Precision Dosing of Oral Ibuprofen for PDA, A Pilot RCT

NCT07143201 | Recruiting Phase 2

• 1 other identifier: HiREB #16287
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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. 1.To assess how well and how safely the personalized (MIPD) method works, using a tool called WAPPS-PDA to guide dosing.
2. 2.To compare the effectiveness and safety of the personalized method with standard ibuprofen dosing.
3. 3.To identify drug levels in the blood (Cmin, AUC0-24, AUC0-72) that are associated with complete, partial, or no response to treatment.

Conditions

Patent Ductus Arteriosus; Preterm

Keywords

MIPD-PDA; PDA; Precision Dosing; Ibuprofen

Outcome Measures

Primary Outcomes (5)

• Recruitment Feasibility

  Feasibility will be assessed by the ability to randomize at least 15% of all eligible patients during the study period.

  From intial dose to 96 hours after.

• Timeliness of PK Sample Result Availability

  Feasibility will be assessed by the ability to obtain results for at least 80% of pharmacokinetic (PK) samples within 4 hours of sample collection.

  From initial dose to 96 hours after

• Timeliness of Top-up Dosing Data for Intervention Arm

  Feasibility will be assessed by the ability to generate dosing data for top-up administration within 14 hours of the previous dose in at least 80% of subjects in the intervention arm.

  From initial dose to 96 hours after

• Timely Completion of Daily Targeted Neonatal Echocardiogram (TnEcho)

  Feasibility will be assessed by the ability to perform daily TnEcho within 4 to 8 hours prior to the next scheduled dose in at least 80% of subjects.

  From initial dose to 96 hours after

• Timely TnEcho Scoring and Model-Informed Precision Dosing (MIPD) Recommendation

  Feasibility will be assessed by the ability to score the TnEcho, assign responsiveness grouping, and provide the MIPD recommendation for the second and third doses of oral ibuprofen within 24 hours of the previous dose in at least 80% of subjects.

  From initial dose to 96 hours after

Secondary Outcomes (8)

• Achievement of Target Trough Concentration and AUC (Intervention Arm Only)

  From first dose to 72 hours

• Maximum Ibuprofen Concentration (Cmax) ≤80 µg/mL (Intervention Arm Only)

  From first dose to 72 hours

• Daily Ibuprofen Dose ≤40 mg/kg (Intervention Arm Only)

  From first dose to 72 hours

• Closure of the Patent Ductus Arteriosus (PDA)

  From first dose to 14 days

• Need for Repeat Pharmacotherapy

  From first dose to 14 Days

Study Arms (2)

Standard Dosing

ACTIVE COMPARATOR

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

Drug: Standard Dose - Ibuprofen oral suspension

Precision Dosing

EXPERIMENTAL

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).

Drug: Precision Dose - Ibuprofen oral suspension

Interventions

Standard Dose - Ibuprofen oral suspension 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.

Standard Dosing

Precision Dose - Ibuprofen oral suspension 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.

Precision Dosing

Eligibility Criteria

• Age: Up to 28 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Hamilton Health Sciences Corporation: lead
• McMaster University: collaborator
• Hamilton Academic Health Sciences Organization: collaborator

Study Sites (1)

McMaster Children's Hospital - Neonatal Intensive Care Unit

Hamilton, Ontario, L8N 3Z2, Canada

RECRUITING

Related Publications (8)

• McEneny-King A, Foster G, Iorio A, Edginton AN. Data Analysis Protocol for the Development and Evaluation of Population Pharmacokinetic Models for Incorporation Into the Web-Accessible Population Pharmacokinetic Service - Hemophilia (WAPPS-Hemo). JMIR Res Protoc. 2016 Dec 7;5(4):e232. doi: 10.2196/resprot.6559.

  PMID: 27927609 BACKGROUND

• Euteneuer JC, Kamatkar S, Fukuda T, Vinks AA, Akinbi HT. Suggestions for Model-Informed Precision Dosing to Optimize Neonatal Drug Therapy. J Clin Pharmacol. 2019 Feb;59(2):168-176. doi: 10.1002/jcph.1315. Epub 2018 Sep 11.

  PMID: 30204236 BACKGROUND

• Van Overmeire B, Touw D, Schepens PJ, Kearns GL, van den Anker JN. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther. 2001 Oct;70(4):336-43.

  PMID: 11673749 BACKGROUND

• Hirt D, Van Overmeire B, Treluyer JM, Langhendries JP, Marguglio A, Eisinger MJ, Schepens P, Urien S. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br J Clin Pharmacol. 2008 May;65(5):629-36. doi: 10.1111/j.1365-2125.2008.03118.x. Epub 2008 Feb 27.

  PMID: 18307541 BACKGROUND

• Engbers AGJ, Voller S, Flint RB, Goulooze SC, de Klerk J, Krekels EHJ, van Dijk M, Willemsen SP, Reiss IKM, Knibbe CAJ, Simons SHP. The Effect of Ibuprofen Exposure and Patient Characteristics on the Closure of the Patent Ductus Arteriosus in Preterm Infants. Clin Pharmacol Ther. 2022 Aug;112(2):307-315. doi: 10.1002/cpt.2616. Epub 2022 May 6.

  PMID: 35429165 BACKGROUND

• Barzilay B, Youngster I, Batash D, Keidar R, Baram S, Goldman M, Berkovitch M, Heyman E. Pharmacokinetics of oral ibuprofen for patent ductus arteriosus closure in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2012 Mar;97(2):F116-9. doi: 10.1136/adc.2011.215160. Epub 2011 Aug 11.

  PMID: 21840880 BACKGROUND

• 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.

  PMID: 33975823 BACKGROUND

• Mitra S, Florez ID, Tamayo ME, Mbuagbaw L, Vanniyasingam T, Veroniki AA, Zea AM, Zhang Y, Sadeghirad B, Thabane L. Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis. JAMA. 2018 Mar 27;319(12):1221-1238. doi: 10.1001/jama.2018.1896.

  PMID: 29584842 BACKGROUND

MeSH Terms

Conditions

Ductus Arteriosus, Patent; Premature Birth

Condition Hierarchy (Ancestors)

Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Study Officials

• Samira Samiee-Zafarghandy, MD, FRCPC

  McMaster University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Samira Samiee-Zafarghandy, MD, FRCPC

CONTACT

1-905-521-2100; samiees@mcmaster.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: The parents of the participants, the professionals performing the echocardiograms and the statistician will be blinded to the study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 8, 2025
• First Posted: August 27, 2025
• Study Start: July 4, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2027
• Last Updated: August 27, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)