Precision Dosing of Oral Ibuprofen for PDA, A Pilot RCT

Official title

Model Informed Precision Dosing of Oral Ibuprofen for Treatment of Persistent Patent Ductus Arteriosus: A Pilot Randomized Controlled Feasibility Trial

Overview

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.

Interventions

• Drug 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.
• 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.

Primary outcome measures

• Recruitment Feasibility [Time frame: From intial dose to 96 hours after.]
• Timeliness of PK Sample Result Availability [Time frame: From initial dose to 96 hours after]
• Timeliness of Top-up Dosing Data for Intervention Arm [Time frame: From initial dose to 96 hours after]
• Timely Completion of Daily Targeted Neonatal Echocardiogram (TnEcho) [Time frame: From initial dose to 96 hours after]
• Timely TnEcho Scoring and Model-Informed Precision Dosing (MIPD) Recommendation [Time frame: From initial dose to 96 hours after]

Secondary outcome measures (8)

• Achievement of Target Trough Concentration and AUC (Intervention Arm Only) [Time frame: From first dose to 72 hours]
• Maximum Ibuprofen Concentration (Cmax) ≤80 µg/mL (Intervention Arm Only) [Time frame: From first dose to 72 hours]
• Daily Ibuprofen Dose ≤40 mg/kg (Intervention Arm Only) [Time frame: From first dose to 72 hours]
• Closure of the Patent Ductus Arteriosus (PDA) [Time frame: From first dose to 14 days]
• Need for Repeat Pharmacotherapy [Time frame: From first dose to 14 Days]
• Need for Surgical Ligation [Time frame: From first dose to 14 Days]
• Treatment Interruption [Time frame: From first dose to 14 Days]
• Occurrence of Adverse Events [Time frame: From first dose to 14 Days]

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Canada · 1 center

• McMaster Children's Hospital - Neonatal Intensive Care Unit — Hamilton

Publications

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

Identifiers

NCT: NCT07143201 · HiREB #16287

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗