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Paracetamol And Ibuprofen/Indomethacin in Closing Patent Ductus Arteriosus (PAI)

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ClinicalTrials.gov Identifier: NCT03648437
Recruitment Status : Recruiting
First Posted : August 27, 2018
Last Update Posted : May 10, 2021
Sponsor:
Collaborators:
Helsinki University Central Hospital
Turku University Hospital
Tartu University Hospital
Information provided by (Responsible Party):
Outi Aikio, University of Oulu

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: multicenter, 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 : September 3, 2018
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: Paracetamol Fresenius Kabi 10mg/mL infusion solution

Drug: Ibuprofen
Standard therapy
Other Name: 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 Name: NATRIUMKLORID BRAUN 4,5 mg/mL infusion solution

Drug: Ibuprofen
Standard therapy
Other Name: 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 Name: Paracetamol Fresenius Kabi 10mg/mL infusion solution

Drug: Indomethacin
Standard therapy
Other Name: 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 Name: NATRIUMKLORID BRAUN 4,5 mg/mL infusion solution

Drug: Indomethacin
Standard therapy
Other Name: Liometacen 50mg/2mL injection


Outcome Measures
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Primary Outcome Measures :
  1. Ductal closure [ Time Frame: 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 :
  1. Need for ductal therapies [ Time Frame: NICU stay up to 12 weeks ]
    Given ductal therapies after the study drug

  2. Cardiac ultrasound findings [ Time Frame: NICU stay up to 12 weeks ]
    Ductal caliber (mm, mm/kg), LA/Ao ratio

  3. Duration of any ventilation assist [ Time Frame: NICU stay up to 12 weeks ]
    The ventilation assist time pediod

  4. Paracetamol serum levels [ Time Frame: Study drug period up to 4 days ]
    Measured paracetamol concentrations (mg/mL)

  5. Paracetamol side effects [ Time Frame: Study drug period plus 7 days, up to 10 days ]
    Observed adverse events linked to study drug

  6. Long term complications of prematurity [ Time Frame: 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

  7. Other long-term morbidity, and mortality [ Time Frame: Hospital stay up to 18 weeks ]
    Other severe diseases


Eligibility Criteria
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Ages Eligible for Study:   up to 4 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03648437


Contacts
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Contact: Outi Aikio, MD, PhD +35883155810 outi.aikio@ppshp.fi
Contact: Aliisa Laitala, MD +35883155823 aliisa.laitala@ppshp.fi

Locations
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Estonia
Tartu University Hospital Not yet recruiting
Tartu, Estonia
Contact: Tuuli Metsvaht, MD, PhD    +37253319550    tuuli.metsvaht@kliinikum.ee   
Finland
Helsinki Univeristy Central Hospital Active, not recruiting
Helsinki, Finland
Department of Pediatrics, Oulu University Hospital Recruiting
Oulu, Finland, 90014
Contact: Outi Aikio, MD, PhD    +358 8 3155810    outi.aikio@ppshp.fi   
Principal Investigator: Outi Aikio, MD, PhD         
Principal Investigator: Antti Harma, MD         
Principal Investigator: Timo Saarela, MD, PhD         
Principal Investigator: Mikko Hallman, MD, PhD         
Principal Investigator: Aliisa Laitala, MD         
Turku University Hospital Recruiting
Turku, Finland
Contact: Hanna Soukka, MD, PhD    +358415053930    hanna.soukka@utu.fi   
Sponsors and Collaborators
University of Oulu
Helsinki University Central Hospital
Turku University Hospital
Tartu University Hospital
Investigators
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Principal Investigator: Outi Aikio, MD, PhD Oulu Univerisity Hospital
  Study Documents (Full-Text)

Documents provided by Outi Aikio, University of Oulu:
Study Protocol and Statistical Analysis Plan  [PDF] March 29, 2019

More Information
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Additional Information:

Publications:

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Responsible Party: Outi Aikio, MD, PhD, Specialist in Peditrics and Neonatology, University of Oulu
ClinicalTrials.gov Identifier: NCT03648437    
Other Study ID Numbers: 38/2018
First Posted: August 27, 2018    Key Record Dates
Last Update Posted: May 10, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Outi Aikio, University of Oulu:
acetaminophen
ibuprofen
preterm infant
near infra-red spectroscopy
indomethacin
Additional relevant MeSH terms:
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Ductus Arteriosus, Patent
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Acetaminophen
Ibuprofen
Indomethacin
Pharmaceutical Solutions
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
 Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antipyretics
Gout Suppressants
Tocolytic Agents
Reproductive Control Agents