Venous Thromboembolism (VTE)
Conditions
Keywords
pediatric, adolescent, critical illness, thromboprophylaxis
Brief summary
Critically ill adolescents are at greatest risk for developing hospital-acquired venous thromboembolism. To date, no phase 3 randomized controlled trials have been conducted for pharmacological thromboprophylaxis as primary venous thromboembolism prevention in children. The investigators will perform a United States definitive multicenter phase 3 randomized controlled trial of the low molecular weight heparin enoxaparin as primary venous thromboembolism prophylaxis among critically ill adolescents who are classified a priori as high risk based upon the investigators validated risk prediction models.
Detailed description
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.
Interventions
DRUGEnoxaparin
Enoxaparin thromboprophylaxis administered subcutaneously twice daily (every 12 hours) from enrollment through pediatric intensive care unit discharge
Sponsors
Johns Hopkins All Children's Hospital
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
Prospective Randomized Open, Blinded-Endpoint study design. There will be a blinded end-point adjudication committee.
Intervention model description
PROBE study design, Randomized allocation 2:1 (Intervention:Standard of care) of enoxaparin thromboprophylaxis versus standard-of-care (i.e., no pharmacological thromboprophylaxis). Analytic study populations will be modified intent-to-treat, per-protocol, and safety populations
Eligibility
Sex/Gender
ALL
Age
12 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Contacts
CONTACTAnthony A Sochet, MD, MSc
CONTACTNeil A Goldenberg, MD, Phd
PRINCIPAL_INVESTIGATORAnthony Sochet, MD, MSc
Johns Hopkins All Children's Hospital
Outcome results
None listed