Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Patent Ductus Arteriosus

Intervention / Treatment
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* Drug: Paracetamol 10Mg/mL
* Drug: 0.45% Sodium Chloride
* Drug: Ibuprofen
* Drug: Indomethacin


Participation Criteria
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Eligibility Criteria
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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.)

Ages Eligible for Study
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Maximum Age: 4 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multicenter, randomized, placebo-controlled, double-blind, clinical trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pedea 5mg/mL and Paracetamol 10mg/mL<br>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<br>* Experimental drug<br>* Other names: Paracetamol Fresenius Kabi 10mg/mL infusion solution;Drug: Ibuprofen<br>* Standard therapy<br>* Other names: Pedea 5mg/mL injection solution;|
| Placebo Comparator: Pedea 5mg/mL and 0.45 sodium chloride<br>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<br>* Placebo comparator<br>* Other names: NATRIUMKLORID BRAUN 4,5 mg/mL infusion solution;Drug: Ibuprofen<br>* Standard therapy<br>* Other names: Pedea 5mg/mL injection solution;|
| Experimental: Indomethacin 25mg/mL and Paracetamol10mg/mL<br>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<br>* Experimental drug<br>* Other names: Paracetamol Fresenius Kabi 10mg/mL infusion solution;Drug: Indomethacin<br>* Standard therapy<br>* Other names: Liometacen 50mg/2mL injection;|
| Placebo Comparator: Indomethacin 25mg/mL and 0.45 sodium chloride<br>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<br>* Placebo comparator<br>* Other names: NATRIUMKLORID BRAUN 4,5 mg/mL infusion solution;Drug: Indomethacin<br>* Standard therapy<br>* Other names: Liometacen 50mg/2mL injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for ductal therapies | Given ductal therapies after the study drug | NICU stay up to 12 weeks | 
| Cardiac ultrasound findings | Ductal caliber (mm, mm/kg), LA/Ao ratio | NICU stay up to 12 weeks | 
| Duration of any ventilation assist | The ventilation assist time pediod | NICU stay up to 12 weeks | 
| Paracetamol serum levels | Measured paracetamol concentrations (mg/mL) | Study drug period up to 4 days | 
| Paracetamol side effects | Observed adverse events linked to study drug | Study drug period plus 7 days, up to 10 days | 
| 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 | 
| Other long-term morbidity, and mortality | Other severe diseases | Hospital stay up to 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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indomethacin, acetaminophen, ibuprofen, preterm infant, near infra-red spectroscopy