline DG 23 (2016): PlGF based testing to help diagnose suspected pre-eclampsia (Triage PlGF test, Elecsys immunoassay sFlt-1/PlGF ratio, DELFIA Xpress PlGF 1-2-3 test, and BRHAMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio). Available at: https://www.nice.org.uk/guidance/dg23/chapter/1-recommendations [Accessed January 2017].</citation>
  </reference>
  <reference>
    <citation>Stepan H, Herraiz I, Schlembach D, Verlohren S, Brennecke S, Chantraine F, Klein E, Lapaire O, Llurba E, Ramoni A, Vatish M, Wertaschnigg D, Galindo A. Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice. Ultrasound Obstet Gynecol. 2015 Mar;45(3):241-6. doi: 10.1002/uog.14799. No abstract available.</citation>
    <PMID>25736847</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>July 24, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2017</study_first_posted>
  <last_update_submitted>August 10, 2022</last_update_submitted>
  <last_update_submitted_qc>August 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 11, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>preeclampsia</keyword>
  <keyword>intrauterine growth restriction</keyword>
  <keyword>angiogenic factors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pre-Eclampsia</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/NCT03231657
org study id: IIBSP-EUR-2017-20
nct id: NCT03231657
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality worldwide.
      The morbidity and mortality of this condition arises from two main causes: 1) the lack of
      specific and sensible methods for its diagnosis and prognosis, 2) and the fact that the
      course of the disease is often unpredictability at its presentation and speed of progression.
      The majority of deaths are undoubtedly avoidable and are due to a substandard care. Nowadays
      it's known that preeclampsia is a placental disorder that is characterized by an unbalance of
      angiogenic and antiangiogenic factors. It has been recently proven that the ratio of sFlt-1
      to PlGF in women who presented with a clinical suspicion of preeclampsia is useful
      distinguishing between women in whom preeclampsia would develop and those in whom it would
      not. A low ratio also predicted the absence of fetal adverse outcomes in the same time frame.
      In addition this ratio demonstrated to be useful to discriminate among patients that would
      developed maternal or fetal adverse outcome. Correct identification and diagnosis of women at
      risk could potentially prevent all these adverse outcomes thus, clinical experience suggests
      that early detection and monitoring are beneficial.

      EuroPE aims to provide evidence that the re-definition of pre-eclampsia as an entity caused
      by a placental unbalance of angiogenic and anti-angiogenic factors and its incorporation in
      the diagnosis and classification of the disease would improve maternal and neonatal health.

      This will be an open, multicentre, international, randomised controlled trial with an
      intention-to -treat analysis. The study is pragmatic: it will be undertaken to reflect real
      clinical practice rather than the very tightly controlled circumstances of explanatory
      trials. The main objective of this study is to determine the effects of the use of the ratio
      as a diagnostic tool in the definition and classification of PE, as compared with its usual
      definition, in triage and delivery decisions and to see whether this new approach is able to
      improve maternal and perinatal outcomes.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Adverse outcomes
time frame: Up to 24 weeks
description: Composite score for adverse outcomes defined as the presence of any of the following: premature placental abruption, cessation of abnormal CTG, fetal death, need for 2 or more antihypertensive drugs, eclampsia, disseminated intravascular coagulation, maternal mortality, postpartum haemorrhage (need for more than 2 concentrated hematies), acute pulmonary edema, cerebral vascular hemorrhage, pulmonary embolism, sepsis, ICU admission, need for second surgery.
arm group label: Incorporation of the sFlt1/P1GF ratio
arm group type: Experimental
description: Incorporation of the ratio in the diagnosis and classification of pre-eclampsia:
sFlt1/PlGF ratio >38: pre-eclampsia risk
sFlt1/PlGF ratio >85: pre-eclampsia
ISSHP pre-eclampsia definition + ratio >210: severe PE
ISSHP pre-eclampsia definition + ratio sFlt1/PlGF ratio >600: consider deliver
arm group label: Routine clinical practice
arm group type: No Intervention
description: Criteria for the definition of PE were those of the International Society for the Study of Hypertension in Pregnancy
intervention type: Diagnostic Test
intervention name: Placental biomarkers
description: sFlt1 and P1GF levels and sFlt1/PlGF ratio
arm group label: Incorporation of the sFlt1/P1GF ratio
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Elisa Llurba, MD, PhD
role: Principal Investigator
affiliation: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
last name: Elisa Llurba, MD, PhD
phone: +34935537041
email: ellurba@santpau.cat
facility: 
status: Recruiting
contact: 
country: Spain
citation: Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-1131. doi: 10.1097/01.AOG.0000437382.03963.88. No abstract available.
PMID: 24150027
citation: Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 2016 Jan 7;374(1):13-22. doi: 10.1056/NEJMoa1414838.
PMID: 26735990
citation: Verlohren S, Herraiz I, Lapaire O, Schlembach D, Zeisler H, Calda P, Sabria J, Markfeld-Erol F, Galindo A, Schoofs K, Denk B, Stepan H. New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Hypertension. 2014 Feb;63(2):346-52. doi: 10.1161/HYPERTENSIONAHA.113.01787. Epub 2013 Oct 28.
PMID: 24166751
citation: von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F, Cote AM, Douglas MJ, Gruslin A, Hutcheon JA, Joseph KS, Kyle PM, Lee T, Loughna P, Menzies JM, Merialdi M, Millman AL, Moore MP, Moutquin JM, Ouellet AB, Smith GN, Walker JJ, Walley KR, Walters BN, Widmer M, Lee SK, Russell JA, Magee LA; PIERS Study Group. Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet. 2011 Jan 15;377(9761):219-27. doi: 10.1016/S0140-6736(10)61351-7. Epub 2010 Dec 23.
PMID: 21185591
citation: National Institute for Health and Care Excellence guideline DG 23 (2016): PlGF based testing to help diagnose suspected pre-eclampsia (Triage PlGF test, Elecsys immunoassay sFlt-1/PlGF ratio, DELFIA Xpress PlGF 1-2-3 test, and BRHAMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio). Available at: https://www.nice.org.uk/guidance/dg23/chapter/1-recommendations [Accessed January 2017].
citation: Stepan H, Herraiz I, Schlembach D, Verlohren S, Brennecke S, Chantraine F, Klein E, Lapaire O, Llurba E, Ramoni A, Vatish M, Wertaschnigg D, Galindo A. Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice. Ultrasound Obstet Gynecol. 2015 Mar;45(3):241-6. doi: 10.1002/uog.14799. No abstract available.
PMID: 25736847
responsible party type: Sponsor
mesh term: Pre-Eclampsia