Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| 1R21HD089131-01A1 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Met protocol defined stopping rule for futility
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| St. Louis Children's Hospital | OTHER |
| Dell Children's Medical Center of Central Texas | OTHER |
| Children's Hospital and Health System Foundation, Wisconsin | OTHER |
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prophylaxis with enoxaparin | Experimental | A clinical nurse will administer enoxaparin subcutaneously <24 hours after insertion of the central venous catheter and then give enoxaparin subcutaneously every 12 hours until the removal of the catheter. |
|
| Control arm | No Intervention | Participants randomized to the control arm will receive no 'placebo' intervention. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Enoxaparin | Drug | The clinical nurse will give enoxaparin subcutaneously every 12 hours at the currently used starting dose of 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for older children. The 1st dose will be given <24 hours after insertion of the catheter. Doses will be adjusted to target an anti-Xa level of 0.2-0.5 IU/mL. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT) | Thrombus in the central vein where the CVC was inserted that is clinically suspected then confirmed radiologically, an incidental radiologic finding, or diagnosed with the study-related active surveillance ultrasound | Up to removal of CVC, an average of 6 days |
| Endogenous Thrombin Potential | An established measure of coagulation status and is the best method to measure thrombin generation. It directly measures the amount of thrombin generation over time capturing the effects of natural (i.e., subject's coagulation status) and pharmacological (e.g., enoxaparin) pro- and anticoagulants. Endogenous thrombin potential is measured using thrombin generation assay. | Day of, day after and day 4 after insertion of the CVC |
| Measure | Description | Time Frame |
|---|---|---|
| Number With Other Thromboembolic Events | Thrombus in the deep vein of any extremity or PE that is clinically suspected then confirmed radiologically, an incidental radiologic finding, excluding DVT diagnosed with the study-related active surveillance ultrasound | Up to removal of CVC, an average of 6 days |
Not provided
Inclusion Criteria
Exclusion Criteria
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| E. Vincent S Faustino, MD, MHS | Associate Professor of Pediatrics, Yale School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Yale University Yale New Haven Health | New Haven | Connecticut | 06520 | United States | ||
| Saint Louis Children's Hospital-Washington University School of Medicine- |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33566465 | Derived | 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. |
Not provided
Not provided
Not provided
One participant in the enoxaparin group was enrolled during a single arm phase and not included in the analysis.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Prophylaxis With Enoxaparin | A clinical nurse will administer enoxaparin subcutaneously <24 hours after insertion of the central venous catheter and then give enoxaparin subcutaneously every 12 hours until the removal of the catheter. Enoxaparin: The clinical nurse will give enoxaparin subcutaneously every 12 hours at the currently used starting dose of 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for older children. The 1st dose will be given <24 hours after insertion of the catheter. Doses will be adjusted to target an anti-Xa level of 0.2-0.5 IU/mL. |
| FG001 | Control Arm | Participants randomized to the control arm will receive no 'placebo' intervention. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Prophylaxis With Enoxaparin | A clinical nurse will administer enoxaparin subcutaneously <24 hours after insertion of the central venous catheter and then give enoxaparin subcutaneously every 12 hours until the removal of the catheter. Enoxaparin: The clinical nurse will give enoxaparin subcutaneously every 12 hours at the currently used starting dose of 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for older children. The 1st dose will be given <24 hours after insertion of the catheter. Doses will be adjusted to target an anti-Xa level of 0.2-0.5 IU/mL. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With Central Venous Catheter (CVC)- Associated Deep Vein Thrombosis (DVT) | Thrombus in the central vein where the CVC was inserted that is clinically suspected then confirmed radiologically, an incidental radiologic finding, or diagnosed with the study-related active surveillance ultrasound | Posted | Count of Participants | Participants | Up to removal of CVC, an average of 6 days |
|
From hospital admission to day of discharge for death, up to 60 days.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Prophylaxis With Enoxaparin | A clinical nurse will administer enoxaparin subcutaneously <24 hours after insertion of the central venous catheter and then give enoxaparin subcutaneously every 12 hours until the removal of the catheter. Enoxaparin: The clinical nurse will give enoxaparin subcutaneously every 12 hours at the currently used starting dose of 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 40 mg) for older children. The 1st dose will be given <24 hours after insertion of the catheter. Doses will be adjusted to target an anti-Xa level of 0.2-0.5 IU/mL. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| acute kidney injury | Renal and urinary disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acidosis | Metabolism and nutrition disorders | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. E. Vincent S Faustino | Yale University | 203-785-4651 | vince.faustino@yale.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| ICF | No | No | Yes | Informed Consent Form | Aug 25, 2017 | Jun 17, 2020 | ICF_000.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 22, 2017 | Jun 17, 2020 | Prot_SAP_001.pdf |
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D020246 | Venous Thrombosis |
| D016638 | Critical Illness |
| D054556 | Venous Thromboembolism |
| ID | Term |
|---|---|
| D013927 | Thrombosis |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D017984 | Enoxaparin |
| ID | Term |
|---|---|
| D006495 | Heparin, Low-Molecular-Weight |
| D006493 | Heparin |
| D006025 | Glycosaminoglycans |
| D011134 | Polysaccharides |
Not provided
Not provided
| Weill Medical College of Cornell University |
| OTHER |
| Maria Fareri Children's Hospital | UNKNOWN |
| University of Rochester | OTHER |
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
Eligible subjects will be randomized 1:1 to treatment or control.
Not provided
Not provided
Not provided
Not provided
|
|
| Length of Stay in the Pediatric Intensive Care Unit in Days |
Duration of stay in the pediatric intensive care unit from the day of enrollment |
| Up to day of discharge from the pediatric intensive care unit, an average of 10 days |
| Length of Stay in the Hospital | Duration of stay in the hospital from the day of enrollment | Up to day of discharge from the hospital, an average of 18 days |
| Number With Clinically Relevant Bleeding | Bleeding that is fatal, associated with a decrease in hemoglobin by ≥2 g/dl in 24 hours, requires medical or surgical intervention to restore hemostasis, or is in the retroperitoneum, pulmonary, intracranial or central nervous system as defined by International Society of Thrombosis and Haemostasis | Up to 30 hours after the last enoxaparin dose |
| Number With Laboratory Confirmed Heparin-induced Thrombocytopenia | Heparin-induced thrombocytopenia that is diagnosed with a positive serotonin release assay | Up to removal of CVC, an average of 6 days |
| Number of Mortality | In-hospital mortality during the subject's admission | Up to day of discharge from the hospital, average of 18 days |
| Number of Enrolled Eligible Children | Number of eligible children enrolled in the study. | Up to 24 hours after insertion of CVC |
| Time to 1st Dose of Enoxaparin | Time to first dose of enoxaparin | Up to 48 hours after insertion of CVC |
| Time to Target Anti-Xa Activity | Time from insertion of the CVC to time that anti-Xa activity was within 0.2-0.5 IU/mL. | Up to removal of CVC, an average of 6 days |
| Number of Missed Doses of Enoxaparin | Number of doses of enoxaparin that were not administered. This outcome measure was only applicable to the enoxaparin arm. | Up to removal of CVC, an average of 6 days |
| Number of Children With Ultrasound | Number of children in whom ultrasound was not performed. | Up to 24 hours after removal of CVC |
| St Louis |
| Missouri |
| 63110 |
| United States |
| Weill Cornell Medicine | New York | New York | 10065 | United States |
| University of Rochester Medical Center-Golisano Children's Hospital- | Rochester | New York | 14642 | United States |
| Maria Fareri Children's Hospital | Valhalla | New York | 10595 | United States |
| Children's Hospital of Wisconsin/Medical College of Wisconsin | Milwaukee | Wisconsin | 53226 | United States |
| 33372745 | Derived | 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. |
| BG001 | Control Arm | Participants randomized to the control arm will receive no 'placebo' intervention. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Size of Central Venous Catheter (CVC) | The size of the CVC may affect the risk of CVC-associated DVT. Larger diameter of the CVC, i.e. higher F, particular relative to the size of the central vein has been associated with higher risk of DVT. The size of the CVC was determined by the clinical team. | Count of Participants | Participants |
|
| Number of Lumens of CVC | Count of Participants | Participants |
|
| Site of Insertion of CVC | Count of Participants | Participants |
|
| OG001 | Control Arm | Participants randomized to the control arm will receive no 'placebo' intervention. |
|
|
|
| Primary | Endogenous Thrombin Potential | An established measure of coagulation status and is the best method to measure thrombin generation. It directly measures the amount of thrombin generation over time capturing the effects of natural (i.e., subject's coagulation status) and pharmacological (e.g., enoxaparin) pro- and anticoagulants. Endogenous thrombin potential is measured using thrombin generation assay. | The numbers analyzed on the day after CVC insertion and four days after CVC insertion differ from the overall number of participants. Participants were excluded if the CVC was removed or if blood was not drawn. | Posted | Median | Inter-Quartile Range | Nanomolar-minute (nM.min) | Day of, day after and day 4 after insertion of the CVC |
|
|
|
|
| Secondary | Number With Other Thromboembolic Events | Thrombus in the deep vein of any extremity or PE that is clinically suspected then confirmed radiologically, an incidental radiologic finding, excluding DVT diagnosed with the study-related active surveillance ultrasound | Posted | Count of Participants | Participants | Up to removal of CVC, an average of 6 days |
|
|
|
|
| Secondary | Length of Stay in the Pediatric Intensive Care Unit in Days | Duration of stay in the pediatric intensive care unit from the day of enrollment | Posted | Median | Inter-Quartile Range | days | Up to day of discharge from the pediatric intensive care unit, an average of 10 days |
|
|
|
|
| Secondary | Length of Stay in the Hospital | Duration of stay in the hospital from the day of enrollment | Posted | Median | Inter-Quartile Range | days | Up to day of discharge from the hospital, an average of 18 days |
|
|
|
|
| Secondary | Number With Clinically Relevant Bleeding | Bleeding that is fatal, associated with a decrease in hemoglobin by ≥2 g/dl in 24 hours, requires medical or surgical intervention to restore hemostasis, or is in the retroperitoneum, pulmonary, intracranial or central nervous system as defined by International Society of Thrombosis and Haemostasis | Posted | Count of Participants | Participants | Up to 30 hours after the last enoxaparin dose |
|
|
|
|
| Secondary | Number With Laboratory Confirmed Heparin-induced Thrombocytopenia | Heparin-induced thrombocytopenia that is diagnosed with a positive serotonin release assay | None of the participants experienced this outcome; hence, a statistical analysis was not performed. | Posted | Count of Participants | Participants | Up to removal of CVC, an average of 6 days |
|
|
|
| Secondary | Number of Mortality | In-hospital mortality during the subject's admission | Posted | Count of Participants | Participants | Up to day of discharge from the hospital, average of 18 days |
|
|
|
|
| Secondary | Number of Enrolled Eligible Children | Number of eligible children enrolled in the study. | Posted | Count of Participants | Participants | Up to 24 hours after insertion of CVC |
|
|
|
| Secondary | Time to 1st Dose of Enoxaparin | Time to first dose of enoxaparin | Posted | Median | Inter-Quartile Range | hours from insertion of CVC | Up to 48 hours after insertion of CVC |
|
|
|
| Secondary | Time to Target Anti-Xa Activity | Time from insertion of the CVC to time that anti-Xa activity was within 0.2-0.5 IU/mL. | This outcome measure is only applicable to subjects in the enoxaparin arm because the control arm did not receive enoxaparin for which anti-Xa activity is used to titrate the dose. Only 12 participants in the enoxaparin arm achieved the target anti-Xa activity. | Posted | Median | Inter-Quartile Range | hours from insertion of CVC | Up to removal of CVC, an average of 6 days |
|
|
|
| Secondary | Number of Missed Doses of Enoxaparin | Number of doses of enoxaparin that were not administered. This outcome measure was only applicable to the enoxaparin arm. | Posted | Number | Doses of enoxaparin | Up to removal of CVC, an average of 6 days | Doses | Doses |
|
|
|
| Secondary | Number of Children With Ultrasound | Number of children in whom ultrasound was not performed. | Posted | Count of Participants | Participants | Up to 24 hours after removal of CVC |
|
|
|
| 5 |
| 27 |
| 2 |
| 27 |
| 9 |
| 27 |
| EG001 | Control Arm | Participants randomized to the control arm will receive no 'placebo' intervention. | 2 | 24 | 0 | 24 | 6 | 24 |
| Cardiac arrest | Cardiac disorders | Non-systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Aspiration | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Edema trunk | General disorders | Non-systematic Assessment |
|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| General disorders and administration site conditions - Other, specify | General disorders | Non-systematic Assessment |
|
| Hematuria | Renal and urinary disorders | Non-systematic Assessment |
|
| Hypernatremia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypoalbuminemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypoglycemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypokalemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypophosphatemia | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Hypotension | Vascular disorders | Non-systematic Assessment |
|
| Oral hemorrhage | Gastrointestinal disorders | Non-systematic Assessment |
|
| Platelet count decreased | Investigations | Non-systematic Assessment |
|
| Seizure | Nervous system disorders | Non-systematic Assessment |
|
| Thromboembolic event | Vascular disorders | Non-systematic Assessment |
|
| Tracheitis | Infections and infestations | Non-systematic Assessment |
|
Not provided
Not provided
| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D013923 | Thromboembolism |
| D002241 |
| Carbohydrates |
| Day After CVC Insertion |
|
|
| Day 4 After CVC Insertion |
|
|