Collaborative Risk-stratified Investigation in Thrombosis-prone Inpatients With Critical Illness: Anticoagulation With LMWH in Teens for ThromboProphylaxis (CRITICAL-Teens-TP).

This trial will establish definitive evidence on the comparative efficacy and safety of pharmacological thromboprophylaxis with the low molecular weight heparin (LMWH) enoxaparin versus no pharmacological thromboprophylaxis for the primary prevention of venous thromboembolism (VTE), including deep vein thrombosis and/or pulmonary embolism) among critically ill adolescents who meet a priori criteria for high risk of hospital-acquired (HA-) VTE. In the past two decades, the diagnosis of pediatric hospital-acquired VTE (HA-VTE) in the U.S. has increased 130-200-fold. The investigators have shown that critically-ill adolescents are one the highest risk subpopulations for HA-VTE, with average occurrence rates of 13.2% (range: 6.3-19.8%), and have derived and prospectively validated risk models for HA-VTE in this population. Despite a simultaneously increased risk of bleeding in critically ill adolescents, particularly after surgery or major trauma, an investigator-initiated multicenter phase 2 trial recently led by the investigators group during the COVID-19 pandemic demonstrated the safety of LMWH for primary HA-VTE prevention. To date, risk-stratified phase 3 Randomized Controlled Trials (RCTs) of LMWH thromboprophylaxis as primary HA-VTE prevention in children have not been performed. The investigators will perform a U.S.-based definitive multicenter phase 3 RCT of the LMWH enoxaparin versus no pharmacological thromboprophylaxis for VTE prevention among critically ill adolescents at highest a priori risk for HA-VTE applying evidence from the investigators published risk prediction models.

• Enoxaparin (Drug): Enoxaparin thromboprophylaxis administered subcutaneously twice daily (every 12 hours) from enrollment through pediatric intensive care unit discharge

Primary outcomes

• Risk (i.e., cumulative incidence) of Symptomatic venous thromboembolism [From randomization through discharge from the pediatric intensive care unit, approximately 1-2 weeks]: International Society on Thrombosis and Haemostasis (ISTH) defined symptomatic venous thromboembolism
• Risk (i.e., cumulative incidence) of Clinically relevant bleeding [From randomization through discharge from the pediatric intensive care unit, approximately 1-2 weeks]: International Society on Thrombosis and Haemostasis (ISTH) defined clinically relevant bleeding (Major bleeding + Clinically relevant Non-major bleeding)

Secondary outcomes

• Net Clinical Benefit - Modelled Attributable Risk Difference in HA-VTE (Efficacy) by Attributable Risk Difference in clinically relevant bleeding (Safety) [From randomization through discharge from the pediatric intensive care unit, approximately 1-2 weeks]: Net clinical benefit is a bivariate endpoint analysis (i.e., trade-off of venous thromboembolism and bleeding risks as described below). One-year risks and corresponding 95% confidence intervals (CI) of hospital-acquired venous thromboembolism and clinically relevant bleeding for each study arm will be calculated from weighted Kaplan-Meier curves. A bivariate decision curve will be specified using the 12-month absolute risk difference for venous thromboembolism and bleeding outcomes. Bivariate outcomes for enoxaparin and no pharmacological thromboprophylaxis will be compared under a hypothesis of superiority using the superiority boundary of a bivariate endpoint analysis, with inference based on the 95% confidence rectangle (i.e., the rectangle defined by the 95% CI for hospital-acquired venous thromboembolism absolute risk difference and the 95% CI for bleeding absolute risk difference). Superiority will be decided if the 95% confidence rectangle rules out the superiority curve.
• Risk (i.e. cumulative incidence) of symptomatic venous thromboembolism [From randomization through 30-days post discharge from the pediatric intensive care unit]: International Society on Thrombosis and Haemostasis-defined symptomatic venous thromboembolism
• Risk (i.e. cumulative incidence) of clinically relevant bleeding [From randomization through 30-days post discharge from the pediatric intensive care unit]: International Society on Thrombosis and Haemostasis-defined clinically relevant bleeding (Major Bleeding + Clinically Relevant Non-Major Bleeding)
• Serious adverse events [From randomization through 30-days post discharge from the pediatric intensive care unit]: As federally defined.

Sex: All, ages: 12 Years to 18 Years

Inclusion Criteria:

* Admission Age between 12- 18 years of age
* Within 24 hours of pediatric intensive care unit (PICU) admission for enrollment
* Presence of a Central Venous Catheter
* Presumed or confirmed infection or systemic inflammatory condition

Exclusion Criteria:

* Active treatment for VTE or known VTE present prior to or on pediatric intensive care unit (PICU) admission
* Current receipt of an antithrombotic agent excluding unfractionated heparin for vascular catheter patency
* Active ISTH-defined clinically relevant bleeding
* Surgery in the last 7-days
* Major trauma within the last 7-days
* Admission for management of congenital heart disease including perioperative management of critical congenital heart disease
* Presence of coagulopathy including:
* International normalized ratio (INR) 2.0 activated partial thromboplastin time (aPTT) 50 seconds Platelet count 50 x103/mL
* Creatinine clearance 30 ml/min/1.73 m2
* Known hypersensitivity to heparin or pork products
* Laboratory confirmed heparin induced thrombocytopenia
* Current pregnancy or lactation,
* Presence of an epidural catheter
* Prior enrollment in the CRITICAL-Teens-TP Trial

• Results publication: Sochet AA, Amankwah EK, Andalib V, Jaffray J, Male C, Faustino EV, Goldenberg NA; Pedi-ATLAS Group and the Antithrombotic Trials Working Party of the Pediatric Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Enhanced trial efficiency of the novel "contemporaneous control recapture" parallel-cohort RCT design: Methods and application in the CRITICAL-Kids-TP trial. Contemp Clin Trials. 2026 Jan;160:108142. doi: 10.1016/j.cct.2025.108142. Epub 2025 Nov 10. PMID 41223938

• Anthony Sochet, MD, MSc, Principal investigator, Johns Hopkins All Children's Hospital