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Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants

Primary Purpose

Patent Ductus Arteriosus After Premature Birth

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Acetaminophen Injection
Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen)
Sodium chloride 0.9% injection
Sponsored by
Mount Sinai Hospital, Canada
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Patent Ductus Arteriosus After Premature Birth focused on measuring Preterm Neonates, Patent Ductus Arteriosus, Echocardiography, Acetaminophen, Ibuprofen

Eligibility Criteria

undefined - 27 Weeks (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Preterm infants born <27+0 weeks gestational age
  • Permission given by the attending clinician to approach and then consent obtained from parents
  • Diagnosis of PDA ≥ 1.5 mm on echocardiography with unrestrictive predominantly left to right shunt
  • Designated to receive first treatment course with intravenous or enteral ibuprofen, as decided by the attending team.

Exclusion Criteria:

  • Chromosomal anomaly
  • Pre-treatment renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L
  • Pre-treatment hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L94
  • Platelet count <50,000 per microliter
  • Permission denied by the attending clinician to approach parents
  • Parental consent not available
  • Previous exposure to PDA medical treatment with any drug (prophylactic indomethacin use for prevention of intraventricular hemorrhage will not be considered as PDA treatment).

Sites / Locations

  • McMaster Children's HospitalRecruiting
  • Sunnybrook Health Sciences CentreRecruiting
  • Mount Sinai HospitalRecruiting
  • The Rotunda Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Combination Therapy

Standard Clinical Practice - Monotherapy

Arm Description

Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And study drug (intravenous acetaminophen 15 mg/kg/dose IV q6h for 3 days).

Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And Placebo [(0.9% saline IV q6h for 3 days).

Outcomes

Primary Outcome Measures

Composite of pre-discharge mortality or any grade BPD
Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA)

Secondary Outcome Measures

PDA treatment success
Defined as PDA closure or becoming insignificant [diameter <1.5 mm]
Renal or hepatic dysfunction
Renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L; hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L
Further exposure to pharmacological PDA treatments
As per units' standard practice (not part of study procedures)
Procedure for PDA closure
Surgical closure for PDA
Mortality
Death during initial tertiary NICU stay
Severity of BPD at 36 weeks PDM using Jensen's criteria
Grade 1, nasal cannula ≤2 L/min; grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure; grade 3, invasive mechanical ventilation
NEC ≥ stage 2A
NEC ≥ stage 2A during NICU stay
Duration (days) of invasive or non-invasive respiratory support
Days of invasive or non invasive support during NICU say
Need for diuretic use
Diuretic use for BPD treatment
Need for systemic steroids
Use for BPD treatment
Sepsis
Diagnosis of sepsis during NICU stay

Full Information

First Posted
March 16, 2022
Last Updated
May 19, 2023
Sponsor
Mount Sinai Hospital, Canada
Collaborators
Sunnybrook Health Sciences Centre, McMaster Children's Hospital, The Rotunda Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05340582
Brief Title
Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants
Official Title
Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants - The ACEDUCT Trial
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 12, 2022 (Actual)
Primary Completion Date
May 2026 (Anticipated)
Study Completion Date
December 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mount Sinai Hospital, Canada
Collaborators
Sunnybrook Health Sciences Centre, McMaster Children's Hospital, The Rotunda Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Patent ductus arteriosus (PDA), the most common cardiovascular complication of prematurity, is associated with higher mortality and morbidities in extremely low gestational age neonates (ELGANs, < 27+0 weeks). Ibuprofen and acetaminophen, which act by reducing prostaglandin synthesis, are the most commonly used first and second line agents for PDA treatment across Canada. However, initial treatment failure with monotherapy is a major problem, occurring in >60% ELGANs. Treatment failure is associated with worsening rates of mortality and bronchopulmonary dysplasia (BPD), while early treatment success can achieve rates comparable to neonates without PDA. Treatment failure resulting in prolonged disease exposure is thought to be a major contributor. Recently, combination therapy with acetaminophen and ibuprofen has emerged as a new treatment regime. Acetaminophen exerts anti-prostaglandin effect through a different receptor site than ibuprofen, providing a biological rationale for their synergistic action. The objective of this study is to evaluate the clinical impact, efficacy and safety of combination regime (Ibuprofen + IV Acetaminophen) for the first treatment course for PDA in ELGANs vs. Ibuprofen alone (current standard treatment).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Patent Ductus Arteriosus After Premature Birth
Keywords
Preterm Neonates, Patent Ductus Arteriosus, Echocardiography, Acetaminophen, Ibuprofen

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Pragmatic, multicenter, double-blinded, placebo controlled, parallel, two-armed, superiority randomized trial comparing two treatment regimens for the first treatment course of PDA in ELGANs
Masking
ParticipantInvestigatorOutcomes Assessor
Masking Description
Double-blinded
Allocation
Randomized
Enrollment
310 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Combination Therapy
Arm Type
Experimental
Arm Description
Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And study drug (intravenous acetaminophen 15 mg/kg/dose IV q6h for 3 days).
Arm Title
Standard Clinical Practice - Monotherapy
Arm Type
Placebo Comparator
Arm Description
Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And Placebo [(0.9% saline IV q6h for 3 days).
Intervention Type
Drug
Intervention Name(s)
Acetaminophen Injection
Intervention Description
Acetaminophen injection solution 1000 mg/100 mL (10 mg/mL) latex-free plastic bag - dosage for this protocol is 15mg/kg/dose IV four times a day for 3 days
Intervention Type
Drug
Intervention Name(s)
Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen)
Intervention Description
Ibuprofen is not a study drug - standard of care in participating NICUs in the standard clinical dose for neonates (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3)
Intervention Type
Other
Intervention Name(s)
Sodium chloride 0.9% injection
Intervention Description
Placebo- IV q6h for 3 days
Primary Outcome Measure Information:
Title
Composite of pre-discharge mortality or any grade BPD
Description
Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA)
Time Frame
36 weeks PMA
Secondary Outcome Measure Information:
Title
PDA treatment success
Description
Defined as PDA closure or becoming insignificant [diameter <1.5 mm]
Time Frame
6-10 days post treatment initiation
Title
Renal or hepatic dysfunction
Description
Renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L; hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L
Time Frame
Occurring within 7 days of treatment initiation
Title
Further exposure to pharmacological PDA treatments
Description
As per units' standard practice (not part of study procedures)
Time Frame
From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization
Title
Procedure for PDA closure
Description
Surgical closure for PDA
Time Frame
From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization
Title
Mortality
Description
Death during initial tertiary NICU stay
Time Frame
From date of randomization until date of death (assessed up to a maximum of 250 days after randomization)
Title
Severity of BPD at 36 weeks PDM using Jensen's criteria
Description
Grade 1, nasal cannula ≤2 L/min; grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure; grade 3, invasive mechanical ventilation
Time Frame
At 36 weeks PDM
Title
NEC ≥ stage 2A
Description
NEC ≥ stage 2A during NICU stay
Time Frame
From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization
Title
Duration (days) of invasive or non-invasive respiratory support
Description
Days of invasive or non invasive support during NICU say
Time Frame
From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization
Title
Need for diuretic use
Description
Diuretic use for BPD treatment
Time Frame
From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization
Title
Need for systemic steroids
Description
Use for BPD treatment
Time Frame
From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization
Title
Sepsis
Description
Diagnosis of sepsis during NICU stay
Time Frame
From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization

10. Eligibility

Sex
All
Maximum Age & Unit of Time
27 Weeks
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Preterm infants born <27+0 weeks gestational age Permission given by the attending clinician to approach and then consent obtained from parents Diagnosis of PDA ≥ 1.5 mm on echocardiography with unrestrictive predominantly left to right shunt Designated to receive first treatment course with intravenous or enteral ibuprofen, as decided by the attending team. Exclusion Criteria: Chromosomal anomaly Pre-treatment renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L Pre-treatment hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L94 Platelet count <50,000 per microliter Permission denied by the attending clinician to approach parents Parental consent not available Previous exposure to PDA medical treatment with any drug (prophylactic indomethacin use for prevention of intraventricular hemorrhage will not be considered as PDA treatment).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Laura Thomas, MSc
Phone
416-586-4800
Ext
172060
Email
laura.thomas@sinaihealth.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amish Jain, MD PhD
Organizational Affiliation
MOUNT SINAI HOSPITAL
Official's Role
Principal Investigator
Facility Information:
Facility Name
McMaster Children's Hospital
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amneet Sidhu, MD
Facility Name
Sunnybrook Health Sciences Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dany Weisz, MD, MSc
First Name & Middle Initial & Last Name & Degree
Dany Weisz, MD, MSc
Facility Name
Mount Sinai Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X5
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Amish Jain, MD PhD
Facility Name
The Rotunda Hospital
City
Dublin
Country
Ireland
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Afif EL Khuffash, MD

12. IPD Sharing Statement

Learn more about this trial

Co-administration of Acetaminophen With Ibuprofen to Improve Duct-Related Outcomes in Extremely Premature Infants

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