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