Clinical trial NCT03648437: Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus
Official title: Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus of Preterm Infants - Randomised, Placebo-controlled Multicentre Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Patent Ductus Arteriosus
Keywords: acetaminophen
ibuprofen
preterm infant
near infra-red spectroscopy
indomethacin
Lead sponsor: University of Oulu
Sponsor class: OTHER
Collaborators: name: Helsinki University Central Hospital
name: Turku University Hospital
name: Tampere University Hospital
First posted: 2018-08-27
Enrollment: 22
Sex: ALL
Maximum age (years): 4
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: multicenter, randomized, placebo-controlled, double-blind, clinical trial
Primary purpose: TREATMENT

Brief summary: The purpose of this pilot trial is to study efficacy and safety of simultaneous intravenous (iv) ibuprofen/indomethacin and paracetamol medications in the closure of patent ductus arteriosus (PDA) in preterm infants. It is randomized, placebo-controlled, double-blind, phase 1, multicenter, clinical trial.

Detailed description: Premature infants (born before 37 weeks gestational age) with patent ductus arteriosus (PDA) are the focus of the study since no trials on the additive efficacy of these two medications on the contraction of ductus arteriosus are available. Preterm infants who are diagnosed to have a hemodynamically significant PDA and who, according to the decision of the attending clinician, need ibuprofen/indomethacin therapy, are eligible to this trial.

If the parents deny the consent, the patient will be treated according to the standard PDA treatment: three days' iv ibuprofen Pedea® 5mg/ml solution infusion (Oulu, Helsinki, Tartu) dosing: 10mg/kg + 5mg/kg + 5mg/kg (q24h); or three days' iv indomethacin (Turku) 0.2mg/kg + 0.1mg/kg + 0.1mg/kg (q24h). In case of any contraindications for ibuprofen/indomethacin, the treatment would be surgical ligation.

Eligibility criteria: Inclusion Criteria:

* Preterm infants (born before 37+0 gestation weeks) who are diagnosed to have a hemodynamically significant PDA and who, according to the decision of the attending clinician, need ibuprofen therapy, are eligible to this trial.

Exclusion Criteria:

* severe malformation or suspected chromosomal defect
* other very severe life-threatening disease (e.g. very severe birth asphyxia or persistent pulmonary hypertension, etc.)

Primary outcomes:
measure: Ductal closure
timeFrame: Neonatal internsive care unit (NICU) stay up to 12 weeks
Secondary outcomes:
measure: Need for ductal therapies
timeFrame: NICU stay up to 12 weeks
measure: Cardiac ultrasound findings
timeFrame: NICU stay up to 12 weeks
measure: Duration of any ventilation assist
timeFrame: NICU stay up to 12 weeks
measure: Paracetamol serum levels
timeFrame: Study drug period up to 4 days
measure: Paracetamol side effects
timeFrame: Study drug period plus 7 days, up to 10 days
measure: Long term complications of prematurity
timeFrame: Hospital stay up to 18 weeks
measure: Other long-term morbidity, and mortality
timeFrame: Hospital stay up to 18 weeks
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki Univeristy Central Hospital
city: Oulu
country: Finland
facility: Department of Pediatrics, Oulu University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
Study officials:
affiliation: Oulu Univerisity Hospital
name: Outi Aikio, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Harkin P, Harma A, Aikio O, Valkama M, Leskinen M, Saarela T, Hallman M. Paracetamol Accelerates Closure of the Ductus Arteriosus after Premature Birth: A Randomized Trial. J Pediatr. 2016 Oct;177:72-77.e2. doi: 10.1016/j.jpeds.2016.04.066. Epub 2016 May 20.
citation: Juujarvi S, Saarela T, Hallman M, Aikio O. Intravenous paracetamol was associated with closure of the ductus arteriosus in extremely premature infants. Acta Paediatr. 2018 Apr;107(4):605-610. doi: 10.1111/apa.14137. Epub 2017 Nov 17.
citation: Harma A, Aikio O, Hallman M, Saarela T. Intravenous Paracetamol Decreases Requirements of Morphine in Very Preterm Infants. J Pediatr. 2016 Jan;168:36-40. doi: 10.1016/j.jpeds.2015.08.003. Epub 2015 Aug 29.
citation: Aikio O, Harkin P, Saarela T, Hallman M. Early paracetamol treatment associated with lowered risk of persistent ductus arteriosus in very preterm infants. J Matern Fetal Neonatal Med. 2014 Aug;27(12):1252-6. doi: 10.3109/14767058.2013.854327. Epub 2013 Oct 31.
citation: Juujarvi S, Kallankari H, Patsi P, Leskinen M, Saarela T, Hallman M, Aikio O. Follow-up study of the early, randomised paracetamol trial to preterm infants, found no adverse reactions at the two-years corrected age. Acta Paediatr. 2019 Mar;108(3):452-458. doi: 10.1111/apa.14614. Epub 2018 Nov 12.