Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen

NCT ID: NCT04459117

Last Updated: 2025-04-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 804 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-29
• Study Completion Date: 2024-06-20

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

Conditions

Patency of the Ductus Arteriosus; Acetaminophen; Extreme Prematurity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Acetaminophen

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

Group Type: ACTIVE_COMPARATOR

Acetaminophen

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

NACL 0.9%

Intervention Type: 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.

Interventions

Acetaminophen

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

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 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

• Minimum Eligible Age: 23 Weeks
• Maximum Eligible Age: 28 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UPCET

UNKNOWN

Sponsor Role: collaborator

PARTNERS for International clinical Research

UNKNOWN

Sponsor Role: collaborator

Connect for Children

UNKNOWN

Sponsor Role: collaborator

Global Foundation for the Care of Newborn Infants

OTHER

Sponsor Role: collaborator

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

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Centre Hospitalier Universitaire de Liège

Liège, , Belgium

The Juliane Marie Centre, Rigshospitalet, Copenhagen University hospital

Copenhagen, , Denmark

East Tallinn Central Hospital

Tallinn, , Estonia

Tallinn Children's Hospital

Tallinn, , Estonia

Tartu University Hospital, Neonatal and Paediatric Intensive Care Unit

Tartu, , Estonia

Helsinki University Hospital, Department of Children and Adolecents, Neonatology

Helsinki, , Finland

Kuopio University Hospital, Department of Pediatrics

Kuopio, , Finland

Oulu University Hospital, Department of Pediatrics

Oulu, , Finland

Tampere University Hospital, Department of Pediatrics

Tampere, , Finland

Turku University Hospital, Department of Peadiatrics

Turku, , Finland

CHU Angers

Angers, , France

Hopital Jeanne de Flandre

Lille, , France

Hôpital Croix-Rousse

Lyon, , France

Hospice civils de Lyon, Hopital Femme Enfant

Lyon, , France

Hôpital Marseille Nord

Marseille, , France

Hôpital de la conception

Marseille, , France

Hôpital Arnaud de Villeneuve, Département de Pédiatrie Néonatale et Réanimation Pédiatrique

Montpellier, , France

CHU Nantes, Hopital mére Enfant

Nantes, , France

Hôpital Necker - Enfants malades

Paris, , France

CENTRE hospitalier intercommunal de Creteil

Paris, , France

Hopital Cochin, Service de Médecine et Réanimation néonatales de Port-Royal

Paris, , France

Hopital Robert Debré, Néonatologie

Paris, , France

CHU Rennes, Hopital Sud

Rennes, , France

CHU Strasbourg, Hôpital de Hautepierre

Strasbourg, , France

Centre Hospitalo-Universitaire de Toulouse

Toulouse, , France

CHRU de Tours

Tours, , France

Bács Kiskun COUNTY HOSPITAL

Kecskemét, , Hungary

Cork University Hospital

Cork, , Ireland

Azienda Ospedaliero - Universitaria delle Marche

Ancona, , Italy

Oslo University Hospital

Oslo, , Norway

Centro Hospitalar Universitário Lisboa Norte, EPE -Hospital Santa Maria

Lisbon, , Portugal

Centro Hospitalar e Universitário do Porto, EPE - Centro Materno Infantil do Norte

Porto, , Portugal

Karolinska University Hospital

Solna, , Sweden

Hopital Universitaire de Geneve (HUG) - Hopital des enfants

Geneva, , Switzerland

University Children's Hospital Lausanne

Lausanne, , Switzerland

University Hospital of Zürich

Zurich, , Switzerland

Countries

Belgium; Denmark; Estonia; Finland; France; Hungary; Ireland; Italy; Norway; Portugal; Sweden; Switzerland

References

Ursino 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.

Reference Type: DERIVED

PMID: 39948605 (View on PubMed)

Bouazza 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.

Reference Type: DERIVED

PMID: 37978159 (View on PubMed)

Other Identifiers

2019-004297-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

C19-29

Identifier Type: -

Identifier Source: org_study_id