Precision Dosing of Oral Ibuprofen for PDA, A Pilot RCT

NCT ID: NCT07143201

Last Updated: 2025-08-27

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-07-04
• Study Completion Date: 2027-07-31

Brief Summary

Newborns born early are at risk for a serious health problem called patent ductus arteriosus (PDA). PDA is a passageway between heart and lung that can cause life-threatening complications such as bleeding in the brain or even death if it remains open and large. When closure of PDA is needed, doctors make every attempt to do it as soon as possible. Ibuprofen is the best drug to close the PDA, but it only works for 50% of small newborns. The investigators have shown before that small newborns handle ibuprofen differently and the amount of active ibuprofen that reaches their blood can be very unpredictable. Studies have shown if enough ibuprofen reaches the body, it can close the PDA. Therefore the investigators designed this study to see whether it is possible to give each newborn the right amount of ibuprofen that their body needs to close the PDA. The investigators will compare two ways to give ibuprofen in a small number of newborns: 1 - standard amount of ibuprofen to everyone, which is the usual care or 2 - ibuprofen doses that will be changed based on how much active ibuprofen has reached the body and how well the newborn's PDA is closing. The investigators will then compare the number of PDAs closed in each group and closely monitor any possible challenges for this new practice. By doing this project, the goals can be summarized as below:

A. Primary goal: To determine if it is feasible to successfully run a larger study in the future.

B. Secondary goals

1. To assess how well and how safely the personalized (MIPD) method works, using a tool called WAPPS-PDA to guide dosing.

2. To compare the effectiveness and safety of the personalized method with standard ibuprofen dosing.

3. To identify drug levels in the blood (Cmin, AUC0-24, AUC0-72) that are associated with complete, partial, or no response to treatment.

Detailed Description

Study Design Overview:

This clinical trial is a single-center, pilot, randomized, controlled, triple-blind study designed to evaluate the feasibility and effectiveness of model-informed precision dosing (MIPD) of oral ibuprofen compared to standard dosing for the treatment of Patent Ductus Arteriosus (PDA) in preterm neonates (≤27+6 weeks gestational age). The trial assesses both operational feasibility and clinical outcomes, with a focus on the use of a pharmacokinetic (PK) prediction module provided by the Web-Accessible Population Pharmacokinetics Service-PDA (WAPPS-PDA).

• Standard Dosing Arm: Participants in this arm receive the standard oral ibuprofen regimen used in the unit. Treatment begins with an initial loading dose, followed by two smaller doses administered at 24-hour intervals. While PK samples and targeted echocardiograms are collected at the same intervals as in the precision dosing arm, these data points do not influence dosing decisions.

• Model-Informed Precision Dosing (MIPD) Arm: Participants in this arm initially receive the same loading dose of ibuprofen as those in the standard dosing arm. Subsequent doses are adjusted using real-time PK data and echocardiographic evaluations through the WAPPS-PDA tool. This tool employs a Bayesian forecasting model to analyze blood samples collected at 6, 30, and 54 hours post-initial dose, combining these results with the PDA response level noted in the targeted echocardiograms to dynamically adjust dosing. Dose adjustments are reviewed every 12 hours to ensure tailored treatment based on the neonate's specific pharmacological response, optimizing the chances of effective PDA closure.

Conditions

Patent Ductus Arteriosus; Preterm

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Standard Dosing

PNA-based standard dosing of ibuprofen \[ \<= 72 hours PNA: 10/5/5 q24hrs vs \>72 hours PNA 20/10/10 q24hrs\].

Group Type: ACTIVE_COMPARATOR

Standard Dose - Ibuprofen oral suspension

Intervention Type: DRUG

Standard dosing administers ibuprofen without adjustments, starting with an initial loading dose followed by two maintenance doses at 24-hour intervals: 10/5/5 mg/kg for infants aged ≤72 hours, and 20/10/10 mg/kg for those \>72 hours old.

Precision Dosing

PNA-based regimen only for the initial dose, the rest of regimen will be guided by a MIPD, using a Web-Accessible Population Pharmacokinetics Service (WAPPS-PDA).

Group Type: EXPERIMENTAL

Precision Dose - Ibuprofen oral suspension

Intervention Type: DRUG

Precision Dosing (Model-Informed Precision Dosing - MIPD): Begins with the same initial loading dose as the Standard Dosing arm, with subsequent doses adjusted based on a Bayesian forecasting model that integrates real-time PK and echocardiographic data.

Interventions

Standard Dose - Ibuprofen oral suspension

Standard dosing administers ibuprofen without adjustments, starting with an initial loading dose followed by two maintenance doses at 24-hour intervals: 10/5/5 mg/kg for infants aged ≤72 hours, and 20/10/10 mg/kg for those \>72 hours old.

Intervention Type: DRUG

Precision Dose - Ibuprofen oral suspension

Precision Dosing (Model-Informed Precision Dosing - MIPD): Begins with the same initial loading dose as the Standard Dosing arm, with subsequent doses adjusted based on a Bayesian forecasting model that integrates real-time PK and echocardiographic data.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Neonates with a gestational age of ≤27+6 weeks
• Admitted to the neonatal intensive care unit (NICU) at McMaster Children's Hospital (MCH)
• Diagnosed with PDA in need of treatment based on targeted neonatal echocardiography (TnEcho) performed prior to 27+6 CGA or postnatal age of 3 days, whichever comes later.
• Obtained parental consent.

Exclusion Criteria

• Major congenital or genetic abnormalities
• Evidence for clinical or biochemical hepatic or renal failure (AST > 225 U/L, ALT > 150 U/L, or serum creatinine > 130 µmol/L)
• Sepsis - as defined by confirmed uncontrolled/active sepsis which will preclude any treatment of PDA
• Contraindications to receive oral ibuprofen:
• Severe hyperbilirubinemia in need for exchange transfusion
• Severe feeding intolerance
• Necrotizing enterocolitis (NEC)
• Gastrointestinal perforation
• Active bleeding
• Severe thrombocytopenia (< 50× 109/L)

• Maximum Eligible Age: 28 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

McMaster University

OTHER

Sponsor Role: collaborator

Hamilton Academic Health Sciences Organization

OTHER

Sponsor Role: collaborator

Hamilton Health Sciences Corporation

OTHER

Sponsor Role: lead

Responsible Party

Samira Samiee-Zafarghandy

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Samira Samiee-Zafarghandy, MD, FRCPC

Role: PRINCIPAL_INVESTIGATOR

McMaster University

Locations

McMaster Children's Hospital - Neonatal Intensive Care Unit

Hamilton, Ontario, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Samira Samiee-Zafarghandy, MD, FRCPC

Role: CONTACT

samiees@mcmaster.ca

1-905-521-2100 ext. 73568

Facility Contacts

Samira Samiee-Zafarghandy, MD, FRCPC

Role: primary

samiees@mcmaster.ca

1-905-521-2100 ext. 73568

Heather Johnson, BScN

Role: backup

johnsh30@mcmaster.ca

References

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Reference Type: BACKGROUND

PMID: 27927609 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 30204236 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 11673749 (View on PubMed)

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

PMID: 21840880 (View on PubMed)

Samiee-Zafarghandy S, van Donge T, Fusch G, Pfister M, Jacob G, Atkinson A, Rieder MJ, Smit C, Van Den Anker J. Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates. Arch Dis Child. 2022 Jan;107(1):86-91. doi: 10.1136/archdischild-2020-321381. Epub 2021 May 11.

Reference Type: BACKGROUND

PMID: 33975823 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 29584842 (View on PubMed)

Other Identifiers

HiREB #16287

Identifier Type: -

Identifier Source: org_study_id