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In the present trial, early, intravenous paracetamol is compared to placebo in extremely premature or low birth weight infants in order to evaluate the effect on ductal closure.
The purpose of this randomized, placebo-controlled, double-blind, phase 2, one center clinical trial is to study the efficacy and safety of early (< 96 h) intravenous paracetamol in prophylactic closure of ductus arteriosus in extremely premature (gestational age <28+0 wk, ELGA) or low birth weight (<1000 g, ELBW) infants. The infants born extremely preterm or low birth weight are a focus of the study, since a small phase 2 study on paracetamol failed to demonstrate contraction of ductus arteriosus.
In the investigator's previous cohort of ELGA/ELBW infants, the numbers of patients who needed any therapies for patent ductus arteriosus (PDA) were 29 (23%) in the paracetamol exposed group, and 90 (54%) in the control group. As demonstrated in a phase 2 study, the early paracetamol treatment induced the closure of ductus arteriosus: the mean (SD) ductal closure age was 177 (338) h in the whole paracetamol group. However, in the subgroup of ELGA infants born before 28 gestation weeks (n=14), the mean (SD) ductal closure ages in the paracetamol and placebo groups were 491 (504) h and 858 (719) h, respectively.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Paracetamol | Experimental | Paracetamol 10 mg/mL infusion solution, intravenous loading dose 20 mg/kg, followed by maintenance dose 7.5 mg/kg every 6 h up to 9 days |
|
| Placebo | Placebo Comparator | 0.45% sodium chloride (NaCl) solution, equal amounts in mL as would have been given the experimental drug |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Paracetamol 10mg/mL infusion solution | Drug | Intravenous paracetamol solution for infusion |
|
| Measure | Description | Time Frame |
|---|---|---|
| Ductal closure | Postnatal age of the observed closure of ductus arteriosus | Neonatal intensive care unit (NICU) treatment period up to 13 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Near-infrared spectroscopy values | Near-infrared spectroscopy values | Study drug period up to 10 days |
| Paracetamol serum levels | Paracetamol serum levels |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Outi Aikio, MD, PhD | Oulu University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Pediatrics, Oulu University Hospital | Oulu | 90014 | Finland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29105147 | Background | 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. | |
| 27215779 | Background | 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. |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 19, 2018 | Aug 20, 2018 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D047928 | Premature Birth |
| D004374 | Ductus Arteriosus, Patent |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 |
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Randomized, controlled, one center trial
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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 NICU, 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.
| Placebo | Other | Half physiological saline solution as the non-active placebo solution |
|
|
| Study drug period up to 10 days |
| Paracetamol side effects | Any observed or detected paracetamol side effects | Neonatal intensive care unit (NICU) treatment period up to 13 weeks |
| PDA | Open ductus arteriosus without any traditional PDA therapies | Neonatal intensive care unit (NICU) treatment period up to 13 weeks |
| PDA, treated | The need for PDA therapies (ibuprofen, paracetamol, ligation) | Neonatal intensive care unit (NICU) treatment period up to 13 weeks |
| Ventilatory assist | The duration of any ventilation assist, days | Neonatal intensive care unit (NICU) treatment period up to 13 weeks |
| Complications of prematurity | The long term complications of prematurity (moderate-to-severe bronchopulmonary dysplasia (BPD), intraventricular hemorrhage gr 2-4, moderate to severe necrotizing enterocolitis, retinopathy of prematurity (ROP) needing therapy) | The first hospitalization period up to 19 weeks |
| Long term morbidity | Other long-term morbidity | The first hospitalization period up to 19 weeks |
| Mortality | Mortality | The first hospitalization period up to 19 weeks |
| 26323200 | Background | 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. |
| 24111688 | Background | 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. |
| 42133561 | Derived | Ukkonen T, Ronkainen E, Laitala A, Saarela T, Hallman M, Aikio O. Prolonged low-dose paracetamol prophylaxis accelerates ductal closure in extremely preterm neonates: a randomised trial. Neonatology. 2026 May 14:1-18. doi: 10.1159/000552204. Online ahead of print. |
| D000091642 | Urogenital Diseases |
| D006330 | Heart Defects, Congenital |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| Aniline Compounds |
| D000588 | Amines |