PAI: Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus

Sponsor

University of Oulu (Other)

Overall Status

Recruiting

CT.gov ID

NCT03648437

Collaborator

Helsinki University Central Hospital (Other), Turku University Hospital (Other), Tartu University Hospital (Other)

Enrollment

Locations

Arms

53.9

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Patent Ductus Arteriosus	Drug: Paracetamol 10Mg/mL Drug: 0.45% Sodium Chloride Drug: Ibuprofen Drug: Indomethacin	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

multicenter, randomized, placebo-controlled, double-blind, clinical trialmulticenter, randomized, placebo-controlled, double-blind, clinical trial

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

Placebo, 0.45 % saline, is similar to paracetamol, both being clear liquids, so the staff will remain unaware which drug the patient receives. The study drug will be kept and prepared away from the neonatal intensive care unit, at the separate ward 55 office, in a locked cabinet. The study drug will be prepared by the research nurse, the pharmacist of the ward, or during nighttime, by a nurse who does not participate in the study patients' treatment in any way.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 3, 2018

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pedea 5mg/mL and Paracetamol 10mg/mL Intravenous (IV) ibuprofen 5mg/mL q 24h for 3 days, dosages: 10mg/kg + 5mg/kg + 5mg/kg and IV paracetamol 10mg/mL for 3 days: loading dose 20mg/kg, following 7.5mg/kg q 6h (up to12 doses)	Drug: Paracetamol 10Mg/mL Experimental drug Other Names: Paracetamol Fresenius Kabi 10mg/mL infusion solution Drug: Ibuprofen Standard therapy Other Names: Pedea 5mg/mL injection solution
Placebo Comparator: Pedea 5mg/mL and 0.45 sodium chloride IV ibuprofen 5mg/mL q 24h for 3 days, dosages: 10mg/kg + 5mg/kg + 5mg/kg and NaCl 0.45% for 3 days, the same amount in mL as would have been given IV paracetamol	Drug: 0.45% Sodium Chloride Placebo comparator Other Names: NATRIUMKLORID BRAUN 4,5 mg/mL infusion solution Drug: Ibuprofen Standard therapy Other Names: Pedea 5mg/mL injection solution
Experimental: Indomethacin 25mg/mL and Paracetamol10mg/mL Intravenous (IV) indometahcin 25mg/mL q 24h for 3 days, dosages: 0.2mg/kg + 0.1mg/kg + 0.1mg/kg and IV paracetamol 10mg/mL for 3 days: loading dose 20mg/kg, following 7.5mg/kg q 6h (up to12 doses)	Drug: Paracetamol 10Mg/mL Experimental drug Other Names: Paracetamol Fresenius Kabi 10mg/mL infusion solution Drug: Indomethacin Standard therapy Other Names: Liometacen 50mg/2mL injection
Placebo Comparator: Indomethacin 25mg/mL and 0.45 sodium chloride Intravenous (IV) indomethacin 25mg/mL q 24h for 3 days, dosages: 0.2mg/kg + 0.1mg/kg + 0.1mg/kg and NaCl 0.45% for 3 days, the same amount in mL as would have been given IV paracetamol	Drug: 0.45% Sodium Chloride Placebo comparator Other Names: NATRIUMKLORID BRAUN 4,5 mg/mL infusion solution Drug: Indomethacin Standard therapy Other Names: Liometacen 50mg/2mL injection

Outcome Measures

Primary Outcome Measures

Ductal closure [Neonatal internsive care unit (NICU) stay up to 12 weeks]
Number of patients with ductal contraction without need for other PDA therapies

Secondary Outcome Measures

Need for ductal therapies [NICU stay up to 12 weeks]
Given ductal therapies after the study drug
Cardiac ultrasound findings [NICU stay up to 12 weeks]
Ductal caliber (mm, mm/kg), LA/Ao ratio
Duration of any ventilation assist [NICU stay up to 12 weeks]
The ventilation assist time pediod
Paracetamol serum levels [Study drug period up to 4 days]
Measured paracetamol concentrations (mg/mL)
Paracetamol side effects [Study drug period plus 7 days, up to 10 days]
Observed adverse events linked to study drug
Long term complications of prematurity [Hospital stay up to 18 weeks]
Moderate-to-severe bronchopulmonary dysplasia, intraventricular hemorrhage grade 2-4, moderate to severe necrotizing enterocolitis, retinopathy of prematurity needing therapy
Other long-term morbidity, and mortality [Hospital stay up to 18 weeks]
Other severe diseases

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 4 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Tartu University Hospital	Tartu	Estonia
2	Helsinki Univeristy Central Hospital	Helsinki	Finland
3	Department of Pediatrics, Oulu University Hospital	Oulu	Finland	90014
4	Turku University Hospital	Turku	Finland