Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus

Patent Ductus Arteriosus Clinical Trial

— PAI  

Official title:

Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus of Preterm Infants - Randomised, Placebo-controlled Multicentre Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03648437
• Other study ID #: 38/2018
• Status: Recruiting
• Phase: Phase 1
• Start date: September 3, 2018
• Est. completion date: March 1, 2024

Study information

• Verified date: June 2023
• Source: University of Oulu
• Contact: Outi Aikio, MD, PhD
• Phone: +35883155810
• Email: outi.aikio[@]pohde.fi
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: March 1, 2024
• Est. primary completion date: January 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 4 Months

Eligibility

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.)

Related Conditions & MeSH terms

• Ductus Arteriosus, Patent
• Patent Ductus Arteriosus

Intervention

Drug:
• Paracetamol 10Mg/mL
Experimental drug
• 0.45% Sodium Chloride
Placebo comparator
• Ibuprofen
Standard therapy
• Indomethacin
Standard therapy

Locations

Country	Name	City	State
Finland	Helsinki Univeristy Central Hospital	Helsinki
Finland	Department of Pediatrics, Oulu University Hospital	Oulu
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital	Turku

Sponsors (4)

Lead Sponsor	Collaborator
University of Oulu	Helsinki University Central Hospital, Tampere University Hospital, Turku University Hospital

Country where clinical trial is conducted

Finland, 

References & Publications (5)

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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ductal closure	Number of patients with ductal contraction without need for other PDA therapies	Neonatal internsive care unit (NICU) stay up to 12 weeks
Secondary	Need for ductal therapies	Given ductal therapies after the study drug	NICU stay up to 12 weeks
Secondary	Cardiac ultrasound findings	Ductal caliber (mm, mm/kg), LA/Ao ratio	NICU stay up to 12 weeks
Secondary	Duration of any ventilation assist	The ventilation assist time pediod	NICU stay up to 12 weeks
Secondary	Paracetamol serum levels	Measured paracetamol concentrations (mg/mL)	Study drug period up to 4 days
Secondary	Paracetamol side effects	Observed adverse events linked to study drug	Study drug period plus 7 days, up to 10 days
Secondary	Long term complications of prematurity	Moderate-to-severe bronchopulmonary dysplasia, intraventricular hemorrhage grade 2-4, moderate to severe necrotizing enterocolitis, retinopathy of prematurity needing therapy	Hospital stay up to 18 weeks
Secondary	Other long-term morbidity, and mortality	Other severe diseases	Hospital stay up to 18 weeks

External Links

•   Thesis, Pia Härkin, MD
•   Thesis, Sanna Juujärvi, MB