Long Term Follow-up of the TREOCAPA Study (TREOCAPA-LT) (TREOCAPA-LT)

Long Term Follow-up of the TREOCAPA (Prophylactic TREatment Of the duCtus Arteriosus in Preterm Infants by Acetaminophen) Study (TREOCAPA-LT)

The ductus arteriosus (DA) is a large channel connecting the main pulmonary trunk with the descending aorta. In extremely preterm infants, the DA frequently fails to close and this results in a condition called patent ductus arteriosus (PDA). In these patients, PDA has been associated with increased mortality and morbidity in the neonatal period, and neonatal morbidities may in turn be associated with later deficits in cognitive functioning. PDA treatment with COX inhibitors, as ibuprofen or indomethacin, aiming at closing the PDA have been associated with numerous adverse effects and failed to demonstrate significant clinical benefits. Early treatment of PDA with paracetamol (acetaminophen ) has been proposed as an alternative to COX inhibitors. The ongoing pan-European TREOCAPA phase III study (NCT04459117) is a multicentre, double-blind, randomised, placebo-controlled superiority trial that assesses prophylactic use of paracetamol to improve survival without severe neonatal morbidity until discharge from hospital in infants of 23-28 weeks of gestational age. As long-term follow-up was not planned by the TREOCAPA protocol, TREOCAPA-LT study will use an existing European research infrastructure, the RECAP Preterm platform (https://recap-preterm.eu/), to follow-up the patients enrolled in the TREOCAPA trial using a parent-report questionnaire at 2 years of corrected age.

The TREOCAPA-LT primary hypothesis is that there will be improved cognitive outcome at 2 years of corrected age in children born at less than 29 weeks of gestational age who were treated with paracetamol during the first 5 days of life in the TREOCAPA phase III trial.

Study Overview

• Status: Recruiting
• Conditions: Patency of the Ductus Arteriosus Acetaminophen Extreme Prematurity
• Intervention / Treatment: Other: 2 year follow-up of neurodevelopment using a parental questionnaire

Detailed Description

The ductus arteriosus (DA) is a large channel found normally in all mammalian foetuses, connecting the main pulmonary trunk with the left-sided descending aorta. During fetal life, it diverts most of the combined ventricular output away from the lungs toward the placenta. In full-term newborns, the DA is functionally open in all newborns and its constriction and closure, within 24 to 48 hours after delivery, are part of the normal process of postnatal adaptation. In extremely preterm infants, ie, those born before 29 weeks of gestation, the DA frequently fails to close and this results in a condition called patent ductus arteriosus (PDA). In these patients, PDA has been associated with increased mortality and morbidity in the neonatal period, and neonatal morbidities may in turn be associated with later deficits in cognitive functioning. Inhibition of prostaglandin synthesis, through inhibition of the cyclo-oxygenase (COX) enzymes, results in ductal constriction. However, treatments with COX inhibitors, as ibuprofen or indomethacin, aiming at closing the PDA have been associated with numerous adverse effects and failed to demonstrate significant clinical benefits. Prophylactic use of indomethacin or ibuprofen has been shown to reduce subsequent development of PDA but not to reduce mortality or morbidity. Further, investigations of early cardiac ultrasound-targeted treatment of a large PDA using indomethacin and ibuprofen do not show efficacy on primary outcomes of neonatal death or morbidity. Although this evidence base shows that prophylactic treatment by indomethacin or ibuprofen cannot be recommended, evidence from observational studies suggests that early (during the first 3 days of life) conservative treatment should not be recommended either. Two observational studies indicated that ignoring a PDA during the first days of life is associated with increase in mortality or morbidity. Our interpretation of these results is that screening echocardiography of large ductus arteriosus and early targeted treatment using echocardiography reduce pulmonary haemorrhage, but that the use of drugs with severe adverse effects may cancel expected beneficial effects on the occurrence of death or morbidity.

The use of a medication with an effect on PDA and that has fewer adverse effects is therefore desirable. Early treatment of PDA with paracetamol (acetaminophen) has been proposed as an alternative to COX inhibitors. According to a recent meta-analysis, use of paracetamol has a comparable effectiveness to close a PDA, and fewer harmful effects. However, only few extremely preterm infants were included in this meta-analysis. Therefore, efficacy and safety of paracetamol for PDA treatment in this population required further studies.

The ongoing pan-European TREOCAPA phase III study (NCT04459117) is a multicentre, double-blind, randomised, placebo-controlled superiority trial that assesses prophylactic use of paracetamol to improve survival without severe neonatal morbidity until discharge from hospital in infants of 23-28 weeks of gestational age.12 The trial has been powered to identify an absolute difference of 10% in the primary outcome, survival without severe neonatal morbidity (defined as any of: bronchopulmonary dysplasia grade 3 according to National Institute of Health criteria, necrotising enterocolitis stage 2 or 3 using Bell's criteria, intraventricular haemorrhage grade III or IV using the classification of Papile et al, or any evidence of cystic periventricular leukomalacia), corresponding to an increase from 50% to 60% in the rate between groups at hospital discharge. It aims to recruit 398 infants born at 27-28 weeks of gestation, and 396 infants born at 23-26 weeks of gestation. The first patients were recruited in October 2020 and the recruitment period is anticipated to last until April 2024 at the latest.

The TREOCAPA phase III trial is ambitious and innovative in its scope, including more than 40 hospitals in 16 countries. However, long-term follow-up was not included in the TREOCAPA protocol. The follow-up of infants enrolled in clinical trials enables to measure the long-term effectiveness and safety of interventions performed in the neonatal period. In particular for exposition to paracetamol in the neonatal period, data from randomized studies are very limited, while long-term adverse effects of paracetamol, including notably behavioral problems, have been raised. There is hence a need to understand longer term outcomes for the infants enrolled in this study, as these longer-term endpoints correspond to important patient-valued outcomes and are critical to determining the comparative effectiveness of interventions. The working hypothesis, if the intervention has a positive impact on short-term endpoints, is that longer term outcomes will be better in the intervention group, reflecting reduced morbidity at discharge home from the neonatal hospitalisation.

As long-term follow-up was not planned by the TREOCAPA phase III protocol, TREOCAPA-LT study will use an existing European research infrastructure, the RECAP Preterm platform to follow-up patients enrolled in the TREOCAPA cohort at 2 years of corrected age. This platform federates 23 European longitudinal observational cohorts of children born very preterm. The platform includes expertise, tools and infrastructure to follow patients enrolled in trials. By integrating trial follow-up in this platform, it is also possible to compare patients enrolled in the TREOCAPA trial with those from population-based samples, allowing assessment of transportability of trial results.

Follow-up at 2 years of age is recommended as the focus for the first phase of long-term outcome monitoring and has become the de facto age which is used in many published and ongoing clinical trials. Furthermore, many hospital services provide follow-up for their patients until at least 2 years of age, and research contact with the families at this point provides an opportunity to maintain contact and demonstrate to patients the ongoing importance of their involvement in the study.

The TREOCAPA-LT primary hypothesis is that there will be improved cognitive outcome at 2 years of corrected age in children born at less than 29 weeks of gestational age who were treated with paracetamol during the first 5 days of life in the TREOCAPA trial.

Secondary hypotheses are that, among children treated with paracetamol/acetaminophen during the first 5 days of life:

1. There will be reduced moderate or severe neurodevelopmental impairment, defined as the presence of at least one of the following: PARCA-R non-verbal cognitive score less than two standard deviations below the mean (score <70) moderate-severe motor impairment, unilateral or bilateral deafness or blindness.
2. There will be reduced need for secondary hospitalisations following the initial neonatal hospitalisation.
3. There will be reduced long term health care utilisation costs associated with extremely preterm birth.

Secondary hypotheses also relate to the use of the RECAP Preterm platform of observational VPT cohorts in this study. These are that:

1. As a trial population, the children born VPT included in the TREOCAPA-LT study will differ from those included in population-based observational cohorts in their perinatal characteristics and possibly in their health and developmental outcomes.
2. That these differences in population characteristics can affect the transportability of the trial results to other populations of VPT infants.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Gilles Cambonie, MD/PHD; Phone Number: +33467336609; Email: g-cambonie@chu-montpellier.fr
• Study Contact Backup: Name: Andrei Morgan, FRCPCH, MSc, PhD; Phone Number: +33171722987; Email: andrei.morgan@inserm.fr

Study Locations

• France
  • Angers, France
    • Recruiting
    • CHU d'Angers
    • Contact: Marion Plourde
  • Bron, France
    • Recruiting
    • Hôpital Femme Mère Enfant
    • Contact: Kim An Nguyen
  • Montpellier, France
    • Recruiting
    • CHU de Montpellier
    • Contact: Gilles Cambonie
  • Nantes, France
    • Recruiting
    • CHU de Nantes
    • Contact: Cyril Flamant
  • Paris, France
    • Recruiting
    • Hôpital Robert Debré
    • Contact: Valérie Biran
  • Paris, France
    • Recruiting
    • Cochin - APHP
    • Contact: Juliana Patkai
  • Strasbourg, France
    • Recruiting
    • CHU de Strasbourg
    • Contact: Pierre Kuhn
  • Tours, France
    • Recruiting
    • CHU de Tours
    • Contact: Antoine Bouissou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population for the follow-up study of the TREOCAPA trial consists of all children included in phase III of the trial from centres participating in the follow-up study. The parents of children who survived to two years corrected age and meet the criteria for inclusion will be offered the opportunity to complete the questionnaire.

Description

Inclusion Criteria:

• were included in the TREOCAPA phase III RCT in participating centres
• are aged between 23.5 and 27.5 months corrected age during the study period

Exclusion Criteria:

• if the local investigator does not have up-to-date contact information allowing contact with parents
• if the child's vital status cannot be ascertained
• if the child is nearing the end of his life or experiencing a severe medical event as assessed by the local investigator
• if the child has become subject to a legal protection measure preventing their ongoing participation in clinical research
• if either parent or guardian opts out of participating
• language barrier

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
patients received the investigational medicinal product acetaminophen in their first 5 days of life; This group of patients received the investigational product in their first 5 days of life during the Treocapa trial	Other: 2 year follow-up of neurodevelopment using a parental questionnaire; A parental questionnaire, using the PARCA-R instrument, is given to measure cognitive outcome at 2 years of corrected age for children included in the Treocapa Trial
patients received the placebo (NaCl) in their first 5 days of life; This group of patients received the placebo in their first 5 days of life during the Treocapa trial	Other: 2 year follow-up of neurodevelopment using a parental questionnaire; A parental questionnaire, using the PARCA-R instrument, is given to measure cognitive outcome at 2 years of corrected age for children included in the Treocapa Trial

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-verbal cognition at 2 years corrected age	Non-verbal cognitive (NVC) scale score from the Parent Report of Children's Abilities-Revised (PARCA-R) questionnaire, administered using an on-line parental questionnaire. The score is standardised such that it has a mean of 100 and a standard deviation of 15. Lower scores mean worse outcomes.	from 23,5 to 27,5 months of corrected age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival without moderate or severe cognitive impairment	Definied as survival to 2 years corrected age with a PARCA-R NVC scale score less than 2 standard deviations below the mean.	from 23,5 to 27,5 months of corrected age
Survival without moderate or severe neurodevelopmental impairment based on the presence of at least one of the impairments in the description :	the PARCA-R NVC < 2 standard deviations below the mean;; moderate to severe motor impairment, as measured using parent reported questions, defined as a child unable to: walk without assistance or aids or sit or hold their head up without support19;; unilateral or bilateral deafness or blindness as measured by parent reported questions: if the child is deaf or has functional hearing loss requiring correction with aids but still has difficulty hearing, or if the child is blind or able to see light only19.	from 23,5 to 27,5 months of corrected age
Health service use and costs	Reported by parents in the questionnaire, using questions on visits to health service providers and other costs associated with care of the children that have been used in previous European studies	from 23,5 to 27,5 months of corrected age

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparisons of the results with observational cohorts of very preterm infants for maternal sociodemographic characteristics	Descriptive statistics on maternal sociodemographic characteristics	This analysis will be carried during the 12 months after the end of data collection.
Comparisons of the results with observational cohorts of very preterm infants for gestational age	Descriptive statistics on gestational age	This analysis will be carried during the 12 months after the end of data collection.
Comparisons of the results with observational cohorts of very preterm infants on sex	Descriptive statistics on sex	This analysis will be carried during the 12 months after the end of data collection.
Comparisons of the results with observational cohorts of very preterm infants for complication of pregnancy	Descriptive statistics on complications of pregnancy	This analysis will be carried during the 12 months after the end of data collection.
Comparisons of the results with observational cohorts of very preterm infants for birth	Descriptive statistics on complication of birth	This analysis will be carried during the 12 months after the end of data collection.
Comparisons of the results with observational cohorts of very preterm infants for neonatal morbidities	Descriptive statistics on neonatal morbidities	This analysis will be carried during the 12 months after the end of data collection.
Comparisons of the results with observational cohorts of very preterm infants for mortality	Descriptive statistics on mortality	This analysis will be carried during the 12 months after the end of data collection.
Comparisons of the results with observational cohorts of very preterm infants for neurodevelopment	Descriptive statistics on two-year neurodevelopment	This analysis will be carried during the 12 months after the end of data collection.

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Study Director: Jennifer Zeitlin, Institut National de la Santé Et de la Recherche Médicale, France

Publications and helpful links

General Publications

• Draper ES, Zeitlin J, Manktelow BN, Piedvache A, Cuttini M, Edstedt Bonamy AK, Maier R, Koopman-Esseboom C, Gadzinowski J, Boerch K, van Reempts P, Varendi H, Johnson SJ; EPICE group. EPICE cohort: two-year neurodevelopmental outcomes after very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2020 Jul;105(4):350-356. doi: 10.1136/archdischild-2019-317418. Epub 2019 Nov 5.
• Clyman RI. Ibuprofen and patent ductus arteriosus. N Engl J Med. 2000 Sep 7;343(10):728-30. doi: 10.1056/NEJM200009073431009. No abstract available.
• Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J, Hansmann G. Patent Ductus Arteriosus of the Preterm Infant. Pediatrics. 2020 Nov;146(5):e20201209. doi: 10.1542/peds.2020-1209.
• Mitra S, de Boode WP, Weisz DE, Shah PS. Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews. Cochrane Database Syst Rev. 2023 Apr 11;4(4):CD013588. doi: 10.1002/14651858.CD013588.pub2.
• Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev. 2010 Jul 7;2010(7):CD000174. doi: 10.1002/14651858.CD000174.pub2.
• Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2018 Sep 28;9(9):CD003481. doi: 10.1002/14651858.CD003481.pub7.
• Kluckow M, Jeffery M, Gill A, Evans N. A randomised placebo-controlled trial of early treatment of the patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed. 2014 Mar;99(2):F99-F104. doi: 10.1136/archdischild-2013-304695. Epub 2013 Dec 6.
• Roze JC, Cambonie G, Le Thuaut A, Debillon T, Ligi I, Gascoin G, Patkai J, Beuchee A, Favrais G, Flamant C, Durrmeyer X, Clyman R. Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial. J Pediatr. 2021 Jun;233:33-42.e2. doi: 10.1016/j.jpeds.2020.12.008. Epub 2020 Dec 9.
• Liebowitz M, Clyman RI. Prophylactic Indomethacin Compared with Delayed Conservative Management of the Patent Ductus Arteriosus in Extremely Preterm Infants: Effects on Neonatal Outcomes. J Pediatr. 2017 Aug;187:119-126.e1. doi: 10.1016/j.jpeds.2017.03.021. Epub 2017 Apr 7.
• Roze JC, Cambonie G, Marchand-Martin L, Gournay V, Durrmeyer X, Durox M, Storme L, Porcher R, Ancel PY; Hemodynamic EPIPAGE 2 Study Group. Association Between Early Screening for Patent Ductus Arteriosus and In-Hospital Mortality Among Extremely Preterm Infants. JAMA. 2015 Jun 23-30;313(24):2441-8. doi: 10.1001/jama.2015.6734.
• Clyman RI, Liebowitz M, Kaempf J, Erdeve O, Bulbul A, Hakansson S, Lindqvist J, Farooqi A, Katheria A, Sauberan J, Singh J, Nelson K, Wickremasinghe A, Dong L, Hassinger DC, Aucott SW, Hayashi M, Heuchan AM, Carey WA, Derrick M, Fernandez E, Sankar M, Leone T, Perez J, Serize A; PDA-TOLERATE (PDA: TO LEave it alone or Respond And Treat Early) Trial Investigators. PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr. 2019 Feb;205:41-48.e6. doi: 10.1016/j.jpeds.2018.09.012. Epub 2018 Oct 16.
• Jasani B, Mitra S, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database Syst Rev. 2022 Dec 15;12:CD010061. doi: 10.1002/14651858.CD010061.pub5.
• Marlow N, Doyle LW, Anderson P, Johnson S, Bhatt-Mehta V, Natalucci G, Darlow BA, Davis JM, Turner MA; International Neonatal Consortium (INC). Assessment of long-term neurodevelopmental outcome following trials of medicinal products in newborn infants. Pediatr Res. 2019 Nov;86(5):567-572. doi: 10.1038/s41390-019-0526-1. Epub 2019 Aug 9.
• Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I. Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies. Am J Epidemiol. 2018 Aug 1;187(8):1817-1827. doi: 10.1093/aje/kwy086.
• Baker BH, Lugo-Candelas C, Wu H, Laue HE, Boivin A, Gillet V, Aw N, Rahman T, Lepage JF, Whittingstall K, Bellenger JP, Posner J, Takser L, Baccarelli AA. Association of Prenatal Acetaminophen Exposure Measured in Meconium With Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity. JAMA Pediatr. 2020 Nov 1;174(11):1073-1081. doi: 10.1001/jamapediatrics.2020.3080.
• Inoue K, Ritz B, Ernst A, Tseng WL, Yuan Y, Meng Q, Ramlau-Hansen CH, Strandberg-Larsen K, Arah OA, Obel C, Li J, Olsen J, Liew Z. Behavioral Problems at Age 11 Years After Prenatal and Postnatal Exposure to Acetaminophen: Parent-Reported and Self-Reported Outcomes. Am J Epidemiol. 2021 Jun 1;190(6):1009-1020. doi: 10.1093/aje/kwaa257.
• Johnson S, Bountziouka V, Brocklehurst P, Linsell L, Marlow N, Wolke D, Manktelow BN. Standardisation of the Parent Report of Children's Abilities-Revised (PARCA-R): a norm-referenced assessment of cognitive and language development at age 2 years. Lancet Child Adolesc Health. 2019 Oct;3(10):705-712. doi: 10.1016/S2352-4642(19)30189-0. Epub 2019 Aug 8.
• Seppanen AV, Bodeau-Livinec F, Boyle EM, Edstedt-Bonamy AK, Cuttini M, Toome L, Maier RF, Cloet E, Koopman-Esseboom C, Pedersen P, Gadzinowski J, Barros H, Zeitlin J; Effective Perinatal Intensive Care in Europe (EPICE) research group. Specialist health care services use in a European cohort of infants born very preterm. Dev Med Child Neurol. 2019 Jul;61(7):832-839. doi: 10.1111/dmcn.14112. Epub 2018 Dec 3.
• Seppanen AV, Draper ES, Petrou S, Barros H, Aubert AM, Andronis L, Kim SW, Maier RF, Pedersen P, Gadzinowski J, Lebeer J, Aden U, Toome L, van Heijst A, Cuttini M, Zeitlin J; SHIPS Research Group. High Healthcare Use at Age 5 Years in a European Cohort of Children Born Very Preterm. J Pediatr. 2022 Apr;243:69-77.e9. doi: 10.1016/j.jpeds.2021.12.006. Epub 2021 Dec 16.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: September 15, 2023
• First Submitted That Met QC Criteria: September 26, 2023
• First Posted (Actual): October 3, 2023

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Premature infants; long term outcome; persistent ductus arteriosus; paracetamol/acetaminophen
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Ductus Arteriosus, Patent
• Other Study ID Numbers: C23-31; 2023-A01418-37 (Registry Identifier: IDRCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO