Extremely Low Gestatonal Age Infants' Paracetamol Study (Paras)

Extremely Low Gestational Age Infants' Paracetamol Study: a Randomized Trial

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.

Study Overview

• Status: Completed
• Conditions: Prematurity; Extreme; Low Birthweight, Extremely (999 Grams or Less)
• Intervention / Treatment: Drug: Paracetamol 10mg/mL infusion solution; Other: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Outi Aikio, MD, PhD; Phone Number: +35883155810; Email: outi.aikio@pohde.fi
• Study Contact Backup: Name: Tiina Ukkonen, MD; Phone Number: +358 8 315 4386; Email: tiina.ukkonen@pohde.fi

Study Locations

• Finland
  • Oulu, Finland, 90014
    • Department of Pediatrics, Oulu University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 4 days (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Premature infants born before 28+0 gestation weeks and/or birth weight less than 1000g

Exclusion Criteria:

• Severe malformation or suspected chromosomal defect or other very severe life-threatening disease (e.g. very severe birth asphyxia or persistent pulmonary hypertension, etc.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Paracetamol; 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	Drug: Paracetamol 10mg/mL infusion solution; Intravenous paracetamol solution for infusion; Other Names: acetaminophen; Paracetamol Fresenius Kabi 10 mg/mL infusion solution
Placebo Comparator: Placebo; 0.45% sodium chloride (NaCl) solution, equal amounts in mL as would have been given the experimental drug	Other: Placebo; Half physiological saline solution as the non-active placebo solution; Other Names: Natriumklorid Braun 4,5mg/mL solution for infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Outi Aikio
• Investigators: Principal Investigator: Outi Aikio, MD, PhD, Oulu University Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2018
• Primary Completion (Actual): November 3, 2023
• Study Completion (Actual): March 1, 2024

Study Registration Dates

• First Submitted: August 3, 2018
• First Submitted That Met QC Criteria: August 20, 2018
• First Posted (Actual): August 21, 2018

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: acetaminophen; intravenous; NIRS; ductus arteriosus
• Additional Relevant MeSH Terms: Body Weight; Birth Weight; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen; Pharmaceutical Solutions
• Other Study ID Numbers: 39/2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No