<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/NCT04459117</url>
  </required_header>
  <id_info>
    <org_study_id>C19-29</org_study_id>
    <secondary_id>2019-004297-26</secondary_id>
    <nct_id>NCT04459117</nct_id>
  </id_info>
  <brief_title>Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen</brief_title>
  <acronym>TREOCAPA</acronym>
  <official_title>Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut National de la Santé Et de la Recherche Médicale, France</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>UPCET</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>PARTNERS for International clinical Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>European Fundation for the Care of the Newborn Infants</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Connect for Children</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut National de la Santé Et de la Recherche Médicale, France</source>
  <oversight_info>
    <has_dmc>Yes</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>
      TREOCAPA is a Phase II/III European Multicentre study concerning the prophylactic treatment&#xD;
      by Acetaminophen of extremely preterm infant during the first five days after birth.&#xD;
&#xD;
      The Phase II is a dose finding phase in order to assess the minimum effective dose regimen of&#xD;
      acetaminophen for the closure of PDA for neonates with a gestational age less than 27 weeks&#xD;
      This part of the study will be conducted in 11 NICUs, in 4 countries (France, UK, Finland and&#xD;
      Denmark).&#xD;
&#xD;
      The Phase III is The phase III is a randomized, multicenter, double-blind, placebo-controlled&#xD;
      superiority trial, two arms in a 1:1 ratio, evaluating an increasing of 10% of the percentage&#xD;
      of survival without severe morbidity at 36 weeks of post menstrual age. In the intervention&#xD;
      arm, 20 mg/kg followed by 7.5 mg/kg quarter in die (QID) will be administered to the 27-28&#xD;
      weeks gestational age group (dosage confirmed through PK/PD data analysis from the previous&#xD;
      Finnian study) and the dosage selected after the conclusion of the Phase II will be&#xD;
      administered to the 23-26 weeks gestational age group. A group sequential design, with a&#xD;
      total of 3 analyses (2 interim analyses and a final) and the O'Brien-Fleming alpha spending&#xD;
      function is chosen for the trial. At the same time, a Bayesian sequential analysis is planned&#xD;
      for safety endpoints&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The Phase II will be conducted in 11 NICUs, in 4 countries (France, UK, Finland and Denmark).&#xD;
      The estimated recruitment period is 6 months to enroll 30 preterm infants of 23-26 weeks of&#xD;
      gestation. Four different loading/maintenance doses will be tested. The first level will be&#xD;
      20 mg/kg followed by 7.5 mg/kg quarter in die (QID) which correspond to the dosage selected&#xD;
      for neonates with a PMA ≥27 weeks in the phase III according to data from Finland (Härkin, J&#xD;
      Pediatr. 2016). The 2nd, 3rd and 4th level doses will stand for 25%, 50%, and 75% increase of&#xD;
      the first level:&#xD;
&#xD;
        -  20 mg/kg loading dose then 7.5 mg/kg/6hours during 5 days (total = 20 doses)&#xD;
&#xD;
        -  25 mg/kg loading dose then 10 mg/kg/6hours during 5 days (total = 20 doses)&#xD;
&#xD;
        -  30 mg/kg loading dose then 12 mg/kg/6hours during 5 days (total = 20 doses)&#xD;
&#xD;
        -  35 mg/kg loading dose then 15 mg/kg/6hours during 5 days (total = 20 doses)&#xD;
&#xD;
      The first cohort of patients will be treated at the lowest starting dose level. Both, the&#xD;
      Data Safety Monitoring Board (DSMB) and the statistician will be informed about the&#xD;
      therapeutic response observed and the safety of treatment. The statistician will use these&#xD;
      data for re-estimation of the posterior probability of success. The DSMB will be then&#xD;
      informed about the statistical recommendation for the next dose level to use in the next&#xD;
      cohort of 3 patients. The decision to go up, go down or stay on the same dose level will&#xD;
      remain to the DSMB who will be free to follow or not the statistical recommendation. Dose&#xD;
      escalation will not increase by more than one level, although dose de-escalations could be&#xD;
      large.&#xD;
&#xD;
      At inclusion, basic data (pregnancy, blood results, birth and transfer) are recorded. After&#xD;
      inclusion, systemic arterial pressure is measured before administration of the first dose of&#xD;
      acetaminophen. Then the preterm infant receives a loading dose of acetaminophen. A first&#xD;
      blood sample is collected just after end of loading dose infusion (T15min) to analyze&#xD;
      Acetaminophen plasma level (0.2mL) ans ALT/AST (0.1ml to 0.3ml, according to local biological&#xD;
      laboratory). Each 6 hours during the first 5 days of life, each preterm infant receives a&#xD;
      perfusion of acetaminophen, so 20 doses are administered in total. Systemic arterial pressure&#xD;
      is measured at 30', 60', 90', 120' after each dose. Each day, a cardiac echography is&#xD;
      performed. After Dose 10, a second blood sample (0.3 ml to 0.5 ml according to local&#xD;
      biological laboratory) is collected to analyze acetaminophen plasma level and ALAT &amp; ASAT.&#xD;
&#xD;
      During visit 1 at day 3, eCRF is completed for period Day 1 to Day 3. A few &quot;bottom of blood&#xD;
      tubes&quot; sampled for routine care will be kept for others acetaminophen plasma level analysis.&#xD;
      This will be done in centres where this procedure is possible.After the last dose of&#xD;
      acetaminophen, a blood sample of 0,3 to 0.5ml (ideally 6 hours after the start of last&#xD;
      infusion) is collected to analyze ALAT &amp; ASAT and Acetaminophen plasma level (0.2 ml).&#xD;
&#xD;
      During visit 2 at Day 5, eCRF is completed for period Day 4 to Day 5. A cardiac echography is&#xD;
      performed after the last dose of acetaminophen. Data from a cerebral echography performed in&#xD;
      routine care during the first week after the first dose will be recorded.&#xD;
&#xD;
      During Visit 3, at Day 7, CRF is completed, and the information about primary outcome&#xD;
      (closure or not of the Ductus Arterosus) is sent by email to experts of the research unit EA&#xD;
      7323 &quot; Evaluation of Therapeutics and pharmacology in perinatality and pediatrics &quot;,&#xD;
      University of Paris-Descartes, Paris, France.&#xD;
&#xD;
      The Phase III is a pragmatic trial. At inclusion, basic data (pregnancy, blood results, birth&#xD;
      and transfert) are recorded. After inclusion, randomization is performed. After&#xD;
      randomization, each infant receives a loading dose of acetaminophen or placebo before 12&#xD;
      hours of life. After the loading dose of Acetaminophen, a supplement of 0.1 to 0.3 ml of&#xD;
      blood will be collected, as supplement of a blood sample performed in routine care for&#xD;
      AST/ALT analysis. Each 6 hours during the first 5 days of life, each preterm infant receives&#xD;
      a perfusion of placebo or acetaminophen, so 20 doses are administered in total. After the&#xD;
      dose 10 of Acetaminophen, a supplement of 0.1 to 0.3 ml of blood will be collected as&#xD;
      supplement of a blood sample performed in routine care for AST/ALT analysis. Few &quot;bottom of&#xD;
      blood tubes&quot; sampled for routine care will be kept for acetaminophen plasma level analysis in&#xD;
      50 first preterm infants (25 in each gestational age group) chosen hospitalized in the NICUs&#xD;
      participating to Phase II. This will be done in NICUs where this procedure is possible).&#xD;
&#xD;
      During visit 1 at Day 7, data describing baby care are recording day by day from Day 0 to Day&#xD;
      7. Around Day 7 (between Day6 and Day 10) one cardiac echography is performed.&#xD;
&#xD;
      During visit 2 at Day 28, a review of different cares received by the baby between Day 8 and&#xD;
      Day 28 is recorded. Data from a cerebral echography performed in routine care, before 36&#xD;
      weeks of postmenstrual age or before discharge if it occurs before will be recorded in the&#xD;
      eCRF. Result of the last ophthalmological examination performed in routine care before 36&#xD;
      weeks of postmenstrual age or before discharge if it occurs before, should be noted in the&#xD;
      eCRF.&#xD;
&#xD;
      During visit 3 at 36 weeks of postmenstrual age or at first discharge home, whatever comes&#xD;
      first, a review of mobidity (BPD, cerebral lesions, retinopathy, necrotizing enterocolitis)&#xD;
      is performed to complete the primary endpoint. At the end of hospitalization, clinical data&#xD;
      at discharge are recorded&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 29, 2020</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2024</primary_completion_date>
  <phase>Phase 2/Phase 3</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>
    <intervention_model_description>Phase II is a dose finding phase Phase III is a randomized, multicenter, double-blind, placebo-controlled superiority trial, two arms in a 1:1 ratio, evaluating an increasing of 10% of the percentage of survival without severe morbidity at 36 weeks of post menstrual age</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN. The placebo product is a polyethylene ampoule of 10ml of NaCL 0.9%, B BRAUN. Polyethylene ampoule of active and placebo products are with the same appearance, in accordance with Good Manufacturing Practices Drugs for Clinical Trials</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Closure of Ductus Arteriosus (Primary endpoint of phase II)</measure>
    <time_frame>Day 7</time_frame>
    <description>Number of participants with closed Ductus Arteriosus (DA) assessed by echocardiography during the first 7 days of life, defined as DA closed at two consecutive echocardiographies or if the DA is closed at echocardiography of Day 7</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The survival without severe morbidity (Primary endpoint of phase III)</measure>
    <time_frame>Up to 36 weeks of post menstrual age</time_frame>
    <description>the survival without severe morbidity at 36 weeks of post menstrual age or at first discharge home, whichever comes first. The severe morbidities include bronchopulmonary dysplasia (BPD Grade 3 according to NIH consensus), necrotizing enterocolitis (NEC) of Bell's stage II or III, intraventricular hemorrhage (IVH) grade III-IV or cystic leukomalacia observed at any time up to 36 weeks of post menstrual age</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Analgesia/sedation drugs consumption during first week after birth (Secondary endpoint of phase III)</measure>
    <time_frame>Day 7</time_frame>
    <description>Number of days during the first week the infants received sedation/analgesia treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Closure of Ductus arteriosus (Secondary endpoint of phase III)</measure>
    <time_frame>Day 7</time_frame>
    <description>Number of patients with a closed Ductus Arteriosus (DA) assessed by echocardiography at Day 7- Day 10</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of back-up treatment of PDA (Secondary endpoint of phase III)</measure>
    <time_frame>At 36 weeks of Post menstrual age</time_frame>
    <description>Number of the patients receiving back-up treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days during the first week after birth with catecholamines administration (Secondary endpoint of phase III)</measure>
    <time_frame>Day 7</time_frame>
    <description>Number of days during the first week the infants received catecholamines in perfusion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early pulmonary hemorrhage (Secondary endpoint of phase III)</measure>
    <time_frame>Day 7</time_frame>
    <description>Number of infants with early pulmonary hemorrhage</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood acetaminophen levels in extrem preterm infant (Secondary endpoint of Phase II and Phase III)</measure>
    <time_frame>Day 7</time_frame>
    <description>Analysis of acetaminophen levels according to the administered dose and the time of sample collection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity of Acetaminophen in extrem preterm infant (Secondary endpoint of Phase II and Phase III)</measure>
    <time_frame>Day 7</time_frame>
    <description>Number of patient with increase of AST/ALT more than 2 times the normal value (according to local standards) or the first AST/ALT dosage before loading dose of Acetaminophen if if available in standard care</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">824</enrollment>
  <condition>Patency of the Ductus Arteriosus</condition>
  <condition>Acetaminophen</condition>
  <condition>Extreme Prematurity</condition>
  <arm_group>
    <arm_group_label>Acetaminophen</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NaCL 0.9%</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The placebo product is a polyethylene ampoule of 10ml of NaCL 0.9%, B BRAUN. Polyethylene ampoule of active and placebo products are with the same appearance, in accordance with Good Manufacturing Practices Drugs for Clinical Trials.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acetaminophen</intervention_name>
    <description>In the 27-28 weeks gestational age group, the dosage is 2 ml/kg loading dose within 12 hours after birth followed by 0.75 ml/kg/ 6 hours during 5 days (total = 20 doses).&#xD;
In the 23-26 weeks gestational age group, the dosage will be minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7, found during the phase II.</description>
    <arm_group_label>Acetaminophen</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NACL 0.9%</intervention_name>
    <description>In the 27-28 weeks gestational age group, the dosage is 2 ml/kg loading dose within 12 hours after birth followed by 0.75 ml/kg/ 6 hours during 5 days (total = 20 doses).&#xD;
In the 23-26 weeks gestational age group, the dosage will be minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7, found during the phase II.</description>
    <arm_group_label>NaCL 0.9%</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Birth between 23-26 W for Phase II, between 23-28 W for Phase III&#xD;
&#xD;
          -  Post natal age &lt; 12 hours&#xD;
&#xD;
          -  Parental or Legal Authority Consent&#xD;
&#xD;
          -  Parents with a social security or health insurance (if applicable according to the&#xD;
             local regulation)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Birth defect / Congenital anomaly&#xD;
&#xD;
          -  Twin-to-twin transfusion syndrome not cured&#xD;
&#xD;
          -  Suspicion of pulmonary hypoplasia&#xD;
&#xD;
          -  Suspicion of hepatic impairment (hemorrhagic syndrome and/or severe hypoglycemia)&#xD;
&#xD;
          -  Clinical instability that can lead to rapid death&#xD;
&#xD;
          -  Impossibility to start treatment before 12 hours of life&#xD;
&#xD;
          -  Parents placed under judicial protection&#xD;
&#xD;
          -  Participation in other clinical trial using acetaminophen during the first 5 days of&#xD;
             life, indomethacin or ibuprofen during the first 3 days of life or using rescue&#xD;
             treatment of PDA not recommended in the TREOCAPA trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>23 Weeks</minimum_age>
    <maximum_age>28 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Jean-Christophe Rozé</last_name>
    <phone>+33625925845</phone>
    <email>jean-christophe.roze@inserm.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Liège</name>
      <address>
        <city>Liège</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Vincent Rigo</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Juliane Marie Centre, Rigshospitalet, Copenhagen University hospital</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Charlotte Kruse</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>East Tallinn Central Hospital</name>
      <address>
        <city>Tallinn</city>
        <country>Estonia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Pille Andresson</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Tallinn Children's Hospital</name>
      <address>
        <city>Tallinn</city>
        <country>Estonia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Mari-Liis Ilmoja</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Tartu University Hospital, Neonatal and Paediatric Intensive Care Unit</name>
      <address>
        <city>Tartu</city>
        <country>Estonia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Tuuli Metsvaht</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Helsinki University Hospital, Department of Children and Adolecents, Neonatology</name>
      <address>
        <city>Helsinki</city>
        <country>Finland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Mirka Lumia</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Kuopio University Hospital, Department of Pediatrics</name>
      <address>
        <city>Kuopio</city>
        <country>Finland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Ulla Sankilampi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Oulu University Hospital, Department of Pediatrics</name>
      <address>
        <city>Oulu</city>
        <country>Finland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Outi Aikio</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Tampere University Hospital, Department of Pediatrics</name>
      <address>
        <city>Tampere</city>
        <country>Finland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Outi Tammela</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Turku University Hospital, Department of Peadiatrics</name>
      <address>
        <city>Turku</city>
        <country>Finland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Hanna Soukka</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Angers</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Cécile Cipierre</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hopital Jeanne de Flandre</name>
      <address>
        <city>Lille</city>
        <zip>59037</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Laurent Storme</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hospice civils de Lyon, Hopital Femme Enfant</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Kim An Nguyen</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital de la conception</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Isabelle Ligi, Dr</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Arnaud de Villeneuve, Département de Pédiatrie Néonatale et Réanimation Pédiatrique</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Gilles Cambonie</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Nantes, Hopital mére Enfant</name>
      <address>
        <city>Nantes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jean-Christophe Rozé</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Necker - Enfants malades</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Elsa Kermorvant</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CENTRE hospitalier intercommunal de Creteil</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Xavier DURRMEYER</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hopital Cochin, Service de Médecine et Réanimation néonatales de Port-Royal</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Juliana Patkai</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hopital Robert Debré, Néonatologie</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Valérie Biran</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Rennes, Hopital Sud</name>
      <address>
        <city>Rennes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pr</last_name>
    </contact>
    <investigator>
      <last_name>Alain Beuchée</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHU Strasbourg, Hôpital de Hautepierre</name>
      <address>
        <city>Strasbourg</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Pierre Kuhn</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>CHRU de Tours</name>
      <address>
        <city>Tours</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Geraldine Favrais, Dr</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Bács Kiskun COUNTY HOSPITAL</name>
      <address>
        <city>Kecskemét</city>
        <zip>H6000</zip>
        <country>Hungary</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Cork University Hospital</name>
      <address>
        <city>Cork</city>
        <zip>T12 DC4A</zip>
        <country>Ireland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Eugene Dempsey</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Oslo University Hospital</name>
      <address>
        <city>Oslo</city>
        <zip>0424</zip>
        <country>Norway</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Arild Rønnestad</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Centro Clínico Académico - Braga</name>
      <address>
        <city>Braga</city>
        <country>Portugal</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Centro Hospitalar Universitário Lisboa Norte, EPE -Hospital Santa Maria</name>
      <address>
        <city>Lisboa</city>
        <country>Portugal</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>André Graça</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Centro Hospitalar e Universitário do Porto, EPE - Centro Materno Infantil do Norte</name>
      <address>
        <city>Porto</city>
        <country>Portugal</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Elisa Proenca</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Solna</city>
        <zip>171 64</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Marco Bartocci</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hopital Universitaire de Geneve (HUG) - Hopital des enfants</name>
      <address>
        <city>Geneva</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Olivier Baud</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Children's Hospital Lausanne</name>
      <address>
        <city>Lausanne</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Sebastian Joye</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Hospital of Zürich</name>
      <address>
        <city>Zürich</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Tolbias Muelhbacher</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Denmark</country>
    <country>Estonia</country>
    <country>Finland</country>
    <country>France</country>
    <country>Hungary</country>
    <country>Ireland</country>
    <country>Norway</country>
    <country>Portugal</country>
    <country>Sweden</country>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 19, 2020</study_first_submitted>
  <study_first_submitted_qc>July 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>May 4, 2023</last_update_submitted>
  <last_update_submitted_qc>May 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ductus Arteriosus, Patent</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetaminophen</mesh_term>
  </intervention_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/NCT04459117
org study id: C19-29
secondary id: 2019-004297-26
nct id: NCT04459117
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
TREOCAPA is a Phase II/III European Multicentre study concerning the prophylactic treatment
      by Acetaminophen of extremely preterm infant during the first five days after birth.

      The Phase II is a dose finding phase in order to assess the minimum effective dose regimen of
      acetaminophen for the closure of PDA for neonates with a gestational age less than 27 weeks
      This part of the study will be conducted in 11 NICUs, in 4 countries (France, UK, Finland and
      Denmark).

      The Phase III is The phase III is a randomized, multicenter, double-blind, placebo-controlled
      superiority trial, two arms in a 1:1 ratio, evaluating an increasing of 10% of the percentage
      of survival without severe morbidity at 36 weeks of post menstrual age. In the intervention
      arm, 20 mg/kg followed by 7.5 mg/kg quarter in die (QID) will be administered to the 27-28
      weeks gestational age group (dosage confirmed through PK/PD data analysis from the previous
      Finnian study) and the dosage selected after the conclusion of the Phase II will be
      administered to the 23-26 weeks gestational age group. A group sequential design, with a
      total of 3 analyses (2 interim analyses and a final) and the O'Brien-Fleming alpha spending
      function is chosen for the trial. At the same time, a Bayesian sequential analysis is planned
      for safety endpoints
The Phase II will be conducted in 11 NICUs, in 4 countries (France, UK, Finland and Denmark).
      The estimated recruitment period is 6 months to enroll 30 preterm infants of 23-26 weeks of
      gestation. Four different loading/maintenance doses will be tested. The first level will be
      20 mg/kg followed by 7.5 mg/kg quarter in die (QID) which correspond to the dosage selected
      for neonates with a PMA ≥27 weeks in the phase III according to data from Finland (Härkin, J
      Pediatr. 2016). The 2nd, 3rd and 4th level doses will stand for 25%, 50%, and 75% increase of
      the first level:

        -  20 mg/kg loading dose then 7.5 mg/kg/6hours during 5 days (total = 20 doses)

        -  25 mg/kg loading dose then 10 mg/kg/6hours during 5 days (total = 20 doses)

        -  30 mg/kg loading dose then 12 mg/kg/6hours during 5 days (total = 20 doses)

        -  35 mg/kg loading dose then 15 mg/kg/6hours during 5 days (total = 20 doses)

      The first cohort of patients will be treated at the lowest starting dose level. Both, the
      Data Safety Monitoring Board (DSMB) and the statistician will be informed about the
      therapeutic response observed and the safety of treatment. The statistician will use these
      data for re-estimation of the posterior probability of success. The DSMB will be then
      informed about the statistical recommendation for the next dose level to use in the next
      cohort of 3 patients. The decision to go up, go down or stay on the same dose level will
      remain to the DSMB who will be free to follow or not the statistical recommendation. Dose
      escalation will not increase by more than one level, although dose de-escalations could be
      large.

      At inclusion, basic data (pregnancy, blood results, birth and transfer) are recorded. After
      inclusion, systemic arterial pressure is measured before administration of the first dose of
      acetaminophen. Then the preterm infant receives a loading dose of acetaminophen. A first
      blood sample is collected just after end of loading dose infusion (T15min) to analyze
      Acetaminophen plasma level (0.2mL) ans ALT/AST (0.1ml to 0.3ml, according to local biological
      laboratory). Each 6 hours during the first 5 days of life, each preterm infant receives a
      perfusion of acetaminophen, so 20 doses are administered in total. Systemic arterial pressure
      is measured at 30', 60', 90', 120' after each dose. Each day, a cardiac echography is
      performed. After Dose 10, a second blood sample (0.3 ml to 0.5 ml according to local
      biological laboratory) is collected to analyze acetaminophen plasma level and ALAT & ASAT.

      During visit 1 at day 3, eCRF is completed for period Day 1 to Day 3. A few "bottom of blood
      tubes" sampled for routine care will be kept for others acetaminophen plasma level analysis.
      This will be done in centres where this procedure is possible.After the last dose of
      acetaminophen, a blood sample of 0,3 to 0.5ml (ideally 6 hours after the start of last
      infusion) is collected to analyze ALAT & ASAT and Acetaminophen plasma level (0.2 ml).

      During visit 2 at Day 5, eCRF is completed for period Day 4 to Day 5. A cardiac echography is
      performed after the last dose of acetaminophen. Data from a cerebral echography performed in
      routine care during the first week after the first dose will be recorded.

      During Visit 3, at Day 7, CRF is completed, and the information about primary outcome
      (closure or not of the Ductus Arterosus) is sent by email to experts of the research unit EA
      7323 " Evaluation of Therapeutics and pharmacology in perinatality and pediatrics ",
      University of Paris-Descartes, Paris, France.

      The Phase III is a pragmatic trial. At inclusion, basic data (pregnancy, blood results, birth
      and transfert) are recorded. After inclusion, randomization is performed. After
      randomization, each infant receives a loading dose of acetaminophen or placebo before 12
      hours of life. After the loading dose of Acetaminophen, a supplement of 0.1 to 0.3 ml of
      blood will be collected, as supplement of a blood sample performed in routine care for
      AST/ALT analysis. Each 6 hours during the first 5 days of life, each preterm infant receives
      a perfusion of placebo or acetaminophen, so 20 doses are administered in total. After the
      dose 10 of Acetaminophen, a supplement of 0.1 to 0.3 ml of blood will be collected as
      supplement of a blood sample performed in routine care for AST/ALT analysis. Few "bottom of
      blood tubes" sampled for routine care will be kept for acetaminophen plasma level analysis in
      50 first preterm infants (25 in each gestational age group) chosen hospitalized in the NICUs
      participating to Phase II. This will be done in NICUs where this procedure is possible).

      During visit 1 at Day 7, data describing baby care are recording day by day from Day 0 to Day
      7. Around Day 7 (between Day6 and Day 10) one cardiac echography is performed.

      During visit 2 at Day 28, a review of different cares received by the baby between Day 8 and
      Day 28 is recorded. Data from a cerebral echography performed in routine care, before 36
      weeks of postmenstrual age or before discharge if it occurs before will be recorded in the
      eCRF. Result of the last ophthalmological examination performed in routine care before 36
      weeks of postmenstrual age or before discharge if it occurs before, should be noted in the
      eCRF.

      During visit 3 at 36 weeks of postmenstrual age or at first discharge home, whatever comes
      first, a review of mobidity (BPD, cerebral lesions, retinopathy, necrotizing enterocolitis)
      is performed to complete the primary endpoint. At the end of hospitalization, clinical data
      at discharge are recorded
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Phase II is a dose finding phase Phase III is a randomized, multicenter, double-blind, placebo-controlled superiority trial, two arms in a 1:1 ratio, evaluating an increasing of 10% of the percentage of survival without severe morbidity at 36 weeks of post menstrual age
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN. The placebo product is a polyethylene ampoule of 10ml of NaCL 0.9%, B BRAUN. Polyethylene ampoule of active and placebo products are with the same appearance, in accordance with Good Manufacturing Practices Drugs for Clinical Trials
measure: Closure of Ductus Arteriosus (Primary endpoint of phase II)
time frame: Day 7
description: Number of participants with closed Ductus Arteriosus (DA) assessed by echocardiography during the first 7 days of life, defined as DA closed at two consecutive echocardiographies or if the DA is closed at echocardiography of Day 7
measure: The survival without severe morbidity (Primary endpoint of phase III)
time frame: Up to 36 weeks of post menstrual age
description: the survival without severe morbidity at 36 weeks of post menstrual age or at first discharge home, whichever comes first. The severe morbidities include bronchopulmonary dysplasia (BPD Grade 3 according to NIH consensus), necrotizing enterocolitis (NEC) of Bell's stage II or III, intraventricular hemorrhage (IVH) grade III-IV or cystic leukomalacia observed at any time up to 36 weeks of post menstrual age
measure: Analgesia/sedation drugs consumption during first week after birth (Secondary endpoint of phase III)
time frame: Day 7
description: Number of days during the first week the infants received sedation/analgesia treatment
measure: Closure of Ductus arteriosus (Secondary endpoint of phase III)
time frame: Day 7
description: Number of patients with a closed Ductus Arteriosus (DA) assessed by echocardiography at Day 7- Day 10
measure: Number of back-up treatment of PDA (Secondary endpoint of phase III)
time frame: At 36 weeks of Post menstrual age
description: Number of the patients receiving back-up treatment
measure: Number of days during the first week after birth with catecholamines administration (Secondary endpoint of phase III)
time frame: Day 7
description: Number of days during the first week the infants received catecholamines in perfusion
measure: Early pulmonary hemorrhage (Secondary endpoint of phase III)
time frame: Day 7
description: Number of infants with early pulmonary hemorrhage
measure: Blood acetaminophen levels in extrem preterm infant (Secondary endpoint of Phase II and Phase III)
time frame: Day 7
description: Analysis of acetaminophen levels according to the administered dose and the time of sample collection
measure: Toxicity of Acetaminophen in extrem preterm infant (Secondary endpoint of Phase II and Phase III)
time frame: Day 7
description: Number of patient with increase of AST/ALT more than 2 times the normal value (according to local standards) or the first AST/ALT dosage before loading dose of Acetaminophen if if available in standard care
arm group label: Acetaminophen
arm group type: Active Comparator
description: The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN.
arm group label: NaCL 0.9%
arm group type: Placebo Comparator
description: The placebo product is a polyethylene ampoule of 10ml of NaCL 0.9%, B BRAUN. Polyethylene ampoule of active and placebo products are with the same appearance, in accordance with Good Manufacturing Practices Drugs for Clinical Trials.
intervention type: Drug
intervention name: Acetaminophen
description: In the 27-28 weeks gestational age group, the dosage is 2 ml/kg loading dose within 12 hours after birth followed by 0.75 ml/kg/ 6 hours during 5 days (total = 20 doses).
In the 23-26 weeks gestational age group, the dosage will be minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7, found during the phase II.
arm group label: Acetaminophen
intervention type: Drug
intervention name: NACL 0.9%
description: In the 27-28 weeks gestational age group, the dosage is 2 ml/kg loading dose within 12 hours after birth followed by 0.75 ml/kg/ 6 hours during 5 days (total = 20 doses).
In the 23-26 weeks gestational age group, the dosage will be minimum effective dose of acetaminophen to close the ductus arteriosus before or at day 7, found during the phase II.
arm group label: NaCL 0.9%
criteria: 
gender: All
minimum age: 23 Weeks
maximum age: 28 Weeks
healthy volunteers: No
last name: Jean-Christophe Rozé
phone: +33625925845
email: jean-christophe.roze@inserm.fr
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Withdrawn
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
facility: 
status: Recruiting
investigator: 
country: Belgium
country: Denmark
country: Estonia
country: Finland
country: France
country: Hungary
country: Ireland
country: Norway
country: Portugal
country: Sweden
country: Switzerland
responsible party type: Sponsor
mesh term: Ductus Arteriosus, Patent
mesh term: Acetaminophen