Clinical trial NCT03003390: Catheter-Related Early Thromboprophylaxis With Enoxaparin (CRETE) Trial
Official title: Prevention of Central Venous Catheter-associated Thrombosis in Critically Ill Children: A Multicenter Phase 2b Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Deep Venous Thrombosis
Keywords: child
critical illness
venous thromboembolism
enoxaparin
thrombin generation
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: St. Louis Children's Hospital
name: Dell Children's Medical Center of Central Texas
name: Children's Hospital and Health System Foundation, Wisconsin
name: Weill Medical College of Cornell University
name: Maria Fareri Children's Hospital
name: University of Rochester
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2016-12-28
Enrollment: 51
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Eligible subjects will be randomized 1:1 to treatment or control.
Primary purpose: PREVENTION

Brief summary: The purpose of this phase 2a, multi-center, randomized controlled study, is to explore the efficacy of early prophylaxis against catheter-associated deep venous thrombosis (CADVT) in critically ill children.

Detailed description: Critical illness and the presence of a central venous catheter (CVC) are the most important risk factors for deep venous thrombosis (DVT) in children. Catheter-associated thrombosis (CADVT) is highly prevalent and associated with poor outcomes in critically ill children. Yet, based on underpowered pediatric trials, prophylaxis against CADVT is not recommended in children. The recommendation to provide prophylaxis against thrombosis in critically ill adults should not be applied to children because the hemostatic system and co-morbidities vastly differ between age groups. Pivotal trials are urgently needed to determine whether prophylaxis can prevent CADVT and its complications in critically ill children. However, the timing and extent of reduction in thrombin generation, the biochemical goal of prophylaxis, needed to prevent CADVT in children are unclear. The goal of this application is to explore the efficacy of early prophylaxis against CADVT in critically ill children. Aim 1 is to obtain preliminary evidence on the effect of early prophylaxis on the incidence of CADVT in critically ill children. Based on the natural history of CADVT, we hypothesize that among critically ill children, prophylaxis administered \<24 hours after catheter insertion decreases the incidence of ultrasound-diagnosed CADVT compared with no prophylaxis. In this phase 2a trial, children admitted to the intensive care unit with a newly inserted central venous catheter will receive enoxaparin adjusted according to anti-Xa activity, a control group will not receive enoxaparin adjusted according to anti-Xa activity. Enoxaparin has become the "standard" pediatric anticoagulant for prophylaxis despite the absence of conclusive data. We will use Bayesian approach to determine whether further trials are warranted. Aim 2 is to evaluate the effect of an anti-Xa activity-directed prophylactic strategy on thrombin generation in critically ill children. We hypothesize that among critically ill children, standard prophylactic dose of enoxaparin adjusted by anti-Xa activity reduces thrombin generation to \<700 nanomolar-minute (nM.min), as measured by endogenous thrombin potential (ETP). In non-critically ill adults, prophylactic dose of enoxaparin proven to prevent DVT reduces ETP to \<700 nM.min. Endogenous thrombin potential is the best available measure of thrombin generation. We will measure endogenous thrombin potential and anti-Xa activity at multiple time points then examine their relationship in all children enrolled in the phase 2a trial. The proposed research challenges the current paradigm on prophylaxis against CADVT in children. High quality evidence is needed to prevent CADVT and its complications in this vulnerable population.

Eligibility criteria: Inclusion Criteria

1. Untunneled CVC inserted in the internal jugular or femoral vein within the past 24 hours
2. Child anticipated to stay in the pediatric intensive care unit ≥48 hours
3. CVC anticipated to be required for ≥24 hours
4. \>36 weeks corrected gestational age to \<18 years old

Exclusion Criteria

1. Coagulopathy (i.e., international normalized ratio \>2.0, activated partial thromboplastin time \>50 seconds or platelet count \<50,000/mm3)
2. Known bleeding disorder
3. Clinically relevant bleeding as defined by the International Society on Thrombosis and Hemostasis (i.e., Hb decreased ≥2 g/dl in 24 hours, required medical or surgical intervention to restore hemostasis, or in a critical organ system \[i.e., retroperitoneum, pulmonary, intracranial or central nervous system\])
4. \<60 days from a clinically relevant bleeding as defined above
5. \<7 days after trauma or surgery
6. Anticipated surgery within 48 hours after insertion of the CVC
7. Renal failure (i.e., creatinine clearance \<30 mL/min)
8. Presence of epidural catheter
9. Currently taking an antithrombotic agent (e.g., low molecular weight heparin (LMWH), unfractionated heparin (UFH) at therapeutic doses, Coumadin or aspirin)
10. Radiologically documented DVT at the site of insertion of the CVC in the previous 6 weeks
11. Known hypersensitivity to heparin or its components, including pork products
12. History of heparin-induced thrombocytopenia (HIT) (i.e., positive serotonin release assay)
13. Currently pregnant
14. Currently lactating
15. Prior enrollment in the study
16. Limitation of care

Primary outcomes:
measure: Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT)
timeFrame: Up to removal of CVC, an average of 6 days
measure: Endogenous Thrombin Potential
timeFrame: Day of, day after and day 4 after insertion of the CVC
Secondary outcomes:
measure: Number With Other Thromboembolic Events
timeFrame: Up to removal of CVC, an average of 6 days
measure: Length of Stay in the Pediatric Intensive Care Unit in Days
timeFrame: Up to day of discharge from the pediatric intensive care unit, an average of 10 days
measure: Length of Stay in the Hospital
timeFrame: Up to day of discharge from the hospital, an average of 18 days
measure: Number With Clinically Relevant Bleeding
timeFrame: Up to 30 hours after the last enoxaparin dose
measure: Number With Laboratory Confirmed Heparin-induced Thrombocytopenia
timeFrame: Up to removal of CVC, an average of 6 days
measure: Number of Mortality
timeFrame: Up to day of discharge from the hospital, average of 18 days
measure: Number of Enrolled Eligible Children
timeFrame: Up to 24 hours after insertion of CVC
measure: Time to 1st Dose of Enoxaparin
timeFrame: Up to 48 hours after insertion of CVC
measure: Time to Target Anti-Xa Activity
timeFrame: Up to removal of CVC, an average of 6 days
measure: Number of Missed Doses of Enoxaparin
timeFrame: Up to removal of CVC, an average of 6 days
measure: Number of Children With Ultrasound
timeFrame: Up to 24 hours after removal of CVC
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University Yale New Haven Health
state: Connecticut
city: Saint Louis
country: United States
facility: Saint Louis Children's Hospital-Washington University School of Medicine-
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center-Golisano Children's Hospital-
state: New York
city: Valhalla
country: United States
facility: Maria Fareri Children's Hospital
state: New York
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin/Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Associate Professor of Pediatrics, Yale School of Medicine
name: E. Vincent S Faustino, MD, MHS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Faustino EVS, Raffini LJ, Hanson SJ, Cholette JM, Pinto MG, Li S, Kandil SB, Nellis ME, Shabanova V, Silva CT, Tala JA, McPartland T, Spinella PC; for the CRETE Trial Investigators and the Pediatric Critical Care Blood Research Network (BloodNet) of the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI); CRETE Trial Investigators: Clinical Coordinating Center:; and; Data Coordinating Center:; and; Outcomes Adjudication Committee:; and; Data and Safety Monitoring Board:; and; Independent Safety Monitor:; and; Children's Hospital Wisconsin:; and; Dell Children's Medical Center:; and; Maria Fareri Children's Hospital:; and; St. Louis Children's Hospital:; and; University of Rochester Golisano Children's Hospital:; and; Weill Cornell Medical Center:; and; and Yale-New Haven Children's Hospital:; and; for the CRETE Trial Investigators and the Pediatric Critical Care Blood Research Network (BloodNet) of the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) and CRETE Trial Investigators: Clinical Coordinating Center: and and and Data Coordinating Center: and and and Outcomes Adjudication Committee: and and and Data and Safety Monitoring Board: and and and Independent Safety Monitor: and and and Children's Hospital Wisconsin: and and and Dell Children's Medical Center: and and and Maria Fareri Children's Hospital: and and and St. Louis Children's Hospital: and and and University of Rochester Golisano Children's Hospital: and and and Weill Cornell Medical Center: and and and and Yale-New Haven Children's Hospital: and and. Age-Dependent Heterogeneity in the Efficacy of Prophylaxis With Enoxaparin Against Catheter-Associated Thrombosis in Critically Ill Children: A Post Hoc Analysis of a Bayesian Phase 2b Randomized Clinical Trial. Crit Care Med. 2021 Apr 1;49(4):e369-e380. doi: 10.1097/CCM.0000000000004848.
citation: Faustino EVS, Shabanova V, Raffini LJ, Kandil SB, Li S, Pinto MG, Cholette JM, Hanson SJ, Nellis ME, Silva CT, Chima R, Sharathkumar A, Thomas KA, McPartland T, Tala JA, Spinella PC; CRETE Trial Investigators and the Pediatric Critical Care Blood Research Network (BloodNet) of the Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI). Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial. Crit Care Med. 2021 Mar 1;49(3):e235-e246. doi: 10.1097/CCM.0000000000004784.