Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen

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Brief Title

Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen

Official Title

Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen

Brief Summary

      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
    

Detailed Description

      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
    

Study Phase

Phase 2/Phase 3

Study Type

Interventional


Primary Outcome

Closure of Ductus Arteriosus (Primary endpoint of phase II)

Secondary Outcome

 Analgesia/sedation drugs consumption during first week after birth (Secondary endpoint of phase III)

Condition

Patency of the Ductus Arteriosus

Intervention

Acetaminophen

Study Arms / Comparison Groups

 Acetaminophen
Description:  The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

824

Start Date

September 2020

Completion Date

July 2023

Primary Completion Date

April 2023

Eligibility Criteria

        Inclusion Criteria:

          -  Birth between 23-26 W for Phase II, between 23-28 W for Phase III

          -  Post natal age < 12 hours

          -  Parental or Legal Authority Consent

          -  Parents with a social security or health insurance (if applicable according to the
             local regulation)

        Exclusion Criteria:

          -  Birth defect / Congenital anomaly

          -  Twin-to-twin transfusion syndrome

          -  Suspicion of pulmonary hypoplasia

          -  Suspicion of hepatic impairment (hemorrhagic syndrome and/or severe hypoglycemia)

          -  Clinical instability that can lead to rapid death

          -  Impossibility to start treatment before 12 hours of life

          -  Parents placed under judicial protection

          -  Participation in other clinical trial using acetaminophen during the first 5 days of
             life, indomethacin or ibuprofen during the first 3 days of life or using rescue
             treatment of PDA not recommended in the TREOCAPA trial
      

Gender

All

Ages

23 Weeks - 28 Weeks

Accepts Healthy Volunteers

No

Contacts

, , 



Administrative Informations


NCT ID

NCT04459117

Organization ID

C19-29

Secondary IDs

2019-004297-26

Responsible Party

Sponsor

Study Sponsor

Institut National de la Santé Et de la Recherche Médicale, France

Collaborators

 UPCET

Study Sponsor

, , 


Verification Date

June 2020