Patency of the Ductus ArteriosusPhase 2/3TREOCAPANCT04459117
Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen
A Phase 2/3 study testing Acetaminophen and NACL 0.9% in people with Patency of the Ductus Arteriosus and Acetaminophen, run by Institut National de la Santé Et de la Recherche Médicale, France at 36 sites in 12 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 23 to 28 weeks
- Conditions the study is for
- Patency of the Ductus Arteriosus, Acetaminophen, Extreme Prematurity
- What is being tested?
- Acetaminophen and NACL 0.9%
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 804 participants
- Where
- 36 sitesin 12 countries
- Study dates
- 29 Oct 2020to 20 Jun 2024
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 23 to 28 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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)
Who cannot join
- Birth defect / Congenital anomaly
- Twin-to-twin transfusion syndrome not cured
- 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
Trial locations and contacts
36 sites in 12 countries.
36 sites in 12 countries
France16 sites
CHU Angers
Angers
Hopital Jeanne de Flandre
Lille, 59037
Hôpital Croix-Rousse
Lyon, 69317
Hospice civils de Lyon, Hopital Femme Enfant
Lyon
Hôpital Marseille Nord
Marseille, 13015
Hôpital de la conception
Marseille
Hôpital Arnaud de Villeneuve, Département de Pédiatrie Néonatale et Réanimation Pédiatrique
Montpellier
CHU Nantes, Hopital mére Enfant
Nantes
Hôpital Necker - Enfants malades
Paris, 75015
CENTRE hospitalier intercommunal de Creteil
Paris
Hopital Cochin, Service de Médecine et Réanimation néonatales de Port-Royal
Paris
Hopital Robert Debré, Néonatologie
Paris
CHU Rennes, Hopital Sud
Rennes
CHU Strasbourg, Hôpital de Hautepierre
Strasbourg
Centre Hospitalo-Universitaire de Toulouse
Toulouse, 31059
CHRU de Tours
Tours
Finland5 sites
Helsinki University Hospital, Department of Children and Adolecents, Neonatology
Helsinki
Kuopio University Hospital, Department of Pediatrics
Kuopio
Oulu University Hospital, Department of Pediatrics
Oulu
Tampere University Hospital, Department of Pediatrics
Tampere
Turku University Hospital, Department of Peadiatrics
Turku
Estonia3 sites
East Tallinn Central Hospital
Tallinn
Tallinn Children's Hospital
Tallinn
Tartu University Hospital, Neonatal and Paediatric Intensive Care Unit
Tartu
Switzerland3 sites
Hopital Universitaire de Geneve (HUG) - Hopital des enfants
Geneva
University Children's Hospital Lausanne
Lausanne
University Hospital of Zürich
Zurich
Portugal2 sites
Centro Hospitalar Universitário Lisboa Norte, EPE -Hospital Santa Maria
Lisbon
Centro Hospitalar e Universitário do Porto, EPE - Centro Materno Infantil do Norte
Porto
Denmark1 site
The Juliane Marie Centre, Rigshospitalet, Copenhagen University hospital
Copenhagen, 2100
About this study
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
Read the 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
- Being tested
- Acetaminophen, NACL 0.9%
- Medical subject headings
- Ductus Arteriosus, Patent
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AcetaminophenDrug
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.
NACL 0.9%Drug
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.
| Study group | Role | What they receive |
|---|---|---|
| Acetaminophen | Active comparator | The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN. Receives: Drug: Acetaminophen |
| NaCL 0.9% | Placebo comparator | 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. Receives: Drug: NACL 0.9% |
What is being measured
The primary outcome is the main question the study is designed to answer.
Closure of Ductus Arteriosus (Primary endpoint of phase II)
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
Measured: Day 7
The survival without severe morbidity (Primary endpoint of phase III)
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
Measured: Up to 36 weeks of post menstrual age
Secondary outcomes (7)
Analgesia/sedation drugs consumption during first week after birth (Secondary endpoint of phase III)
Number of days during the first week the infants received sedation/analgesia treatment
Measured: Day 7
Closure of Ductus arteriosus (Secondary endpoint of phase III)
Number of patients with a closed Ductus Arteriosus (DA) assessed by echocardiography at Day 7- Day 10
Measured: Day 7
Number of back-up treatment of PDA (Secondary endpoint of phase III)
Number of the patients receiving back-up treatment
Measured: At 36 weeks of Post menstrual age
Number of days during the first week after birth with catecholamines administration (Secondary endpoint of phase III)
Number of days during the first week the infants received catecholamines in perfusion
Measured: Day 7
Early pulmonary hemorrhage (Secondary endpoint of phase III)
Number of infants with early pulmonary hemorrhage
Measured: Day 7
Blood acetaminophen levels in extrem preterm infant (Secondary endpoint of Phase II and Phase III)
Analysis of acetaminophen levels according to the administered dose and the time of sample collection
Measured: Day 7
Toxicity of Acetaminophen in extrem preterm infant (Secondary endpoint of Phase II and Phase III)
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
Measured: Day 7
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jul 2020
- Study start29 Oct 2020
- Primary completion20 Jun 2024
- Study completion20 Jun 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Patency of the Ductus ArteriosusStudies of the same condition, open and under way.
- More trials run by Institut National de la Santé Et de la Recherche Médicale, FranceThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 804 participants (actual)
Sponsor and investigators
- Sponsor type
- Other government
- Collaborators
- UPCET, PARTNERS for International clinical Research, Connect for Children, Global Foundation for the Care of Newborn Infants
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04459117
- Sponsor's protocol ID
- C19-29
- Other IDs
- 2019-004297-26, 2019
- Acronym
- TREOCAPA
- Status last verified
- Mar 2026
- First submitted
- 19 Jun 2020
- Last updated
- 16 Mar 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Padavia F, Treluyer JM, Cambonie G, Flamant C, Rideau A, Tauzin M, Patkai J, Gascoin G, Lumia M, Aikio O, Foissac F, Urien S, Benaboud S, Lui G, Froelicher Bournaud L, Zheng Y, Kemper R, Tortigue M, Baruteau AE, Kallio J, Hallman M, Diallo A, Levoyer L, Roze JC, Bouazza N. Paracetamol Concentrations and Time-Course of Ductus Arteriosus Diameter in Extremely Preterm Neonates: A Population Pharmacokinetic-Pharmacodynamic Analysis. Clin Pharmacokinet. 2025 Nov;64(11):1681-1691. doi: 10.1007/s40262-025-01567-4. Epub 2025 Sep 1.
PubMed 40889095Ursino M, Alberti C, Cambonie G, Kemp R, Vanhecke A, Levoyer L, Diallo A, Hallman M, Roze JC; TREOCAPA study group. TREOCAPA: prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen-statistical analysis plan for the randomized phase III group sequential trial. Trials. 2025 Feb 13;26(1):52. doi: 10.1186/s13063-025-08751-8.
PubMed 39948605Bouazza N, Cambonie G, Flamant C, Rideau A, Tauzin M, Patkai J, Gascoin G, Lumia M, Aikio O, Lui G, Bournaud LF, Walsh-Papageorgiou A, Tortigue M, Baruteau AE, Kallio J, Hallman M, Diallo A, Levoyer L, Treluyer JM, Roze JC. Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach. Paediatr Drugs. 2024 Jan;26(1):83-93. doi: 10.1007/s40272-023-00602-w. Epub 2023 Nov 17.
PubMed 37978159Padavia F, Treluyer JM, Cambonie G, Flamant C, Rideau A, Tauzin M, Patkai J, Gascoin G, Lumia M, Aikio O, Foissac F, Urien S, Benaboud S, Lui G, Froelicher Bournaud L, Zheng Y, Kemper R, Tortigue M, Baruteau AE, Kallio J, Hallman M, Diallo A, Levoyer L, Roze JC, Bouazza N. Population Pharmacokinetics of Intravenous Paracetamol and Its Metabolites in Extreme Preterm Neonates in the Context of Patent Ductus Arteriosus Treatment. Clin Pharmacokinet. 2024 Dec;63(12):1689-1700. doi: 10.1007/s40262-024-01439-3. Epub 2024 Nov 22.
PubMed 39578300Wan M, Turner MA, Cambonie G, Kemper R, Bouafia N, Levoyer L, Diallo A, Hallman M, Roze JC. Experience and lessons learned relating to investigational product supply in the design and delivery of a paediatric investigator-initiated clinical trial. Contemp Clin Trials Commun. 2025 Jun 30;46:101517. doi: 10.1016/j.conctc.2025.101517. eCollection 2025 Aug.
PubMed 40678377Roze JC, Cambonie G, Flamant C, Patkai J, Muhlbacher T, Gascoin G, Rideau Batista Novais A, Tauzin M, Le Duc K, Beuchee A, Joye S, Babacheva E, Bouissou A, Ligi I, Tammela O, Plourde M, Dempsey E, Tosello B, Nguyen K, Vincent M, Andresson P, Binder C, Kruse C, Barcos Munoz F, Kuhn P, Proenca E, Bartocci M, Kermorvant-Duchemin E, Nellis G, Lumia M, Giapros V, Rigo V, Sankilampi U, Mendes da Graca A, Ronnestad A, Soukka H, Mondi V, Aikio O, Torre-Monmany N, Ruegger C, Baud O, Zeitlin J, Morgan AS, Baruteau AE, Ancel PY, Carbajal R, Bouazza N, Diallo A, Levoyer L, Kemper R, Hallman M, Alberti C, Ursino M; TREOCAPA Study Group. Prophylactic Treatment of Patent Ductus Arteriosus With Acetaminophen: A Randomized Clinical Trial. JAMA Pediatr. 2026 Apr 1;180(4):374-383. doi: 10.1001/jamapediatrics.2025.6150.
PubMed 41697673
Study at a glance
From the registry record, last updated by the sponsor on 16 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen
- ClinicalTrials.gov ID
- NCT04459117
- Acronym / sponsor ID
- TREOCAPA / C19-29
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 804 participants (actual)
- Lead sponsor
- Institut National de la Santé Et de la Recherche Médicale, FranceOther government
- Collaborators
- UPCET, PARTNERS for International clinical Research, Connect for Children, Global Foundation for the Care of Newborn Infants
- Study start
- 29 Oct 2020 (actual)
- Primary completion
- 20 Jun 2024 (actual)
- Study completion
- 20 Jun 2024 (actual)
- First posted
- 7 Jul 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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
| Arm | Type | Receives |
|---|---|---|
| Acetaminophen | Active comparator | Drug: AcetaminophenThe active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN. |
| NaCL 0.9% | Placebo comparator | Drug: NACL 0.9%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. |
Who may qualify
- Ages
- 23 to 28 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- 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)
Key exclusion criteria (8 listed)
- Birth defect / Congenital anomaly
- Twin-to-twin transfusion syndrome not cured
- Suspicion of pulmonary hypoplasia
- Suspicion of hepatic impairment (hemorrhagic syndrome and/or severe hypoglycemia)
- Clinical instability that can lead to rapid death
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AcetaminophenIn 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. | Drug | Acetaminophen |
| NACL 0.9%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. | Drug | NaCL 0.9% |
Primary outcome
Closure of Ductus Arteriosus (Primary endpoint of phase II)
Time frame: Day 7
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
The survival without severe morbidity (Primary endpoint of phase III)
Time frame: Up to 36 weeks of post menstrual age
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
7 secondary outcomes
Analgesia/sedation drugs consumption during first week after birth (Secondary endpoint of phase III)
Time frame: Day 7
Closure of Ductus arteriosus (Secondary endpoint of phase III)
Time frame: Day 7
Number of back-up treatment of PDA (Secondary endpoint of phase III)
Time frame: At 36 weeks of Post menstrual age
Number of days during the first week after birth with catecholamines administration (Secondary endpoint of phase III)
Time frame: Day 7
Early pulmonary hemorrhage (Secondary endpoint of phase III)
Time frame: Day 7
Blood acetaminophen levels in extrem preterm infant (Secondary endpoint of Phase II and Phase III)
Time frame: Day 7
Toxicity of Acetaminophen in extrem preterm infant (Secondary endpoint of Phase II and Phase III)
Time frame: Day 7
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Mar 2026.
- Results publication: PubMed 40889095Padavia F, Treluyer JM, Cambonie G, Flamant C, Rideau A, Tauzin M, Patkai J, Gascoin G, Lumia M, Aikio O, Foissac F, Urien S, Benaboud S, Lui G, Froelicher Bournaud L, Zheng Y, Kemper R, Tortigue M, Baruteau AE, Kallio J, Hallman M, Diallo A, Levoyer L, Roze JC, Bouazza N. Paracetamol Concentrations and Time-Course of Ductus Arteriosus Diameter in Extremely Preterm Neonates: A Population Pharmacokinetic-Pharmacodynamic Analysis. Clin Pharmacokinet. 2025 Nov;64(11):1681-1691. doi: 10.1007/s40262-025-01567-4. Epub 2025 Sep 1.
- Results publication: PubMed 39948605Ursino M, Alberti C, Cambonie G, Kemp R, Vanhecke A, Levoyer L, Diallo A, Hallman M, Roze JC; TREOCAPA study group. TREOCAPA: prophylactic treatment of the ductus arteriosus in preterm infants by acetaminophen-statistical analysis plan for the randomized phase III group sequential trial. Trials. 2025 Feb 13;26(1):52. doi: 10.1186/s13063-025-08751-8.
- Results publication: PubMed 37978159Bouazza N, Cambonie G, Flamant C, Rideau A, Tauzin M, Patkai J, Gascoin G, Lumia M, Aikio O, Lui G, Bournaud LF, Walsh-Papageorgiou A, Tortigue M, Baruteau AE, Kallio J, Hallman M, Diallo A, Levoyer L, Treluyer JM, Roze JC. Prophylactic Intravenous Acetaminophen in Extremely Premature Infants: Minimum Effective Dose Research by Bayesian Approach. Paediatr Drugs. 2024 Jan;26(1):83-93. doi: 10.1007/s40272-023-00602-w. Epub 2023 Nov 17.
- Results publication: PubMed 39578300Padavia F, Treluyer JM, Cambonie G, Flamant C, Rideau A, Tauzin M, Patkai J, Gascoin G, Lumia M, Aikio O, Foissac F, Urien S, Benaboud S, Lui G, Froelicher Bournaud L, Zheng Y, Kemper R, Tortigue M, Baruteau AE, Kallio J, Hallman M, Diallo A, Levoyer L, Roze JC, Bouazza N. Population Pharmacokinetics of Intravenous Paracetamol and Its Metabolites in Extreme Preterm Neonates in the Context of Patent Ductus Arteriosus Treatment. Clin Pharmacokinet. 2024 Dec;63(12):1689-1700. doi: 10.1007/s40262-024-01439-3. Epub 2024 Nov 22.
- Results publication: PubMed 40678377Wan M, Turner MA, Cambonie G, Kemper R, Bouafia N, Levoyer L, Diallo A, Hallman M, Roze JC. Experience and lessons learned relating to investigational product supply in the design and delivery of a paediatric investigator-initiated clinical trial. Contemp Clin Trials Commun. 2025 Jun 30;46:101517. doi: 10.1016/j.conctc.2025.101517. eCollection 2025 Aug.
- Derived from this study: PubMed 41697673Roze JC, Cambonie G, Flamant C, Patkai J, Muhlbacher T, Gascoin G, Rideau Batista Novais A, Tauzin M, Le Duc K, Beuchee A, Joye S, Babacheva E, Bouissou A, Ligi I, Tammela O, Plourde M, Dempsey E, Tosello B, Nguyen K, Vincent M, Andresson P, Binder C, Kruse C, Barcos Munoz F, Kuhn P, Proenca E, Bartocci M, Kermorvant-Duchemin E, Nellis G, Lumia M, Giapros V, Rigo V, Sankilampi U, Mendes da Graca A, Ronnestad A, Soukka H, Mondi V, Aikio O, Torre-Monmany N, Ruegger C, Baud O, Zeitlin J, Morgan AS, Baruteau AE, Ancel PY, Carbajal R, Bouazza N, Diallo A, Levoyer L, Kemper R, Hallman M, Alberti C, Ursino M; TREOCAPA Study Group. Prophylactic Treatment of Patent Ductus Arteriosus With Acetaminophen: A Randomized Clinical Trial. JAMA Pediatr. 2026 Apr 1;180(4):374-383. doi: 10.1001/jamapediatrics.2025.6150.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
36 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Acetaminophen and NACL 0.9% in people with Patency of the Ductus Arteriosus and Acetaminophen, run by Institut National de la Santé Et de la Recherche Médicale, France at 36 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 36 sites in France, Finland, Estonia, Switzerland, Portugal and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Closure of Ductus Arteriosus (Primary endpoint of phase II) (time frame: Day 7). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04459117, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2026.