Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen

NCT04459117 | Completed Phase 2 DMC

• 2 other identifiers: C19-292019-004297-26
• Study Type: interventional
• Target: 804
• Locations: 12 countries
• Sites: 36

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

Conditions

Patency of the Ductus Arteriosus; Acetaminophen; Extreme Prematurity

Outcome Measures

Primary Outcomes (2)

• 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

  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

  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)

  Day 7

• Closure of Ductus arteriosus (Secondary endpoint of phase III)

  Day 7

• Number of back-up treatment of PDA (Secondary endpoint of phase III)

  At 36 weeks of Post menstrual age

• Number of days during the first week after birth with catecholamines administration (Secondary endpoint of phase III)

  Day 7

• Early pulmonary hemorrhage (Secondary endpoint of phase III)

  Day 7

Study Arms (2)

Acetaminophen

ACTIVE COMPARATOR

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

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.

Drug: NACL 0.9%

Interventions

Acetaminophen 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.

Acetaminophen

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.

NaCL 0.9%

Eligibility Criteria

• Age: 23 Weeks - 28 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: lead
• UPCET: collaborator
• PARTNERS for International clinical Research: collaborator
• Connect for Children: collaborator
• Global Foundation for the Care of Newborn Infants: collaborator

Study Sites (36)

Centre Hospitalier Universitaire de Liège

Liège, Belgium

Location

The Juliane Marie Centre, Rigshospitalet, Copenhagen University hospital

Copenhagen, 2100, Denmark

Location

East Tallinn Central Hospital

Tallinn, Estonia

Location

Tallinn Children's Hospital

Tallinn, Estonia

Location

Tartu University Hospital, Neonatal and Paediatric Intensive Care Unit

Tartu, Estonia

Location

Helsinki University Hospital, Department of Children and Adolecents, Neonatology

Helsinki, Finland

Location

Kuopio University Hospital, Department of Pediatrics

Kuopio, Finland

Location

Oulu University Hospital, Department of Pediatrics

Oulu, Finland

Location

Tampere University Hospital, Department of Pediatrics

Tampere, Finland

Location

Turku University Hospital, Department of Peadiatrics

Turku, Finland

Location

CHU Angers

Angers, France

Location

Hopital Jeanne de Flandre

Lille, 59037, France

Location

Hôpital Croix-Rousse

Lyon, 69317, France

Location

Hospice civils de Lyon, Hopital Femme Enfant

Lyon, France

Location

Hôpital Marseille Nord

Marseille, 13015, France

Location

Hôpital de la conception

Marseille, France

Location

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

Montpellier, France

Location

CHU Nantes, Hopital mére Enfant

Nantes, France

Location

Hôpital Necker - Enfants malades

Paris, 75015, France

Location

CENTRE hospitalier intercommunal de Creteil

Paris, France

Location

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

Paris, France

Location

Hopital Robert Debré, Néonatologie

Paris, France

Location

CHU Rennes, Hopital Sud

Rennes, France

Location

CHU Strasbourg, Hôpital de Hautepierre

Strasbourg, France

Location

Centre Hospitalo-Universitaire de Toulouse

Toulouse, 31059, France

Location

CHRU de Tours

Tours, France

Location

Bács Kiskun COUNTY HOSPITAL

Kecskemét, H6000, Hungary

Location

Cork University Hospital

Cork, T12 DC4A, Ireland

Location

Azienda Ospedaliero - Universitaria delle Marche

Ancona, 60126, Italy

Location

Oslo University Hospital

Oslo, 0424, Norway

Location

Centro Hospitalar Universitário Lisboa Norte, EPE -Hospital Santa Maria

Lisbon, Portugal

Location

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

Porto, Portugal

Location

Karolinska University Hospital

Solna, 171 64, Sweden

Location

Hopital Universitaire de Geneve (HUG) - Hopital des enfants

Geneva, Switzerland

Location

University Children's Hospital Lausanne

Lausanne, Switzerland

Location

University Hospital of Zürich

Zurich, Switzerland

Location

Related Publications (6)

• 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.

  PMID: 40889095 RESULT

• 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.

  PMID: 39948605 RESULT

• 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.

  PMID: 37978159 RESULT

• 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. 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.

  PMID: 39578300 RESULT

• Wan 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.

  PMID: 40678377 RESULT

• Roze 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 Feb 16:e256150. doi: 10.1001/jamapediatrics.2025.6150. Online ahead of print.

  PMID: 41697673 DERIVED

MeSH Terms

Conditions

Ductus Arteriosus, Patent

Interventions

Acetaminophen; Sodium Chloride

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: June 19, 2020
• First Posted: July 7, 2020
• Study Start: October 29, 2020
• Primary Completion: June 20, 2024
• Study Completion: June 20, 2024
• Last Updated: March 16, 2026

Record last verified: 2026-03

Locations

ES (3); FI (5); BE (1); PT (2); SE (1); IE (1); NO (1); FR (16); CH (3); DK (1); HU (1); IT (1)