Model Informed Precision Dosing of Oral Ibuprofen for Treatment of Persistent Patent Ductus Arteriosus: A Pilot Randomized Controlled Feasibility Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Recruitment Feasibility
研究概览
简要总结
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
- To assess how well and how safely the personalized (MIPD) method works, using a tool called WAPPS-PDA to guide dosing.
- To compare the effectiveness and safety of the personalized method with standard ibuprofen dosing.
- To identify drug levels in the blood (Cmin, AUC0-24, AUC0-72) that are associated with complete, partial, or no response to treatment.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Care Provider, Outcomes Assessor)
盲法说明
The parents of the participants, the professionals performing the echocardiograms and the statistician will be blinded to the study.
入排标准
- 年龄范围
- — 至 28 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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)
研究组 & 干预措施
Standard Dosing
PNA-based standard dosing of ibuprofen [ <= 72 hours PNA: 10/5/5 q24hrs vs >72 hours PNA 20/10/10 q24hrs].
干预措施: Standard Dose - Ibuprofen oral suspension (Drug)
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).
干预措施: Precision Dose - Ibuprofen oral suspension (Drug)
结局指标
主要结局
Recruitment Feasibility
时间窗: From intial dose to 96 hours after.
Feasibility will be assessed by the ability to randomize at least 15% of all eligible patients during the study period.
Timeliness of PK Sample Result Availability
时间窗: From initial dose to 96 hours after
Feasibility will be assessed by the ability to obtain results for at least 80% of pharmacokinetic (PK) samples within 4 hours of sample collection.
Timeliness of Top-up Dosing Data for Intervention Arm
时间窗: From initial dose to 96 hours after
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.
Timely Completion of Daily Targeted Neonatal Echocardiogram (TnEcho)
时间窗: From initial dose to 96 hours after
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.
Timely TnEcho Scoring and Model-Informed Precision Dosing (MIPD) Recommendation
时间窗: From initial dose to 96 hours after
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.
次要结局
- 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)
- Need for Surgical Ligation(From first dose to 14 Days)
- Treatment Interruption(From first dose to 14 Days)
- Occurrence of Adverse Events(From first dose to 14 Days)
研究者
Samira Samiee-Zafarghandy
Principal Investigator
Hamilton Health Sciences Corporation