R01HD106326

Age-Dependent Heterogeneity in the Efficacy of Prophylaxis with Enoxaparin against Catheter-Associated Thrombosis in Critically Ill Children - Project Summary

Pediatric venous thromboembolism (VTE), predominantly deep venous thrombosis (DVT), is a top contributor to harm in hospitalized children. Critical illness and central venous catheter (CVC) are the most important risk factors for VTE in children. Among critically ill children, the risk of CVC-associated DVT (CADVT) is as high as 54%, with 72% of cases occurring in infants under 1 year old. Despite ongoing national initiatives to prevent VTE in children, the incidence of pediatric VTE has not decreased in two decades. Pharmacologic prophylaxis is uncommon in children due to a lack of age-appropriate evidence on its efficacy against CADVT. Extrapolating evidence from adults is inappropriate because the coagulation system changes significantly with age.

We recently completed a Bayesian Phase 2B randomized clinical trial funded by NICHD. In this trial, we randomized critically ill children to early administration of prophylactic dose of enoxaparin, the most commonly used anticoagulant for prophylaxis, or usual care. Prophylaxis with enoxaparin appeared to reduce the risk of CADVT by half. However, in post hoc analyses, the reduction was limited to older children (1 year old and above).

The goal of the proposed Catheter-Related Early Thromboprophylaxis with Enoxaparin (CRETE) studies is to investigate this newly identified age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children. To achieve this goal, we aim to:

1. Confirm the efficacy and safety of early administration of prophylactic dose of enoxaparin in reducing the risk of CADVT in critically ill older children.
2. Determine the efficacy and safety of early administration of therapeutic dose of enoxaparin in reducing the risk of CADVT in critically ill infants.
3. Probe the mechanisms that underlie the age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children.

We will conduct two multicenter Bayesian explanatory randomized clinical trials in parallel to address specific aims 1 and 2. Depending on age, subjects will be randomized to different doses of enoxaparin versus usual care. Subjects will be systematically assessed for the development of CADVT using ultrasonography and clinically for bleeding.

Using plasma obtained from subjects in the two trials, we will conduct an exploratory mechanistic nested case-control study to address specific aim 3. Biomarkers of the different mechanisms underlying CVC-associated thrombus formation, particularly thrombin generation, will be compared between subjects with and without CADVT.

We will use Bayesian methods to improve the efficiency in the conduct and analyses of these studies. The proposed CRETE studies address NICHD's research priorities on child development, critical illness, therapeutics, and innovative clinical trial design. They will provide high-quality age-appropriate evidence that will inform preventive strategies against CADVT and decrease harm in hospitalized children.

Yale Univ

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

New Haven, Connecticut 065103221 United States

Single Zip Code

NICHD Research Project Grant (R01 - Clinical Trial Required) (PA-18-480)

Amendment Since initial award the total obligations have increased 363% from $800,627 to $3,703,719.