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Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen (TREOCAPA)

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ClinicalTrials.gov Identifier: NCT04459117
Recruitment Status : Not yet recruiting
First Posted : July 7, 2020
Last Update Posted : July 7, 2020
Sponsor:
Collaborators:
UPCET
PARTNERS for International clinical Research
European Fundation for the Care of the Newborn Infants
Connect for Children
Information provided by (Responsible Party):
Institut National de la Santé Et de la Recherche Médicale, France

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


Condition or disease Intervention/treatment Phase
Patency of the Ductus Arteriosus Acetaminophen Extreme Prematurity Drug: Acetaminophen Drug: NACL 0.9% Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 824 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: 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
Primary Purpose: Treatment
Official Title: Prophylactic Treatment of the Ductus Arteriosus in Preterm Infants by Acetaminophen
Estimated Study Start Date : September 2020
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : July 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Acetaminophen
The active product is a 10 ml polyethylene ampoule of acetaminophen containing 100 mg of acetaminophen, solution for infusion, B BRAUN.
Drug: 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.


Placebo Comparator: 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.
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.





Primary Outcome Measures :
  1. 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

  2. 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


Secondary Outcome Measures :
  1. Analgesia/sedation drugs consumption during first week after birth (Secondary endpoint of phase III) [ Time Frame: Day 7 ]
    Number of days during the first week the infants received sedation/analgesia treatment

  2. Closure of Ductus arteriosus (Secondary endpoint of phase III) [ Time Frame: Day 7 ]
    Number of patients with a closed Ductus Arteriosus (DA) assessed by echocardiography at Day 7- Day 10

  3. Number of back-up treatment of PDA (Secondary endpoint of phase III) [ Time Frame: At 36 weeks of Post menstrual age ]
    Number of the patients receiving back-up treatment

  4. Number of days during the first week after birth with catecholamines administration (Secondary endpoint of phase III) [ Time Frame: Day 7 ]
    Number of days during the first week the infants received catecholamines in perfusion

  5. Early pulmonary hemorrhage (Secondary endpoint of phase III) [ Time Frame: Day 7 ]
    Number of infants with early pulmonary hemorrhage

  6. Blood acetaminophen levels in extrem preterm infant (Secondary endpoint of Phase II and Phase III) [ Time Frame: Day 7 ]
    Analysis of acetaminophen levels according to the administered dose and the time of sample collection

  7. Toxicity of Acetaminophen in extrem preterm infant (Secondary endpoint of Phase II and Phase III) [ Time Frame: Day 7 ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   23 Weeks to 28 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
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Responsible Party: Institut National de la Santé Et de la Recherche Médicale, France
ClinicalTrials.gov Identifier: NCT04459117    
Other Study ID Numbers: C19-29
2019-004297-26 ( EudraCT Number )
First Posted: July 7, 2020    Key Record Dates
Last Update Posted: July 7, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Heart Defects, Congenital
Cardiovascular Diseases
Heart Diseases
Ductus Arteriosus, Patent
Cardiovascular Abnormalities
Congenital Abnormalities
Acetaminophen
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics