Paracetamol in Patent Ductus Arteriosus

Study Overview
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Brief Summary
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The purpose of the study is to assess the efficacy and safety of paracetamol in comparison to ibuprofen in the treatment of patent ductus arteriosus (PDA) in preterm infants.

Detailed Description
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Although patency of the ductus arteriosus is essential for fetal circulation, the postnatal ductal closure is critical for postnatal circulatory adaptation. In premature infants the circulating prostaglandin levels are higher than at term, and respiratory difficulties may lead to a state of hypoxia, which contribute to the failure of the ductus closure. Recently, an incidental finding in one preterm infant led to look at paracetamol, one of the most common drugs available, as an alternative therapeutic approach to ductal closure. If paracetamol is proven to be effective, it could become the treatment of choice for the management of PDA, mainly due to its more favorable safety profile. Although the recent results available in the literature demonstrates an highly success rate in ductal closure with paracetamol, all case studies are not powered to show efficacy of paracetamol for PDA closure. Further prospective randomized-controlled trials are needed to evaluate the efficacy of paracetamol versus ibuprofen for the closure of PDA. If paracetamol is indeed proven to be effective, it could become the treatment of choice for the management of PDA, mainly due to its more favorable side effect profile. In order to test this hypothesis, a randomized, open label, parallel groups, comparator controlled, multicentre, prospective study is proposed.

Official Title
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Efficacy and Safety of Paracetamol in Comparison to Ibuprofen for Patent Ductus Arteriosus Treatment in Preterm Infants: A Randomized, Open Label, Comparator-controlled, Prospective Study

Conditions
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Ductus Arteriosus, Patent

Intervention / Treatment
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* Drug: Paracetamol
* Drug: Ibuprofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female preterm infants with no limitation of race. Gestational age 25(+0) - 31(+6) weeks. Age 24-72 hours. Echocardiographic evidence of hemodynamically significant patent ductus arteriosus at the first 24-72 hours of life. The diagnosis of hemodynamically significant PDA requiring treatment will be made by echocardiographic demonstration of a ductal left-to-right shunt, with a left atrium-to-aortic root ratio >1.3 or a ductal size >1.5 mm and excluding the cases in which the closing flow pattern suggests a restrictive PDA. Willingness of the parents/legally authorized representative/child to sign the Consent Informed Form. Exclusion Criteria: Outborn patients. Major congenital anomalies, including but not limited to congenital heart defects, Down syndrome newborn and/or new born suffering from congenital anomalies diagnosed during the fetal period. Known positive HIV and/or known positive Hepatitis C Virus newborn's mother. Life threatening infection, complicated or not by multiple organ dysfunction and failure syndrome. Fetal hydrops. Pulmonary hypertension diagnosed in the first 24-48 hours of life by means of heart ultrasound when the presence of a right-to-left shunt through the foramen ovale or ductus arteriosus is demonstrated, or when the estimated pulmonary pressure, in terms of the tricuspid regurgitation jet, is greater than two-thirds of the systemic arterial pressure. Grade 3 or 4 intraventricular haemorrhage (IVH). Urine output <1 ml/kg of body weight/h during a 24 h collection period or urine output <0.5 ml/kg of body weight/h in case it is measured at 24 hours of life of newborn. Serum creatinine concentration > 1.5 mg/dl (132 μmol/l). Platelet count < 50,000/mm3. Major bleeding, as revealed by hematuria, or blood in the endotracheal aspirate, gastric aspirate, or stools, or consistent oozing of blood from puncture sites. Severe liver failure, defined as elevated liver enzymes (ALT/Glutamate-Pyruvate Transaminase and Aspartate aminotransferase/GOT) > 2 times the upper boundary of the normal range. For this kind of population the following normal ranges will be considered [Rosenthal, 1997]: ALT/Glutamate-pyruvate transaminase: 6-50 U/L Aspartate aminotransferase/GOT: 35-140 U/L Medical need of administering other Nonsteroidal Antiinflammatory Drug (NSAID) different from ibuprofen. Participation to another trial involving any investigational drug.

Ages Eligible for Study
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Minimum Age: 25 Weeks
Maximum Age: 31 Weeks

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paracetamol<br>Paracetamol intravenous solution 15 mg/kg (corresponding to 1.5 ml/kg) per dose every 6 hours for 3 days, for a total amount of 12 doses. | Drug: Paracetamol<br> <br> * Other names: Acetaminophen;|
| Active Comparator: Ibuprofen<br>Ibuprofen intravenous solution at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 5 mg/kg at 48 h. | Drug: Ibuprofen<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| success rate in closing PDA using paracetamol in comparison to ibuprofen. | assessed echocardiographically. | at Visit 3 (day 3). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| number of re-openings. | assessed echocardiographically. | at Follow-up 3 (day 30). | 
| success rate in closing PDA after the second treatment course of ibuprofen as rescue medication. | assessed echocardiographically. | at Visit 6 (day 6). | 
| success rate of closing PDA after the first day of the first treatment course. | assessed echocardiographically. | at Visit 1 (day 1). | 
| success rate of closing PDA after the second day of the first treatment course. | assessed echocardiographically. | at Visit 2 (day 2). | 
| incidence of surgical ligation. |  | at Follow-up 3 (day 30). | 
| incidence of renal failure, liver failure and gastrointestinal complications (including isolated intestinal perforation). | assessed by laboratory analysis. | at Follow-up 3 (day 30). | 
| incidence of death, |  | at Follow-up 3 (day 30). | 
| incidence of death. |  | at Follow-up 4 (40 weeks post-conception). | 
| incidence of sepsis. |  | at Follow-up 3 (day 30). | 
| hospital-stay duration in Neonatal Intensive Care Unit. |  | at Follow-up 4 (40 weeks post-conception). | 
| occurrence of adverse effects. |  | at Follow-up 3 (day 30). |