Clinical trial NCT06626035: Evaluation of Analgesia for Cardiac Elective Surgery in Children
Official title: Prospective Randomized Evaluation of Analgesia for Cardiac Elective Surgery in Children (PRECISE Cardiac Trial)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Pediatric Cardiac Surgery
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2024-10-03
Enrollment: 500
Sex: ALL
Minimum age (years): 3
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Clinical Trial
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to look at a standardized methadone-based enhanced recovery after surgery protocol following pediatric cardiac surgery. This study will consist of randomly assigning children to receive the methadone-based recovery procedures or to receive current standard of care recovery procedures. Randomly assigning means that there is a 50/50 chance, like a coin flip, of being assigned to either research group.

Detailed description: The investigator's long-term goal is to proactively improve the safety and efficacy of surgical pain control while reducing opioid AEs (adverse events) and the opioid epidemic burden in all children undergoing inpatient surgeries. The investigator's central hypothesis is that a standardized, multidose, methadone-based ERAS (Enhanced Recovery After Surgery) protocol will reduce acute surgical pain, overall opioid use, RD (Respiratory Depression), PONV (Postoperative Nausea and Vomiting), and CPSP (Chronic Persistent Surgical Pain) compared with standard-of-care short-acting opioid-based analgesia in children undergoing CS (Cardiac Surgery) (Aim 1). Investigators will use PK (Pharmacokinetic) and genetic variations along with CPB (Cardiopulmonary Bypass) related dilution and clinical factors to develop optimal intra- and post-operative methadone dosing in children to enable precision analgesia in the future (Aim 2). The investigators will identify patient profiles with genetic, epigenetic, PK, clinical, and psychological factors to predict benefit from assigned analgesia for optimal clinical outcomes (Aim 3). The investigators expert multidisciplinary and multicenter team will enroll a total of 500 children to conduct two parallel randomized clinical trials for CS (500 children 1 month-10 years from 5 clinical sites). In this study, specifically, the investigators will:

Aim 1. Conduct two randomized clinical trials in CS to compare acute pain relief, opioid-sparing efficacy, and safety of standardized perioperative multidose methadone-based ERAS vs. standard-of-care non-methadone-based analgesia. Acute surgical pain, opioid needs (morphine equivalents), RD, PONV, and CPSP will be lower in methadone-based analgesia compared to short-acting opioid-based analgesia.

Aim 2. Develop precision methadone dosing based on age, CYP2B6 and ORM1 variants, AAG, and CPB. Age, CYP2B6 and ORM1 variants, AAG levels, and CPB-related dilution will explain methadone's PK variability and dose adjustments that correlate with optimal clinical outcomes among 500 children receiving methadone.

Aim 3. Identify patient profiles that predict benefits from the assigned analgesia protocol to optimize clinical outcomes. Personalized risk prediction models will be developed and validated including genetic variants (i.e., CYP2B6, CYP2D6, ABCB1, OPRM1, and FAAH), and psychological and clinical factors to predict benefit with the assigned treatments (methadone or non-methadone) for pre-specified clinical endpoints.

Overall Impact: The investigators will develop actionable evidence for the efficacy of standardized, multidose, methadone-based ERAS protocols and will harness genetic, clinical, and psychological factors contributing to variability in methadone and oxycodone PK, acute surgical pain, transition to CPSP, opioid-induced PONV, RD, and dependence to develop personalized analgesia strategy and dosing for children undergoing CS. Implementation of evidence-based standardized methadone-based ERAS pain management and individualized risk prediction will maximize acute surgical pain relief while minimizing opioid use and AEs in millions of children.

Eligibility criteria: Inclusion Criteria:

* Children aged 3-years - \<18 years
* ASA physical status 1, 2, or 3
* Participant or legal guardian can speak and read English or Spanish
* Undergoing the following cardiac surgeries (Categories 1 \& 2) that are associated with significant acute surgical pain

STS Category 1:

* ASD, PFO closure
* VSD repairs,
* Aortic stenosis sub-valvular repair
* ASD and Partial anomalous venous return repair
* AV canal transitional
* Conduit replacement
* Valve replacement (AVR, PVR)
* TOF repair without ventriculostomy

STS Category 2:

* Glenn shunt (on Bypass only)
* Fontan surgery (on Bypass only)
* Pulmonary artery plasty (main)
* Left Atrium (LA) to Pulmonary Artery (PA) conduit replacement.

Exclusion Criteria:

* Pregnant patients
* Methadone/oxycodone allergy
* Preoperative prolonged QTc more than 460 msec (-30 days to 0 day)
* Subjects undergoing concomitant treatment with known cytochrome P450 inhibitors included in methadone labeling (i.e. macrolides (e.g. erythromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole), protease inhibitors (e.g. ritonavir), fluconazole, SSRIs (e.g. sertraline, fluvoxamine)
* Preoperative opioid use within 30 days before surgery
* History of severe sleep apnea (have a sleep study with an AHI index score more than 10 or clinical signs of sleep disordered breathing - snoring, daytime drowsiness)
* Significant liver, kidney, neurological disease, developmental delay, or any other co-existing medical condition per discretion of the clinical investigator

Primary outcomes:
measure: Average postoperative pain scores
timeFrame: Postoperative 48 hours
measure: Total postoperative opioid use
timeFrame: Postoperative 48 hours
Secondary outcomes:
measure: Length of Stay (LOS)
timeFrame: Up to 1-week post-operative
measure: Post discharge opioid use
timeFrame: Post-op 3 months
measure: Patient Health Questionnaire (PHQ-9)
timeFrame: Up to 1-week post-operative, Week 1 post-discharge, Month 1, and Month 3
measure: Pain Catastrophizing Scale (PCS) for Children
timeFrame: Up to 1-week post-operative, Week 1 post-discharge, Month 1, and Month 3
measure: Generalized Anxiety Disorder-2 (GAD-2)
timeFrame: Up to 1-week post-operative, Week 1 post-discharge, Month 1, and Month 3
measure: Presence of Chronic Persistent Surgical Pain (CPSP)
timeFrame: Week 1 post-discharge, Month 1, and Month 3
measure: Opioid Dependence
timeFrame: Week 1 post-discharge, Month 1, and Month 3
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Senthilkumar Sadhasivam, MD
role: PRINCIPAL_INVESTIGATOR
References: