Conditions: Deep Venous Thrombosis
Keywords: child critical illness venous thromboembolism enoxaparin thrombin generation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: Participants randomized to the control arm will receive no 'placebo' intervention.

Interventions: intervention 1: Enoxaparin
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_001.pdf: 
STUDY PROTOCOL 
 
 
Title: Prevention of central venous catheter-associated thrombosis in critically 
ill children: A multicenter phase 2b trial. 
 
NCT Number: 03003390 
 
Date: August 22, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
STUDY TITLE:  Prevention of central venous catheter-associated thrombosis in critically 
ill children: A multicenter phase 2b trial. 
 
Collaborating Sites: St. Louis Children’s Hospital: Philip Spinella, PI 
Dell Children’s Medical Center of Central Texas: Renee Higgerson, PI 
 
 
  Children’s Hospital of Wisconsin: Sheila Hanson, PI 
 
 
  Maria Fareri Children’s Hospital: Simon Li, PI 
 
 
  Golisano Children’s Medical Center: Jill Cholette, PI 
  
 
ClinicalTrials.gov Identifier:  NCT03003390 
 
IND Number: 133096 
 
Investigational Product: Enoxaparin 
 
Yale Protocol Number: 1302011506 
 
Version and Date: V5 August 22, 2017  
 
 
 
Sponsor Principal Investigator:  
 
 
E. Vincent S. Faustino, MD, MHS 
333 Cedar Street P.O. Box 208064  
New Haven, CT 06520-8064 
 
203-785-4651 
Fax: 203-785-6925  
 
vince.faustino@yale.edu  
 
Study Biostatistician  
Marilyn Stolar, Ph.D. 
Yale Center for Analytical Sciences 
300 George Street, Ste 555  
New Haven, CT 06511  
203.737.8330 
marilyn.stolar@yale.edu 
 
Study Investigational Pharmacy Coordinator 
Asaad Awan, PharmD 
55 Park Street, LL – 15 
New Haven, CT 06511 
203-688-4872 
Fax:  203-688-4890 
asaad.awan@ynhh.org


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Version 5 August 22, 2017 
 
Table of Contents 
STUDY SCHEMA..........................................................................................................................5 
LIST OF ABBREVIATIONS ........................................................................................................6 
RATIONALE AND BACKGROUND ..........................................................................................7 
Disease ...............................................................................................................................7 
Clinical Trial Data ..............................................................................................................9 
Rationale for Trial and Selected Patients ....................................................................10 
STATEMENT OF PURPOSE/OBJECTIVES .........................................................................12 
Product Description .........................................................................................................13 
Pharmacokinetics ............................................................................................................13 
Metabolism .......................................................................................................................14 
Excretion ...........................................................................................................................14 
Drug Interactions .............................................................................................................14 
Drug Supply......................................................................................................................14 
Drug Dose ........................................................................................................................14 
Rationale for Dose Selection/Regimen ........................................................................15 
Reconstitution ..................................................................................................................15 
Storage and Stability Requirements .............................................................................15 
Handling ............................................................................................................................15 
Ordering ............................................................................................................................16 
Accountability ...................................................................................................................16 
Destruction .......................................................................................................................16 
Contraindications .............................................................................................................16 
Warnings and Precautions .............................................................................................17 
Adverse Reactions ..........................................................................................................17 
Study Population .............................................................................................................19 
Screening Procedures ....................................................................................................19 
Parental Permission and Assent Process ...................................................................20 
Study Entry/Registration ................................................................................................20 
RANDOMIZATION......................................................................................................................20 
TREATMENT REGIMEN WITH ENOXAPARIN ....................................................................22 
Discontinuing enoxaparin ...............................................................................................23 
Holding the Dose .............................................................................................................23 
Restarting the Dose ........................................................................................................24 
Safety Laboratory Procedures and Assessments ......................................................24 
Bleeding Assessment .....................................................................................................24 
Concomitant Medications ...............................................................................................24 


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Diet and Other Considerations ......................................................................................24 
Rescue Medication and Supportive Case ...................................................................24 
Duration of Therapy ........................................................................................................25 
OTHER STUDY PROCEDURES..............................................................................................26 
Physical Exam and Medical History .............................................................................26 
Ultrasound ........................................................................................................................26 
ASSESSING AND REPORTING ADVERSE EVENTS ........................................................27 
Definition ...........................................................................................................................27 
AE Expectedness ............................................................................................................28 
AE Attribution ...................................................................................................................28 
Procedure for Reporting Adverse Events ....................................................................29 
Adverse Event Committee (AEC) .................................................................................30 
Minimizing Risks ..............................................................................................................30 
CORRELATIVE SAMPLES ......................................................................................................32 
STATISTICAL CONSIDERATIONS ........................................................................................35 
DATA MANAGEMENT AND RECORD KEEPING ...............................................................37 
ADMINISTRATIVE AND REGULATORY ...............................................................................38 
Multicenter Management and Coordination ................................................................38 
Data safety and monitoring plan ...................................................................................38 
Quality Management / Monitoring .................................................................................40 
Project Team Meetings ..................................................................................................40 
TRIAL FLOW CHART ................................................................................................................42 
REFERENCES ............................................................................................................................43 
ACKNOWLEDGMENT OF THE INVESTIGATORS ..............................................................48 
APPENDIX I .................................................................................................................................49 
APPENDIX II ................................................................................................................................52 
APPENDIX III ...............................................................................................................................53 
 
 


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TRIAL SUMMARY 
 
Abbreviated Title 
Catheter-Related Early Thromboprophylaxis with Enoxaparin 
(CRETE) Trial 
Trial Phase 
2b 
Indication 
Critically ill children admitted to the pediatric ICU with a CVC 
Trial Type 
Double arm phase 2b 
Control 
Concurrent 
Product 
Enoxaparin 
Number of Subjects 
100 
Estimated Enrollment 
Period 
21 months 
Aims 
Aim 1 – To obtain preliminary evidence on the effect of early 
prophylaxis on the incidence of CADVT in critically ill children 
Aim 2 – To evaluate the effect of an anti-Xa activity-directed 
prophylactic strategy on thrombin generation in critically ill children 
Inclusion Criteria 
1. <24 hours after insertion of an untunneled CVC in the 
internal jugular or femoral vein  
2. Admitted to the ICU with an anticipated stay of ≥48 hours 
3. CVC 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. Admitted for trauma, or neurologic or spine surgery) 
5. <60 days from a clinically relevant bleeding as defined 
above  
6. <7 days after trauma or surgery 
7. Anticipated surgery within 48 hours after insertion of the 
CVC 
8. Renal failure (i.e., creatinine clearance <30 mL/min) 
Presence of epidural catheter  
9. Currently taking an antithrombotic agent (e.g., LMWH, 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 HIT (i.e., positive serotonin release assay)  


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13. Currently pregnant  
14. Currently lactating  
15. Prior enrollment in the study 
16. Limitation of care 
 
Treatment Plan 
Eligible subjects will be randomized 1:1 to treatment or control. In 
subjects randomized to treatment, noxaparin will be given within 
the first 24 hours after CVC insertion and then every 12 hours (+/-2 
hours) thereafter until removal of the CVC. Dosing will start at 0.75 
mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 30 mg) 
for older children and will be titrated to a target anti-Xa activity of 
0.2-0.5 IU/mL. Safety assessments for bleeding will be completed 
daily.  In subjects randomized to control, no placebo will be given. 


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STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>36 weeks corrected gestational age 
to <18 years old presenting in a 
participating pediatric ICU with CVC 
inserted <24 hours ago 
Screen patient for eligibility 
Obtain parental permission/assent 
Randomize 1:1 to  
treatment vs. control 
TREATMENT: 
Administer enoxaparin 
q12 hours until removal 
of CVC 
Measure anti-Xa 
activity 4-6 
hours after the 
3rd dose 
Efficacy, safety 
and compliance 
DVT in the site of insertion of the CVC confirmed by 
ultrasound <24 hours after the end of the study period 
CONTROL:  
No placebo 


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LIST OF ABBREVIATIONS 
 
AE – adverse event 
CADVT – catheter-associated deep venous thrombosis 
CAT - Calibrated Automated Thrombogram 
Co-I – co-investigator  
CRF – case report form 
CVC – central venous catheter 
DSMB – data and safety monitoring board 
DVT – deep venous thrombosis 
EDTA –ethylenediaminetetraacetic acid 
ETP – endogenous thrombin potential 
FDA – Food and Drug Administration 
Hb – hemoglobin 
HIPAA – Health Insurance Portability and Accountability Act 
HIT – heparin-induced thrombocytopenia 
ICU – intensive care unit 
IL – interleukin  
IP – Investigational Product 
IRB – institutional review board 
LMWH – low molecular weight heparin 
MCU – Multicenter Unit 
NDA – new drug application 
PI – principal investigator 
PROTEKT – Prophylaxis of Thromboembolism in Kids Trial 
RCT – randomized controlled trial 
RLD – reference listed drug 
UFH – unfractionated heparin 
SAE – serious adverse event 
SD – standard deviation 
TFPI – tissue factor pathway inhibitor 
UFH – unfractionated heparin 
USP – U.S. Pharmacopeia 
YCCI – Yale Center for Clinical Investigation 
 
 


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RATIONALE AND BACKGROUND 
 
Disease 
 
DVT, a potentially preventable pediatric condition, is associated with nearly $400 million 
of excess cost in children in the United States annually. Excess inpatient stay accounts 
for $200 million and another $200 million are needed to treat DVT and its complications 
outpatient.1, 2 Co-I Raffini reported an annual 10% increase in the incidence of DVT in 
children suggesting that the cost of DVT is expected to increase if it is not prevented.3  
 
Critical illness and CVC are the most important risk factors for DVT in children.4 Each 
increases the risk of DVT at least 2-fold. In our recent meta-analysis of 11 studies in 
which 676 critically ill children with untunneled CVC, the most commonly used type, 
were actively surveilled radiologically, we showed that the frequency of CADVT was 
0.18 (95% CI: 0.12-0.25).5 In children, >85% of DVT and nearly all DVT-related deaths 
are related to CVC.6, 7 PI Faustino has shown that children with symptomatic CADVT, 
on average, stay in the ICU in excess of 16 days, significantly increasing their cost of 
care.8 Even when not symptomatic, DVT is associated with significant morbidity and 
mortality. Nearly 50% of cases of pulmonary embolism in children are from 
asymptomatic DVT and 83% of cases of pulmonary embolism in children that 
contributed to death did not have symptoms.9, 10 CADVT also serves as a nidus of 
infection increasing the risk of catheter-associated bloodstream infection at least 3-
fold.11 
 
Data from adults should not be generalized to children. In the absence of well-
conducted pediatric RCTs, prophylaxis against CADVT is not recommended in 
children.12 The recommendation in critically ill adults, >85% of whom have CVC, to 
provide prophylaxis against DVT should not be applied to children because the 
hemostatic system evolves with age affecting the risk of DVT and anticoagulant 
effects.12-14 Co-morbidities and 
medications, which differ between 
children and adults, affect hemostasis 
and the effects of prophylaxis. 
Smaller veins in children, vs. adults, 
likely increase the risk of CADVT. 
Well-conducted pivotal trials are 
urgently needed to determine whether 
prophylaxis can safely prevent 
CADVT in critically ill children. 
However, timing and extent of 
reduction in thrombin generation 
needed to safely prevent CADVT in 
children are unclear. The goal of this 
trial is to explore the efficacy of early 
prophylaxis against CADVT in 
Figure 1. Central role of thrombin in coagulation. → 
stimulate; → inhibit. 


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Version 5 August 22, 2017 
critically ill children. 
 
Reduction of thrombin generation is biochemically the goal of prophylaxis. All 
known drugs that reduce thrombin generation have an antithrombotic effect regardless 
of their mode of action.15 Endothelial injury while inserting a CVC increases thrombin 
generation through factor Xa (Figure 1).16 Thrombin produces fibrin, and activates 
platelets and other coagulation factors, particularly factor VIIIa, to amplify thrombin 
generation. The result is a mesh of fibrin and platelets than can lead to CADVT. It is 
logical that prophylaxis should be started soon after insertion of the CVC to maximize 
the likelihood of preventing CADVT because it would reduce thrombin generation.  
 
Enoxaparin has become the “standard” anticoagulant for prophylaxis in children despite 
the lack of conclusive data.12, 17 Like other LMWH, it reduces thrombin generation by 
inhibiting factor Xa (Figure 1).  
 
Timing of prophylaxis against CADVT is unclear. The natural history of CADVT 
suggests that prophylaxis should be started <24 hours after insertion of the CVC 
because, although CADVT develops in <2.5% of critically ill children at this time, nearly 
all CADVT have developed by 4 days after insertion of the CVC.18 The PROTEKT trial 
studied reviparin, a LMWH.19 It is the largest trial of prophylaxis against CADVT in 
children (186 children from 20 centers) though it was stopped early due to poor 
enrollment. The risk ratio of CADVT with reviparin vs. placebo was 1.2 (95% CI: 0.4-
3.2). Reviparin was started late at a mean of 2.6 days after insertion of the CVC when 
nearly 50% of the CADVT would have already developed.19, 20 In contrast, a cohort 
study of children with leukemia showed that enoxaparin given before inserting a CVC 
might reduce the risk of CADVT (risk ratio: 0.2; 95% CI: 0.03-1.1).21 This study supports 
the use of early prophylaxis though it may be biased because it only included 
symptomatic CADVT as outcome. Misclassification of cases may have occurred 
because symptoms of CADVT are difficult to detect in children.22 Before conducting a 
pivotal trial, it is essential to establish whether early prophylaxis may be effective 
against CADVT in critically ill children. 
 
Extent of reduction in thrombin generation needed to prevent CADVT is unknown. 
Based on limited evidence from adults, prophylaxis with LMWH is dosed to an anti-Xa 
activity of 0.2-0.5 IU/mL.12, 23 Although anti-Xa activity is the current standard for 
monitoring the effect of LMWH, studies suggest that anti-Xa activity weakly correlates 
with clinical outcome. Anti-Xa activity does not account for LMWH’s effect on thrombin 
generation through its actions on thrombin (i.e., anti-IIa activity) and TFPI, and the 
subject’s coagulation status (Figure 1).23-27  
 
ETP is the best measure of thrombin generation among all currently available 
measures.27 Using a chromogenic or fluorogenic assay, thrombin generation is triggered 
in vitro in the patient’s plasma by tissue factor.28 ETP is a direct measure of the total 
amount of thrombin generated over time and includes all biologic effects on thrombin 
generation, i.e., natural and pharmacologic pro- and anticoagulants, occurring in the 


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patient.27 Other available markers of thrombin generation, e.g., prothrombin fragment, 
thrombin-antithrombin complex, D-dimer and fibrin degradation products, do not 
accurately measure thrombin generation because their levels are influenced by factors 
other than thrombin generation, have very short half-lives, and provide limited 
assessment of thrombin generation.28, 29  
 
Studies on ETP and prophylaxis with LMWH are limited to non-critically ill adults. At 
doses proven to prevent DVT without increasing the risk of bleeding in women after 
Caesarian delivery and adults after arthroplasty, enoxaparin and other LMWH reduce 
ETP by 10% of pre-operative levels at 24 hours after the 1st dose.29, 30 The reduction in 
ETP is sustained for at least 4 days while on prophylaxis.31 These findings are 
corroborated by in vitro studies showing similar reductions in ETP after LMWH is added 
to plasma of healthy volunteers.32 In these non-critically ill adults, prophylactic doses of 
enoxaparin reduce ETP from 1630 nM.min to 543 nM.min.26 This level of anticoagulation 
is considered effective in preventing DVT (<700 nM.min) and safe in avoiding clinically 
relevant bleeding (>300 nM.min).15  
 
Although a reduction in ETP mediates the prevention of DVT in non-critically ill adults, it 
is unclear whether this is also true in critically ill children because thrombin generation 
increases with age and critical illness.15, 33 High levels of factor VIIIa, IL-6 and IL-8 
during critical illness increase thrombin generation and may explain the increased risk of 
DVT with trauma, cancer, cardiac disease, systemic infection, or after surgery (Figure 
1).34-38 Before a pivotal trial of prophylaxis against CADVT is conducted, it is essential to 
determine the extent to which current dosing of enoxaparin reduces thrombin 
generation. 
 
Clinical Trial Data 
 
Prophylaxis in critically ill children. PI Faustino, co-PI Spinella and Site PIs 
Higgerson, Hanson, Li and Cholette conducted a cross-sectional study of prophylaxis in 
critically ill children.17, 39 Of 2,484 children from 59 pediatric ICUs in 7 countries, 53% 
had ≥1 CVC with the untunneled type being most common (45%). Nearly 90% of the 
untunneled CVC were inserted in the internal jugular or femoral vein. Only 27% of those 
with untunneled CVC received anticoagulation, with enoxaparin as the most commonly 
used agent.  
 
Frequency of CADVT in critically ill children. In 2 prospective cohort studies, PI 
Faustino and co-PI Spinella enrolled 69% of 284 critically ill children <24 hours after 
insertion of an untunneled CVC over 34 months.40, 41 The frequency of ultrasound-
diagnosed CADVT was 0.30 (95% CI: 0.23-0.37). Due to unexpected death or transfer, 
4% of children did not have ultrasound. Co-I Silva led a team of pediatric radiologists 
that centrally and blindly reviewed all images. Between radiologists, chance-corrected 
agreement was 0.77.42 Mean catheterization was 6 days (standard deviation [SD]: 5 
days), which was similar between those with and without CADVT. 
 


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Bleeding assessment tool. PI Faustino recently completed the development of a web-
based bleeding assessment tool that operationalizes 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; admitted for trauma, or neurologic or spine surgery).22 Using 
medical records of 35 children admitted to the ICU with a diagnosis of bleeding, 4 
physicians blindly and independently determined the presence of clinically relevant 
bleeding. Using the tool, the chance corrected agreement between physicians was 0.82. 
 
ETP and anti-Xa activity in critically ill children. Co-PI Spinella analyzed ETP and 
anti-Xa activity in 9 samples of platelet-poor plasma from 4 critically ill children on 
heparin. ETP was measured with the CAT (Thrombinoscope, Netherlands) using 1 pM 
of tissue factor to trigger thrombin generation. Anti-Xa activity was measured using 
STA® Liquid Anti-Xa assay in the fully automated STA® analyzer (Diagnostica Stago 
S.A.S., France). The mean (SD) of ETP was 394 (326) nM.min and that for anti-Xa 
activity was 0.3 (0.2) IU/mL. The intra- and inter-individual correlation coefficients 
between ETP and anti-Xa activity were −0.59 and −0.51, respectively. 
 
Biomarkers of inflammation in critically ill children. In a prospective cohort study, PI 
Faustino measured plasma factor VIIIa after insertion of an untunneled CVC in 85 
critically ill children.41 Factor VIIIa was measured at the Clinical Laboratory at Yale-New 
Haven Hospital with a 1-stage clotting assay (Dade® Actin® FSL, Siemens Healthcare) 
using the BCS XP System (Siemens Healthcare, Germany). Mean (SD) of factor VIIIa 
was 133 (61) IU/dL. The incidence of CADVT doubled (95% CI: 1.1-3.6) for every SD 
increase in factor VIIIa. 
 
PI Faustino measured IL-6 and IL-8 in platelet-poor plasma from 10 critically ill 
adolescents using Milliplex® MAP kits and the Millipore Luminex 200 System (EMD 
Millipore Corp., Germany) located at the Immune Monitoring Core Facility at Yale. Mean 
(SD) of IL-6 was 129 (199) pg/mL and 97 (161) pg/mL for IL-8.  
 
Rationale for Trial and Selected Patients 
 
CADVT is a significant problem in critically ill children. It occurs in 18% of children with 
untunneled CVC and is associated with adverse outcomes.5 These outcomes include 
prolonged stay in the ICU, increased risks of catheter-associated bloodstream infection, 
pulmonary embolism, and mortality, and increased costs of care.1, 2, 6, 7, 9-11 Despite the 
adverse outcomes associated with CADVT, prophylaxis is not recommended in children 
because of the absence of data on its efficacy in preventing CADVT in children.5 The 
recommendation to provide prophylaxis in critically ill adults should not be routinely 
applied to children because of differences in the hemostatic system between these age 
groups.12 This trial will explore the efficacy of early prophylaxis against CADVT in 
critically ill children.  
 
We will enroll children >36 weeks corrected gestational age to <18 years old. This age 


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range represents the patient population admitted to the pediatric ICU. PROTEKT 
enrolled children in the same age range.19 We will only enroll children with untunneled 
CVC, the most common type used in critically ill children, to minimize confounding 
based on type of CVC.5 Only children with CVC in the internal jugular or femoral veins 
will be eligible to minimize bias related to the accuracy of ultrasound in diagnosing 
CADVT.22 We will exclude children at high risk of bleeding such as those with 
coagulopathy, known bleeding disorder, recent history of clinically relevant bleeding, 
surgery or trauma, in renal failure, or those on another antithrombotic agent, to minimize 
the risk of bleeding. 
 
Bidlingmaier et al conducted the most comprehensive literature review of the safety and 
efficacy of LMWH in children up to 18 years old.43 They reviewed 8 studies in which 
LWMH was used as prophylaxis against DVT. Of 305 children analyzed, only 7 (2.3%) 
developed DVT and 7 (2.3%) had clinically relevant bleeding while on the drug. 
 
Recently, co-I Raffini studied enoxaparin as prophylaxis against DVT that was not 
associated with a CVC in critically ill adolescents as part of a quality improvement 
initiative.6 Enoxaparin was given subcutaneously every 12 hours at 0.5 mg/kg 
(maximum of 30 mg). No DVT that was not associated with a CVC and no clinically 
relevant bleeding occurred in 90 adolescents in the study 
 
 
 


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STATEMENT OF PURPOSE/OBJECTIVES 
 
Aim 1: To obtain preliminary evidence on the effect of early prophylaxis on the 
incidence of CADVT in critically ill children.  
 
Hypothesis – Among critically ill children, prophylaxis administered <24 hours after 
insertion of the CVC decreases the incidence of ultrasound-diagnosed CADVT 
compared with no prophylaxis. The natural history of CADVT in children suggest that 
prophylaxis needs to be administered <24 hours after the insertion of the CVC to 
maximize the likelihood of preventing CADVT.18, 19, 21  
 
Aim 2: To evaluate the effect of an anti-Xa activity-directed prophylactic strategy on 
thrombin generation in critically ill children 
 
Hypothesis –Among critically ill children, standard prophylactic dose of enoxaparin 
adjusted by anti-Xa activity reduces thrombin generation to <700 nM.min, as measured 
by ETP. In non-critically ill adults, prophylactic dose of enoxaparin proven to prevent 
DVT reduces ETP to <700 nM.min.15, 26 
 
 
 


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PHARMACEUTICAL AND THERAPEUTIC BACKGROUND 
 
Product Description  
 
Enoxaparin is a LMWH produced from UFH that exerts its anticoagulant effects by 
binding to and inducing a conformational change in antithrombin to accelerate the 
inactivation of factor Xa and thrombin.12, 44 Enoxaparin is the most commonly used 
thromboprophylactic agent in adults and children. It is equipotent with other LMWH. In 
contrast to UFH, enoxaparin has significantly greater inhibitory activity against factor Xa 
and has lower risk of bleeding and HIT. It has good bioavailability with predictable 
pharmacokinetics requiring less monitoring compared with UFH.  
 
Lovenox® (enoxaparin sodium injection, Aventis Pharmaceuticals Inc.) was initially 
approved in the United States in 1993 for prophylaxis of DVT, and inpatient and 
outpatient treatment of acute DVT.45 FDA approved the generic version of Lovenox® in 
July 2010. Both approvals were for use in adults only. In double blind multicenter RCTs, 
enoxaparin was shown to be superior to placebo in preventing DVT in adults recovering 
from hip or knee replacement surgery (10-11% with enoxaparin vs. 46-62% with 
placebo) and in acutely ill medical patients (4.4% with enoxaparin vs. 11.3% with 
placebo).45 The drug was not inferior to UFH in preventing DVT in adults recovering 
from abdominal surgery (7.0-9.7% with enoxaparin vs. 6.5-10.9% with UFH).45 Similar 
efficacy data is not available in children although the incidence of DVT of 4.7-5.2% in 
children receiving prophylactic doses of LMWH suggests that the drug is also 
efficacious in children.43 
 
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester 
derived from porcine intestinal mucosa.45 Its structure is characterized by a 2-O-sulfo-4 
enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-
glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 
25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing 
end of the polysaccharide chain. The drug substance is the sodium salt. The average 
molecular weight is about 4.5 kDa. The molecular weight distribution is <2 kDa (20%), 2 
kDa to 8 kDa (68%), and >8 kDa (18%).  
 
Pharmacokinetics 
 
Maximum anti-Xa and anti-IIa activities occur 3 to 5 hours after subcutaneous injection 
of enoxaparin in adults.45 Mean peak anti-Xa activity was 0.16 IU/mL (1.58 µg/mL) and 
0.38 IU/mL (3.83 µg/mL) after the 20 mg and the 40 mg clinically tested subcutaneous 
doses, respectively. Mean (n = 46) peak anti-Xa activity was 1.1 IU/mL at steady state 
in patients with unstable angina receiving 1 mg/kg subcutaneous every 12 hours for 14 
days. Mean absolute bioavailability of enoxaparin, after 1.5 mg/kg given 
subcutaneously, based on anti-Xa activity is approximately 100% in healthy adult 
volunteers. After repeated subcutaneous administration of 40 mg once daily and 1.5 
mg/kg once-daily regimens in healthy adult volunteers, the steady state is reached on 


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day 2 with an average exposure ratio of about 15% higher than after a single dose. 
Steady-state enoxaparin activity levels are well predicted by single-dose 
pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice 
daily regimen, the steady state is reached from day 4 with mean exposure about 65% 
higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 
IU/mL, respectively. Based on enoxaparin sodium pharmacokinetics, this difference in 
steady state is expected and within the therapeutic range.  
 
Metabolism 
 
Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or 
depolymerization to lower molecular weight species with much reduced biological 
potency.45  Renal clearance of active fragments represents about 10% of the 
administered dose and total renal excretion of active and non-active fragments 40% of 
the dose. 
 
Excretion 
 
Following intravenous dosing, the total body clearance of enoxaparin is 26 mL/min.45 
After intravenous dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 40% of 
radioactivity and 8 to 20% of anti-Xa activity were recovered in urine in 24 hours. 
Elimination half-life based on anti-Xa activity was 4.5 hours after a single subcutaneous 
dose to about 7 hours after repeated dosing. Following a 40 mg subcutaneously once a 
day dose, significant anti-Xa activity persists in plasma for about 12 hours. Following 
subcutaneous dosing, the apparent clearance of enoxaparin is approximately 15 
mL/min 
 
Drug Interactions 
 
Unless really needed, agents which may enhance the risk of hemorrhage should be 
discontinued prior to initiation of Lovenox Injection therapy. These agents include 
medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, 
salicylates. If co-administration is essential, conduct close clinical and laboratory 
monitoring. 
 
Drug Supply 
 
Specific manufacturer/supplier of Enoxaparin Sodium Injection, USP is up to the 
discretion of the participating site as long as the product’s FDA application has NDA 
020164 as the RLD. 
 
Drug Dose 
 
For prophylaxis, enoxaparin is started at 0.75 mg/kg subcutaneously every 12 hours for 
children ≤2 months old or 0.5 mg/kg (maximum dose of 30 mg) subcutaneously every 


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Version 5 August 22, 2017 
12 hours for children >2 months old.12, 23 The dose is adjusted to a target anti-Xa activity 
of 0.2-0.5 IU/mL.23, 46, 47 In the absence of prior trials in children, the same target anti-Xa 
activity recommended in adults will be used in this trial.23 Among post-operative 
orthopedic patients on prophylactic dose of LMWH, the mean peak anti-Xa activity on 
Days 1, 3, 4 and 10 were 0.29, 0.25, 0.33 and 0.37 IU/mL. In acutely ill medical 
patients, the prophylactic dose of LMWH achieved anti-Xa activity of 0.21 to 0.41 IU/mL. 
Dose calculations are completed per local standards.  An example dose calculation 
work sheet is provided in Appendix 2.   
 
Rationale for Dose Selection/Regimen 
 
The selection of doses to be used in this trial is based on commonly used doses for the 
drug.17 When prescribing enoxaparin in children as prophylaxis against DVT, the 
starting dose is typically 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum 
of 30 mg) for older children. The present trial will utilize this dose as a starting point 
because of the proven tolerability in clinical care. The maximum dose is based on FDA-
approved doses in adults. At these doses, enoxaparin has been shown to be safe 
without any significant increase in the risk of clinically relevant bleeding.43   
 
Reconstitution 
 
Dilute Enoxaparin Sodium Injection, USP with sterile water for injection or normal saline. 
Draw up the appropriate dose in a polypropylene plastic tuberculin syringe sealed with a 
rubber tip cap.  
 
Storage and Stability Requirements 
 
Enoxaparin should not be stored above 25oC and should not be frozen.45 When stored 
at 20oC to 22oC, enoxaparin, 1.2 mg/ml in normal saline, was stable for up to 48 hours. 
Enoxaparin when repackaged from commercial 0.3 mg syringes of enoxaparin, 100 
mg/mL, into tuberculin syringes retained activity and sterility and remained pyrogen free 
for up to 10 days at 3oC. Undiluted enoxaparin lost activity within 2 days at 22oC. 
Enoxaparin diluted with sterile water for injection to 20 mg/ml, and stored at room 
temperature or under refrigeration, was stable for up to 4 weeks in glass or prefilled 
syringes, as measured by anti-Xa activity. 
 
Handling  
 
Enoxaparin must be handled and administered according to the local study site’s  
regulations for the handling and administration of these products. The product storage  
manager should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by the  
sponsor. If concerns regarding the quality or appearance of the study drug arise, do not  
dispense the study drug and contact the sponsor immediately. Used (and/or empty)  
syringes of enoxaparin will be destroyed locally. The method of destruction will be  


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Version 5 August 22, 2017 
reported on the Drug Destruction Form filed in the pharmacy/investigator site file.  
Unused syringes will be destroyed locally per local policy.  
 
Availability  
  
Enoxaparin will be ordered directly by each participating site’s investigational pharmacy 
and shipped directly to each investigational pharmacy.  
 
Ordering 
 
Commercially available product will be shipped to the investigational pharmacies and  
over labeled as an IP.  The label will include sponsor name, address and telephone 
number, the protocol number, IP name, dosage form and strength (where applicable), 
amount of IP per container, lot number, expiration date (where applicable), medication 
identification/kit number, dosage instructions, storage conditions, and required caution 
statements and/or regulatory statements as applicable, as per local regulations. 
Additional information may be included on the label as applicable per local regulations.  
 
Accountability 
 
Only the pharmacist or designee will dispose study drug. A record of drug dispensed 
and administered to each patient must be maintained. The pharmacist will document the 
dose dispensed in the appropriate study records which will be reviewed during 
monitoring visits. In addition, the pharmacist needs to maintain an inventory log of all IP 
delivered, stored, dispensed and destroyed at the site (including expiry date and batch 
number). 
 
The investigational drug accountability record (see Pharmacy Manual) must be 
completed with permanent ink. Errors cannot be covered up with scratch outs or 
correction fluid. Cross through any errors with a single pen stroke. Initial and date the 
crossed-out errors 
 
Destruction 
 
The sponsor (or designee) will review with the investigator and relevant site personnel 
the procedures for documenting receipt of IP, as well as the procedures for counting, 
reconciling IP, and documenting this process. Used (and/or empty) syringes of 
enoxaparin will be destroyed locally. Unused syringes will be destroyed locally after 
sponsor’s approval for destruction. Documentation of all used and unused drug disposal 
must be maintained on site for review during monitoring visits. 
 
Contraindications 
 
Enoxaparin is contraindicated in patients with active major bleeding, in patients with 
thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the 


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Version 5 August 22, 2017 
presence of enoxaparin sodium, or in patients with hypersensitivity to enoxaparin 
sodium. Patients with known hypersensitivity to heparin or pork products should not be 
treated with enoxaparin or any of its constituents. 
 
Warnings and Precautions 
 
Enoxaparin is not intended for intramuscular administration. Enoxaparin cannot be used 
interchangeably (unit for unit) with UFH or other LMWH as they differ in manufacturing 
process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. 
Each of these medicines has its own instructions for use. Enoxaparin should be used 
with extreme caution in patients with a history of HIT. Please refer to package insert for 
additional information.  
 
Hemorrhage. Enoxaparin, like other anticoagulants, should be used with extreme 
caution in conditions with increased risk of hemorrhage. Cases of epidural or spinal 
hematomas have been reported with the associated use of enoxaparin and 
spinal/epidural anesthesia or spinal puncture resulting in long-term or permanent 
paralysis.  
 
Major hemorrhages including retroperitoneal and intracranial bleeding have been 
reported. Some of these cases have been fatal. Bleeding can occur at any site during 
therapy with enoxaparin. An unexplained fall in hematocrit or blood pressure should 
lead to a search for a bleeding site. 
 
Thrombocytopenia. Thrombocytopenia can occur with the administration of 
enoxaparin in adults. Moderate thrombocytopenia (platelet counts between 
100,000/mm3 and 50,000/mm3) occurred at a rate of 1.3% in patients given enoxaparin, 
1.2% in adults given UFH, and 0.7% in adults given placebo in clinical trials.45 Platelet 
counts less than 50,000/mm3 occurred at a rate of 0.1% in adults given enoxaparin, in 
0.2% of adults given UFH, and 0.4% of adults given placebo in the same trials. 
Thrombocytopenia of any degree should be monitored closely. Cases of HIT with 
thrombosis have also been observed in clinical practice.  
 
Elevations of serum aminotransferases. Asymptomatic increase in aspartate and 
alanine aminotransferase levels greater than 3x the upper limit of normal of the 
laboratory reference range have been reported in up to 6.1% and 5.9% of patients, 
respectively, during treatment with enoxaparin. 
 
Adverse Reactions 
 
Hemorrhage. The incidence of major hemorrhagic complications with enoxaparin 
treatment has been low. 
 
Local Reactions. Mild local irritation, pain, hematoma, ecchymosis, and erythema may 
follow subcutaneous injection of enoxaparin. 


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Version 5 August 22, 2017 
 
Other Reactions. Diarrhea and nausea have also been reported with enoxaparin 
treatment. 
 
 
 


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STUDY PLAN AND PROCEDURES 
 
Study Population 
 
We will enroll 100 critically ill children between the ages >36 weeks corrected gestation 
age and <18 years admitted to the pediatric ICUs of the six participating sites and with a 
CVC.   
 
Screening Procedures 
 
Subjects will be identified through regular clinical care in the pediatric ICU by the 
participating investigators and research staff. All children who had a CVC inserted within 
the prior 24 hours will be included in a screening log maintained in the pediatric ICU at 
each site. The screening log will be used to identify potential study participants to be 
screened for eligibility, record the number of eligible, and ineligible children and reason 
for exclusion. Eligible children who were not enrolled will also be captured in this log 
and the reason they were not enrolled (parental refusal, time, etc.). It will also track 
those children who were eligible and consented but not treated. Treatment with 
enoxaparin needs to be started within 24 hours after insertion of the CVC, therefore 
children can be screened for study if CVC insertion occurred within 24 hours of 
admission to the pediatric ICU or during their stay in the ICU.  If a child meets all 
eligibility criteria, parental permission/assent will be obtained. 
 
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 ICU ≥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) 


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Version 5 August 22, 2017 
8. Presence of epidural catheter  
9. Currently taking an antithrombotic agent (e.g., LMWH, UFH at therapeutic 
doses, Coumadin and 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 HIT (i.e., positive serotonin release assay)  
13. Currently pregnant  
14. Currently lactating  
15. Prior enrollment in the study 
16. Limitation of care 
 
Parental Permission and Assent Process 
 
Parents or guardians of eligible children will be approached for permission to participate 
in the trial. Assent from children aged 7-17 years old, when feasible will be obtained as 
required per local site IRB policy. Research staff and investigators permitted to consent 
parents will describe the trial in detail including the data collection requirements, risks, 
procedures, and alternative treatments. Parents will be made aware that they are under 
no obligation to allow their child to participate, that failure to participate will not 
adversely affect their child’s care, and that they may withdraw permission for 
participation at any time. Data will continue to be collected until the parents withdraw 
permission to use it. They will be given an opportunity to ask questions and have these 
answered to their satisfaction. The parental permission form will then be signed and 
dated by both the parent and the study personnel obtaining consent. If there are any 
questions regarding parental/guardian competence, the trial will not be offered to the 
patient. The Consent and Assent process will be documented in the medical record per 
local site policy. 
 
Study Entry/Registration 
 
Eligibility will be determined locally by the site PI and/or research team using an 
eligibility checklist. Once a child is confirmed eligible and parental permission is 
obtained, the child will be assigned a unique study ID. A list of study IDs will be provided 
to each site at start-up and assigned to each enrolled child consecutively. The study ID 
will be used when the child is registered into OnCore, Yale’s Clinical Trials Management 
System and included on all correlative lab samples and related study documents. 
Subjects will be entered into OnCore by the local site data manager.  
 
Randomization 
 
Eligible subjects will be randomized 1:1 to treatment vs. control using a permuted block 
design with variable block sizes that will be developed by the data coordinating center. 
Randomization will be stratified by ICU and age (i.e., <1 year, 1-13 years and >13 
years) to reflect the known epidemiology of DVT in children.3, 48 Randomization will 


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Version 5 August 22, 2017 
occur at the time of registration into OnCore. The computerized randomization scheme 
will be entered in OnCore, such that allocation will only be known after the subject is 
registered.  
 
Subjects randomized to the treatment arm will receive enoxaparin adjusted to the target 
anti-Xa activity. Subjects randomized to the control arm will not receive placebo 
because of ethical concerns of inducing pain with subcutaneous administration without 
any potential for direct benefit. All subjects in the study will undergo the remaining study 
procedures. 
 
 


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Version 5 August 22, 2017 
TREATMENT REGIMEN WITH ENOXAPARIN 
 
The 1st dose of enoxaparin be given <24 hours after insertion of the CVC. The initial 
dose will be 0.75 mg/kg for children ≤2 months old or 0.5 mg/kg (maximum of 30 mg) for 
older children (Table 1). The initial dose will be doubled in obese children (refer to 
Appendix I and II) and halved in children with renal insufficiency (estimated creatinine 
clearance calculated by the Schwartz equation <75 mL/min/1.73 m2).49. The clinical 
nurse will give enoxaparin subcutaneously every 12±2 hours after the first dose until 
removal of the CVC, or earlier upon discharge from the ICU, radiologic diagnosis of 
CADVT, start of therapeutic anticoagulation, clinically relevant bleeding develops, HIT is 
diagnosed, or 28 days after insertion of the CVC. 
 
Administration 
 
Route. Enoxaparin is to be administered by subcutaneous route per local site clinical 
procedures. 
 
Site. In children <10 kg or <1 year of age, the thigh is the preferred site of 
administration. Alternate between the left and right thigh. In children ≥10 kg or ≥1 year 
of age, the abdomen is the preferred site. For children who do not have sufficient 
subcutaneous tissue in the abdomen, the anterolateral thigh may be used as secondary 
site for administration.   
 
Table 1: Initial dose 
Age 
Drug 
Dose/ 
Potency* 
Dose 
Frequency 
Route  
Regimen/ 
Treatment 
Period† 
Use 
Children 
≤2 mos. 
Enoxaparin 0.75 
mg/kg  
Q12 hours 
Subcutaneous Until CVC 
is 
removed 
Experimental 
Children 
>2 mos. 
Enoxaparin 0.5 mg/kg 
(maximum 
of 30 mg)  
Q12 hours 
Subcutaneous Until CVC 
is 
removed 
Experimental 
 
*The initial dose will be doubled in obese children (refer to Appendix I and II) and halved 
in children with renal insufficiency (estimated creatinine clearance calculated by the 
Schwartz equation <75 mL/min/1.73 m2).49 †Enoxaparin treatment will stop before the 
CVC is removed upon discharge from the ICU, radiologic diagnosis of CADVT, start of 
therapeutic anticoagulation, clinically relevant bleed develops, HIT is diagnosed, or 28 
days after insertion of the CVC, whichever comes first. 
 
Titrating dose 


23 
Version 5 August 22, 2017 
 
The dose of enoxaparin will be adjusted to a target anti-Xa activity of 0.2-0.5 IU/mL.23, 46, 
47 The target anti-Xa activity is a peak level and, therefore, timing is extremely 
important. The peak level must be drawn 4-6 hours after the dose is actually 
administered. If the child has other labs ordered which are not time dependent, the 
other labs should be drawn at the same time the enoxaparin peak level is needed. 
 
Using standard methods, anti-Xa activity will be measured 4-6 hours after a dose at the 
following time points: 
1. After the first 3 doses. If needed, the dose will be adjusted to achieve the 
target anti-Xa activity. See Table 2 for dose titration. 
2. After the 3rd dose of a dose titration until the target anti-Xa activity is reached. 
Once the anti-Xa activity is within target, the dose will be maintained.  See 
Table 2 for dose titration.  
3. Weekly to ensure adequate dosing. Similar dose titration as listed in Table 2 
will be done to achieve adequate dosing. 
 
Table 2: Enoxaparin Dosage Titration 
Anti-Xa Activity 
Enoxaparin Dose Titration 
Next Anti-Xa Activity Check 
<0.10 IU/mL 
Increase dose by 20% 
After 3rd dose.  
0.10-0.19 IU/mL 
Increase dose by 10%  
After 3rd dose.  
0.20-0.50 IU/mL 
Keep same dosage  
Weekly 
0.51-1.00 IU/mL 
Decrease dose by 10% 
After 3rd dose.  
>1.00 IU/mL 
Hold all doses until anti-Xa is 0.3, 
IU/mL, then decrease dose by 20% 
Before next dose and every 12 
hours, until anti-Xa <0.3 IU/mL 
 
 
  
(Modified from Monagle P, et al. Chest, 2001, 119:344S)50 
 
Discontinuing enoxaparin  
 
The child will be removed from the study and Enoxaparin will be discontinued for the 
purposes of the study if ANY the following occur: 
1. A clinically relevant bleeding event  
a. Drop in Hb of ≥2 g/dl in 24 hours 
b. Blood product transfused for the bleeding event 
c. Required medical or surgical intervention to restore hemostasis 
d. In a critical organ (i.e., retroperitoneum, pulmonary, intracranial or 
central nervous system) 
2. HIT is diagnosed (i.e., positive serotonin release assay) 
 
Holding the Dose 
 
Enoxaparin will be stopped temporarily if ANY the following occur  
1. Coagulopathy (i.e., international normalized ratio >2.0, activated partial 
thromboplastin time >50 seconds or platelet count <50,000/mm3) develops  


24 
Version 5 August 22, 2017 
2. 12 hours before surgery or invasive procedure  
3. In cases of suspected HIT (i.e., an unexplained decrease in platelet count 
<50,000/mm3 or by 50% of baseline value in the ICU). 
Another agent will not be used while enoxaparin is held. Activities related to the 
management of the dose of enoxaparin will be the purview of the study. However, the 
clinical care of the child remains with the treating physician.  
 
Restarting the Dose 
 
Timing for restarting treatment 
1. 24 hours after coagulopathy is corrected  
2. 24 hours after surgery or procedure 
3. After exclusion of HIT (i.e., negative serotonin release assay) 
 
Safety Laboratory Procedures and Assessments 
 
Complete blood count, renal function tests (BUN and creatinine), and serum 
aminotransferases will be done within 48 hours of enrollment and at least weekly±2 
days, thereafter. An unexplained decrease in platelet count <50,000/mm3 or by 50% of 
baseline value in the ICU will trigger a work up for HIT (i.e., send blood for serotonin 
release assay). Stool occult bleed will be done if clinically indicated as determined by 
the local investigator.  
 
Bleeding Assessment  
 
Bleeding assessments will be completed by the site study team on a daily basis. The 
team will interview the clinical care team and review the medical records for the 
presence of a bleed. The Bleeding Assessment Tool (Appendix III) will be completed for 
each episode of bleeding. This tool contains questions regarding the site, severity and 
timing of bleeding.  
 
Concomitant Medications 
 
Antithrombotic agents, including other LMWH, UFH at therapeutic doses, Coumadin 
and aspirin, are not allowed during the trial.  
 
Diet and Other Considerations 
 
There are no dietary or food restrictions with enoxaparin 
 
Rescue Medication and Supportive Case 
 
In case of a clinically relevant bleed, the clinical team will decide whether blood 
products should be administered. Protamine may also be used to control the bleeding. 
For suspected HIT, serotonin release assay will be done. Aside from stopping all 


25 
Version 5 August 22, 2017 
heparin or heparin-related products, no other therapies are needed for HIT. 
 
Duration of Therapy 
 
Enoxaparin will be administered every 12±2 hours until CVC removal, or earlier if the 
following occur: 
1. Discharge from the ICU  
2. Radiologic diagnosis of CADVT  
3. Start of therapeutic anticoagulation 
4. Clinically relevant bleed develops 
5. HIT is diagnosed 
6. 28 days after insertion of the CVC  
 
The child will be off treatment once any of these events occur. Children will be followed 
for adverse events for 30 hours after the last dose of enoxaparin in the trial. This time 
period corresponds to 5 half-lives of the drug.44 The child will be considered off study 
after this time period or after the study ultrasound (see below), whichever is later. 
 
 


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Version 5 August 22, 2017 
OTHER STUDY PROCEDURES 
 
Physical Exam and Medical History 
 
A physical exam of the arms or legs will be performed on all patients at time of 
enrollment and at the end of treatment. If patient has a CVC in the internal jugular vein, 
only arms need to be examined. If patient has a CVC in the femoral vein, only legs need 
to be examined. 
 
The following data collected at the time of admission to the PICU will be extracted from 
the patient chart and entered into OnCore; 
1. CVC characteristics such as time of insertion, length, post insertion 
interventions and vasopressors administered 
2. Components of the Pediatric Risk of Mortality 3 (PRISM 3) score  
3. Components of the Pediatric Index of Mortality 2 (PIM) score 
4. Patient characteristics including diagnosis, age weight, height, laboratory 
values, and personal or family history of venous thromboembolism 
 
Ultrasound 
 
Children in the trial will have an ultrasound of the site of insertion of the CVC within 24 
hours of removal of the CVC, or earlier upon 
1. Discharge from the ICU  
2. Radiologic diagnosis of CADVT  
3. Start of therapeutic anticoagulation 
4. Clinically relevant bleed develops 
5. HIT is diagnosed 
6. 28 days after insertion of the CVC  
 
The vein will be scanned proximal and distal to the site of insertion. Images in the 
transverse and longitudinal planes, with and without compression, and with and without 
color Doppler will be acquired.42, 51 Co-I Silva will collaborate with certified sonographers 
from each ICU to maintain consistent imaging of the central veins. They will be blinded 
to study-related and clinical information for the trial. 
 
 
 


27 
Version 5 August 22, 2017 
ASSESSING AND REPORTING ADVERSE EVENTS 
 
Definition 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event 
can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product or protocol-specified procedure, whether or not considered 
related to the medicinal product or protocol-specified procedure.  Any worsening (i.e., 
any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of enoxaparin is also an adverse 
event. 
 
Adverse events may occur during the course of the use of the IP in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
Serious adverse event. A serious adverse event is an AE occurring during any study 
phase (i.e., treatment, follow-up), that fulfills one or more of the following criteria: 
1. Results in death 
2. Is immediately life-threatening 
3. Requires in-patient hospitalization or prolongation of existing hospitalization 
4. Results in persistent or significant disability or incapacity 
5. Results in a congenital abnormality or birth defect 
6. Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above 
 
Each AE will be graded for severity per the NCI CTCAE version 4.0, and these criteria 
must be used in grading the severity of AEs. The criteria can be found at: 
http://ctep.cancer.gov/reporting/ctc.html 
 
For those AEs, which are not listed as part of the NCI CTCAE version 4.0, the same 
grading system should be used, where:  
• Mild corresponds to an event not resulting in disability or incapacity and 
which resolves without intervention  
• Moderate corresponds to an event not resulting in disability or incapacity but 
which requires intervention  
• Severe corresponds to an event resulting in temporary disability or incapacity 
and which requires intervention  
• Life-threatening corresponds to an event in which the patient was at risk of 
death at the time of the event  
• Fatal corresponds to an event that results in the death of the patient  


28 
Version 5 August 22, 2017 
 
AE Expectedness 
 
AEs can be ‘Unexpected’ or ‘Expected’. Expected AEs include Bleeding development of 
HIT, pain from subcutaneous administration of the drug, and anemia from blood draws. 
 
Unexpected AEs are those AEs occurring in one or more patients participating in the 
research protocol, the nature, severity, or frequency of which is not consistent with 
either: 
• The known or foreseeable risk of AEs associated with the procedures 
involved in the research that are described in (a) the protocol-related 
document, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent 
document, and other relevant sources of information, such as product labeling 
and package inserts; or 
• The expected natural progression of any underlying disease, disorder, or 
condition of the patient(s) experiencing the AE and the patient’s predisposing 
risk factor profile for the AE. 
 
AE Attribution 
 
The participating site investigator must attempt to determine if an AE is in some way 
related to the use of the study drug and define an attribution category. This relationship 
should be described as follows: 
• Definite – The AE is clearly related to the study treatment. 
 
The event follows a reasonable temporal sequence from administration of the 
study drug, the event follows a known response pattern to the study drug and 
based on the known pharmacology of the study drug, the event is clearly 
related to the effect of the study drug. The AE improves upon discontinuation 
of the study drug and reappears upon repeat exposure. 
 
• Probable – The AE is likely related to the study treatment. 
 
The event follows a reasonable temporal sequence from administration of the 
study drug, the event follows a known response pattern to the study drug 
AND the event cannot have been reasonably explained by an intercurrent 
medical condition OR the event cannot be the effect of a concomitant 
medication. 
 
• Possible – The AE may be related to the study treatment. 
 
The event follows a reasonable temporal sequence from administration of the 
study drug and the event follows a known response pattern to the study drug 
BUT the event could have been produced by an intercurrent medical 


29 
Version 5 August 22, 2017 
condition which, based on the pathophysiology of the condition, and the 
pharmacology of the study drug, would be unlikely related to the use of the 
study drug OR the event could be the effect of a concomitant medication. 
 
• Unlikely – The AE is doubtfully related to the study treatment. 
 
AE does not have temporal relationship to intervention, could readily have 
been produced by the patient’s clinical state, could have been due to 
environmental or other interventions, does not follow known pattern of 
response to intervention, does not reappear or worsen with reintroduction of 
intervention 
 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 
The event is clearly due to causes distinct from the use of the study drug, such as a 
documented preexisting condition, the effect of a concomitant medication, or a new 
condition which, based on the pathophysiology of the condition, and the pharmacology 
of the study drug, would be unrelated to the use of the study. All SAEs will be reported 
to the project manager within 24 hours of the site becoming aware of the event. 
 
Procedure for Reporting Adverse Events 
 
All AEs will be recorded from the time the permission form is signed through 30 hours 
after the last dose of enoxaparin in the trial. AEs will be recorded on an Adverse Event 
log at each site and entered in OnCore within 72 hours of the site becoming aware of 
the event. 
 
All AEs will be reported to regulatory authorities, IRB and investigators in accordance 
with all local applicable laws and regulations.  
 
AE reporting must also be carried out by each participating site PI, according to their 
local policy and procedures, to the IRB responsible for oversight of their patients. A 
copy of the local IRB’s acknowledgement should be forwarded to the project manager. 
All SAEs must be followed until resolution or stabilization. Unanticipated problems 
involving risk to patients or others and all SAEs related to participation in the study 
should be promptly reported to the project manager. The project manager shall report 
all SAEs to the FDA. 
 
All SAEs that are unexpected, which occur any time after the patient has consented up  
to 30 hours after the last dose of enoxaparin in the trial and are possibly, probably, or 
definitely related to the research must be reported by the participating site to the project 
manager within 24 hours of becoming aware of the event. The project manager is 
responsible for reporting to the FDA (via MedWatch report) according to FDA 
21CFR312.32 within 15 calendar days of the event occurring. The project manager will 
also notify the Yale Human Investigation Committee (within 5 days) and all participating 


30 
Version 5 August 22, 2017 
site investigators within 15 calendar days. 
 
A safety monitor is responsible for ongoing timely monitoring of reports of all SAEs 
submitted by site PIs, or other sources to ensure high-quality reporting, good clinical 
care and to quickly identify safety concerns. The identification of SAEs will begin when a 
member of the local research team reports an adverse event. The local research team 
will monitor each child daily for pre-defined adverse events, particularly clinically 
relevant bleeding. The research team will interview the clinical team and review the 
medical records daily for these events. The site PI or his/her designee will conduct 
prompt investigations of all reported adverse events, especially bleeding. All SAEs will 
be documented on a SAE form, entered in OnCore and communicated to the PM as 
soon as possible and <24 hours of the site PI knowing the event.  
 
SAEs will be reported to the Yale Human Investigation Committee and the IRBs of the 
participating sites per policy.  
 
Adverse Event Committee (AEC) 
 
PI Faustino will assemble an independent 3-member AEC composed of a pediatric 
hematologist (chair), a pediatric intensivist and a nurse. The responsibility of the AEC is 
to classify all AEs for publication and presentation purposes.  
 
Minimizing Risks 
 
To minimize the risk of bleeding, we will exclude children at high risk of bleeding. 
Enoxaparin will be held immediately and permanently after a clinically relevant bleeding 
event as defined by the International Society on Thrombosis and Hemostasis.52 
Bleeding from enoxaparin can be reversed with protamine or administration of fresh 
frozen plasma. See section on Holding the Dose, which contains criteria for holding 
enoxaparin temporarily and when to restart the drug. Enoxaparin will not be replaced 
with another agent while the drug is on hold.  
 
Platelet count will be monitored for the development of HIT. Enoxaparin and all heparin-
related products will be held temporarily for unexplained decrease in platelet count.14, 53 
Enoxaparin will not be restarted until the child tests negative for HIT.  
 
Subcutaneous administration of enoxaparin may cause pain. As per local ICU practice, 
enoxaparin may be given through a subcutaneous catheter.  
 
It is unlikely that the blood draws will result in anemia. Packed red blood cells can be 
transfused for anemia per the direction of the clinical team. 
 
The frequency of clinically relevant bleeding in critically ill children in the absence of 
anticoagulation is 0%-3% while that of children on prophylaxis with LMWH is 2.3%.43, 54-
57 If ≥5 clinically relevant bleeding events (100 children x 5.3% ≈ 5 events) occur, the 


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safety monitor will notify the chair of the data DSMB. The DSMB chair may convene a 
meeting or teleconference of the DSMB to consider the concerns and plan appropriate 
action, including temporarily putting the trial on hold. Because of the difficulty in 
determining the relationship between bleeding events and enoxaparin in critically ill 
children, all bleeding events will be conservatively attributed to the drug unless the child 
has not received a dose for ≥30 hours, which corresponds to 5 half-lives of the drug.   
 
 
 


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CORRELATIVE SAMPLES 
 
Blood 
 
Blood for correlative studies will be drawn from the CVC into two 2.7 mL citrated tubes 
at the following four time points 
1. Draw 1 (D1): <24 hours after insertion of CVC (and before enoxaparin is 
administered for subjects in the control arm) 
2. Draw 2 (D2): 24±6 hours after D1 (or together with the blood draw for the anti-
Xa activity for subjects in the treatment arm) 
3. Draw 3 (D3): 4 days after insertion of CVC (if the child is still in the study at 
that time)  
4. Draw 4 (D4): At the end of the study period  
 
Blood will be processed locally using standard procedures for obtaining platelet-poor 
plasma. It will then be frozen at −70oC.58 All specimens will be shipped to Yale for 
banking and will be analyzed every 6 months.   
 
At any one of the time points specified above, additional blood will be drawn into one 
0.5 mL EDTA tube for future genetic analysis. No processing is needed prior to freezing 
this sample. 
 
Urine 
 
At time points (D1-4) specified above for blood collection, 2-5 mL of urine will also be 
collected in urine collection tubes for correlative studies. No processing will be needed 
prior to freezing the urine locally at −70oC. Administration of enoxaparin should not be 
delayed if urine is not available before first dose of the drug is administered. 
 
Please refer to laboratory manual for specific instructions on processing, storage and 
shipment of blood and urine samples to Central Laboratories for analyses and storage. 
Blinded personnel at each Central Laboratory will perform all assays in duplicate on 
platelet-poor plasma collected at all time points. Results will be averaged for analysis. 
 
 
 


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CORRELATIVE STUDIES 
 
ETP. This will be measured at the Spinella Laboratory using CAT, a fully automated, 
computer-controlled fluorometric microplate reader and its specified software 
(Thrombogram Thrombinoscope Synapse, Netherlands). Calibration will be conducted 
with each test to guarantee correction for color of the tested plasma sample. Reagents 
containing 1 pM and 5 pM of tissue factor (to account for the presence of enoxaparin) 
plus 4 μM of phospholipid will be used to trigger the thrombin generation reaction.59  
 
Factor VIIIa and anti-Xa activities. These will be measured at the Clinical Laboratories 
at Yale-New Haven Hospital, except for anti-Xa activity that is used to titrate the 
enoxaparin dose in subjects in the treatment arm, which is measured locally. Factor 
VIIIa will be measured using a 1-stage clotting assay with the BCS XP System following 
the manufacturer’s recommendations. To minimize variability in its measurement in our 
analysis for this Aim, we will centrally measure anti-Xa activity using STA® Liquid Anti-
Xa assay with the fully automated STA® line analyzer.60 
 
IL-6 and IL-8. These will be measured at the Immune Monitoring Core Facility at Yale 
University using Milliplex® MAP assay kits and the Millipore Luminex 200 System. This 
is a bead-based system that allows analysis of up to 100 analytes per well.  Samples 
will be analyzed using Milliplex® Analyst software (EMD Millipore Corp., Germany). 
 
Anti-IIa and TFPI. These will be measured at the Yale Center for Clinical Investigation 
Core Laboratory at Yale University using commercially available ELISA kits. 
 
 
 


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Version 5 August 22, 2017 
OUTCOME MEASURES 
 
The primary outcome is the presence of CADVT, defined as DVT in the site of insertion 
of the CVC confirmed by ultrasound <24 hours after the end of the study period.19, 61 
Co-I Silva will lead a 3-member outcomes adjudication committee that will blindly and 
independently diagnose CADVT.40, 41 CADVT will be diagnosed if at least 2 are present: 
(1) intravenous echogenic material adherent to the venous wall, (2) non-compressibility 
of the vein, or (3) abnormal venous Doppler.18, 42, 62  
 
Secondary outcomes include measures of efficacy (other thromboembolic events 
including pulmonary embolism, and length and cost of stay in the ICU and the hospital), 
safety (clinically relevant bleeding, confirmed HIT and mortality), feasibility (proportion of 
enrolled eligible children, time to 1st dose of enoxaparin, and time to target anti-Xa 
activity), and compliance (proportion of missed doses, and proportion of children with 
ultrasound). Outcomes will be measured from insertion of the CVC. Imaging for other 
thromboembolic events will depend on the clinical team but all images will be centrally 
adjudicated for the trial. Bleeding will be monitored, recorded and classified using our 
bleeding assessment tool. Costs will be estimated from inpatient charges using each 
hospital’s cost-to-charge ratio.  
 
 
 
 


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STATISTICAL CONSIDERATIONS 
 
This trial is designed to inform: (1) beliefs regarding the posterior probability distribution 
for the prophylaxis treatment effect size, defined as the difference (pS – pE) of the 
proportion of subjects developing CADVT among those receiving the current standard 
of no prophylaxis (pS) vs. the proportion among those receiving the early prophylaxis 
(pE), (2) the decision whether to proceed to a phase 3 trial, and (3) appropriate and 
necessary design features of a phase 3 trial.  
 
For Aim 1, we will use a Bayesian statistical approach for modeling and data analysis, 
for formulating decision rules, and for interpreting results. We will also provide 
analogous frequentist results for reporting purposes only. We will use our empirical 
results to decide between 2 hypotheses regarding the difference of proportions δ = pS – 
pE of subjects who develop CADVT: δ ≤ 0 (prophylaxis is not efficacious) vs. δ ≥ 0.06 
(prophylaxis is efficacious).  
 
We define clinically significant efficacy of prophylaxis as δ ≥ 0.06. The absolute 
proportion reduction ≥ 0.06 (i.e., relative risk reduction ≥ 33%, relative to 0.18) is 
considered clinically significant in prior pediatric RCTs of prophylaxis against CADVT 
and is consistent with that achieved in RCTs of prophylaxis in critically ill adults.5, 63 In 
our recent meta-analysis, we showed that the proportion of children with no enoxaparin 
prophylaxis who developed CADVT was pS = 0.18 (95% CI: 0.12-0.25).5 Based on the 
finding from this meta-analysis, we will use an informative prior of pS ~ B(18,82). 
Because we know very little about pE, a non-informative prior of pE ~ B(1,1) will be 
used. We will assess the robustness of our results via sensitivity analyses that are 
based on other choices for hyper-parameters α, β for pE ~ B(α,β) and pS ~ B(α,β) that 
may have implications for salient results.   
 
The accepted threshold of posterior probability for not proceeding with a phase 3 trial 
after a phase 2 trial for success is >0.90, while the threshold for not proceeding for 
futility is unique to each study.64, 65 If our results suggest that the posterior probability of 
δ ≥ 0.06 is less than 0.60, then we will not proceed with a phase 3 trial using the same 
dose of enoxaparin. We will determine whether a higher dose is appropriate from the 
results of Aim 2.  
 
Subjects will be randomized 1:1 to the 2 treatment arms. An interim analysis of the 
binary outcome CADVT status consisting of the first 50 subjects enrolled will be 
performed to assess if the futility boundary has been crossed. Futility in the interim 
analysis will be defined as a predictive probability <0.10 for δ ≥ 0.06. The same primary 
analysis priors for pS and pE mentioned above will be used for the interim analysis. 
There will be no interim stopping or adaptation based on efficacy.    
  
For Aim 2, we will calculate the posterior probability that the ETP with enoxaparin is 
<700 nM.min for difference of means of ETP at D2 after 100 subjects complete the trial. 
We chose D2 because anticoagulation should be achieved as soon as possible. We 


36 
Version 5 August 22, 2017 
used an informative prior of ETP without enoxaparin ~N(1443, 356) from healthy 
children and a non-informative prior ~N(0, ∞) for ETP without enoxaparin due to lack of 
data in critically ill children.48,94 The posterior probability that ETP with enoxaparin <700 
nM.min is ≥ 0.60 will be used to decide on the dose for a phase 3 trial. For secondary 
analysis, we will analyze the primary outcome of ETP over time (D1-D4) using intent-to-
treat principle and Bayesian linear mixed effects model with treatment arm as the main 
predictor of interest, adjusted for the stratifying variables of age and ICU. We will 
analyze the relationship of ETP with anti-Xa level using linear mixed effects model, then 
identify explanatory variables from the coagulation-related markers. From the clinical 
variables, we will identify those that are associated with achieving the target ETP and 
anti-Xa level using generalized estimating equations. Using a joint model of linear mixed 
effects model for ETP or anti-Xa level, and generalized linear model for CADVT or 
bleeding, we will examine the relationship of ETP and anti-Xa level with CADVT and 
clinically relevant bleeding. We will use SAS® v9.4, WinBUGS, or R packages to 
perform Bayesian modeling and data analysis. 
 


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DATA MANAGEMENT AND RECORD KEEPING 
 
The investigators are required to prepare and maintain adequate and accurate case 
histories designed to record all observations and other data pertinent to the 
investigation on each individual treated in the investigation. Data that are derived from 
source documents and reported on the CRF must be consistent with the source 
documents or the discrepancies must be explained. OnCore will be the designated 
electronic data capture tool. All data should be entered onto OnCore within 1 week of 
study entry.  AEs need to be entered within 72 hours and SAEs need to be entered 
within 24 hours of the site becoming aware of the event.   
 
 
 
 


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Version 5 August 22, 2017 
ADMINISTRATIVE AND REGULATORY  
 
Multicenter Management and Coordination 
 
The YCCI MCU will support PI Faustino with the multi-site management aspects of this 
trial. This includes, but is not limited to, study start-up, regulatory assistance (IRB 
submissions, amendments, and renewals), provision of template study forms (tracking 
and eligibility checklists, etc.), site qualification and activation, training, and overall 
project management. The MCU will provide tools to assist the study teams in 
conducting the trial appropriately and according to Good Clinical Practice Standards. 
 
The MCU will ensure that all participating sites undergo remote training in which all key 
study personnel will be instructed study procedures, informed consent, source 
documentation requirements, safety and adverse event reporting, Good Clinical 
Practice guidelines and additional study related topics. This training will be conducted 
by the YCCI Study Monitor and/or MCU staff and documentation of completion will be 
required for all personnel. Co-I Silva will remotely collaborate with certified 
sonographers from each ICU to maintain consistent imaging of the central veins. PI 
Faustino will be available to site investigators for questions and re-training (if 
necessary). 
 
Data safety and monitoring plan 
 
Authority for monitoring data and safety will reside exclusively with the DSMB. The 
DSMB will hold the investigative sites responsible for data quality and completeness, 
and ensure the safety of children. The DSMB will be composed of a pediatric intensivist 
(chair), a pediatric hematologist, a biostatistician and a patient advocate who are not 
involved in the trial. The DSMB will review this protocol at a minimum of once every six 
months. Information to be provided to the DSMB includes: a study narrative by the 
Sponsor PI, a summary DSMB report produced by OnCore (which includes participant 
accrual, response, trial status history, SAEs, AEs, deviations and survival); and audit 
results and monitoring reports as applicable. Other information (e.g. scans, laboratory 
values) will be provided upon request. At the conclusion of each DSMB meeting, the 
chair will provide a written summary of the recommendations to PI Faustino. PI Faustino 
will forward this promptly to participating sites for submission to their local IRBs. The 
DSMB has the authority to recommend that the study protocol be terminated, 
temporarily suspended, or amended.  
 
Responsibilities of the DSMB. The DSMB is responsible for assuring that children in 
the study are not exposed to unnecessary or unreasonable risks and that the study is 
being conducted according to high scientific and ethical standards. Specifically, the 
DSMB will: 
1. Assess the performance of the study with respect to recruitment, retention, 
follow-up, protocol adherence, and data quality and completeness. 
2. Monitor interim data regarding the safety of the study regimen. 


39 
Version 5 August 22, 2017 
3. Review and consider protocol modifications or ancillary studies proposed by 
the investigators after the study begins to ensure that these do not negatively 
impact the trial 
4. Advise the investigators as to whether the protocol should continue as 
scheduled or undergo modification due to a finding from the monitoring 
process. 
 
Membership. The DSMB will be composed of a pediatric intensivist (chair), a pediatric 
hematologist a biostatistician and a patient advocate. Members will not be involved in 
the trial, and will have no vested interest in its outcome.  
 
Initial meeting: Before the study opens to enrollment, the DSMB will meet with PI 
Faustino and other key investigators to review the research protocol. Particular attention 
will be paid to the outcome definitions, analysis plan, procedures for recording and 
reporting serious adverse events, the interim monitoring plan, and the informed consent 
documents. At this meeting, the DSMB may recommend amendments or clarification of 
the protocol, and it will formulate its operating procedures (e.g., meeting schedule, 
reports due from the study statistician, and what interim data may be released to the 
investigators).   
 
Meeting format. The DSMB will meet as often as needed but the minimum will be at 
least once before the start of enrollment, after 10, 25 and 50 children have been 
enrolled, and after enrollment is completed (100 children enrolled). The DSMB will 
monitor the study according to guidelines specified in the research protocol and the 
operating procedures established at the initial meeting, unless the DSMB determines 
during the course of the study that modification of the guidelines is in the best interest of 
the study or the children in the study. The DSMB chair will set the meeting agenda. The 
DSMB members, the study statistician, project manager and the Sponsor PI will attend 
the session, at which time data concerning study conduct and aggregate safety data are 
discussed. Minutes of the meeting will be taken by staff of the DSMB. 
 
Interim data summary reports. The study statistician will prepare data summary 
reports and send these directly to the DSMB members and the study team ≥7 days prior 
to the meeting. The report will focus on patient enrollment and demographics, data 
completeness, other study performance measures, and rates of serious adverse events. 
In addition to reports prepared by the statistician, PI Faustino may prepare a report 
addressing concerns he anticipates the DSMB will have regarding the conduct of the 
study.  
 
Communication of DSMB recommendations. At the conclusion of each DSMB 
meeting, the DSMB will provide a verbal report to PI Faustino indicating areas of 
concern regarding performance and safety. Soon after the meeting, the chair will 
provide a written report to PI Faustino, including a summary of the DSMB’s 
recommendations. In addition, the chair will provide a memorandum to PI Faustino 
(including date of the meeting, a listing of data reviewed, recommendations, and date of 


40 
Version 5 August 22, 2017 
next review). PI Faustino will forward this promptly to each participating site for 
submission to their IRBs, including the Yale Human Investigation Committee and the 
Project Management team. 
 
The DSMB has the authority to recommend that the study protocol be terminated, 
temporarily suspended, or amended. This recommendation will be discussed with PI 
Faustino before any action is taken. If the DSMB recommends a protocol amendment, 
the Yale Human Investigation Committee and site IRBs must approve the amendment 
before it is implemented.  
 
Quality Management / Monitoring  
 
PI Faustino and YCCI are responsible for monitoring the performance of all of the 
participating sites. This will be performed by conducting a study site initiation visit, as 
well as regularly scheduled monitoring visits throughout the life of the protocol. At the 
end of the trial, the monitor will then perform study site close-outs for all participating 
sites.  
 
YCCI will utilize their institution’s initiation, monitoring and close-out visit reports. 
Following monitoring, a monitoring report will be generated containing information on 
site activities, and a summary of pertinent points and action items together with a copy 
of the follow-up letter will be sent to each investigative site.  
 
During these monitoring visits, some of the items that will be reviewed are the following:  
1. Training of the sites  
2. Site personnel qualifications to participate in the trial  
3. That study related documents are current  
4. That regulatory compliance is accomplished  
5. That a parent has signed the permission form 
6. That the child has signed the assent form (if applicable)  
7. That the protocol is complied with (including reporting and logging of all 
protocol deviations)  
8. That all SAEs and AEs have been reported to the local regulatory 
committees, IRB, YCCI and the FDA, as applicable 
9. That source documentation matches CRFs  
10. That required procedures for study drug accountability, distribution, and 
storage are followed 
 
YCCI will document the required study monitoring activities in a Study Monitoring Plan.  
 
Project Team Meetings 
 
Scheduled meetings will be held and will include the site investigators and research 
staff involved with the conduct of the protocol. 
 


41 
Version 5 August 22, 2017 
During these meetings, the investigators will discuss: 
1. Safety of protocol participants (adverse events and reporting) 
2. Validity and integrity of the data (data completeness on CRFs and complete 
source documentation) 
3. Enrollment rate relative to expectation of target accrual (eligible and ineligible 
participants) 
4. Retention of participants, adherence to the protocol and protocol violations 
5. Protocol amendments 
 
CONFIDENTIALITY & SECURITY OF DATA 
 
Data will be entered into OnCore. De-identified data will then be downloaded in Excel 
format for statistical analysis, which will be done on a HIPAA compatible, password 
protected encrypted laptop computer by biostatistician co-I Stolar for use. All data entry 
will be performed by the local study site personnel. All source documentation will be 
retained at the local study site per local site regulations and monitored during regularly 
scheduled monitoring visits. 
 
 


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Version 5 August 22, 2017 
TRIAL FLOW CHART 
Procedure 
Screening 
Period 
Treatment 
Period 
End of Study 
CVC Removal 
Parental permission/assent 
x 
 
 
Review of eligibility criteria 
x 
 
 
Randomization 
x 
 
 
Medical record review and data 
collection from ICU admission 
 
x 
 
Physical exam of arms or legs, 
and for sexual maturity rating a 
 
x 
x 
Administration of enoxaparin b 
 
x 
 
Measure Anti-Xa activity c 
 
x 
 
Ultrasound d 
 
 
x 
Bleeding assessment e 
 
x 
x 
Assess for AEs e, f 
x 
x 
x 
CBC with differential g 
 
x 
 
Renal function tests (BUN, 
creatinine) g 
 
x 
 
Serum aminotransferases g 
 
x 
 
Stool occult bleed h 
 
x 
 
Blood collection for correlatives 
 
x i 
x 
Urine collection for correlatives 
 
x i 
x 
a: At time of enrollment for physical exam of arms or legs (if patient has a CVC in the internal jugular vein, 
only arms need to be examined; if the CVC is inserted in the femoral vein, only legs need to be 
examined), and at any time during the admission for the sexual maturity rating. 
b: 1st dose <24 hours after insertion of the CVC, then every 12±2 hours until CVC removal. Only for 
subjects randomized to the treatment arm. 
c: Anti-Xa activity will be measured 4-6 hours after the 3rd dose, then every 3rd dose until target is 
achieved. After target achieved, measurement is weekly.  
d: Within 24 hours of removal of the CVC, or earlier upon discharge from the ICU, radiologic diagnosis of 
CADVT, start of therapeutic anticoagulation, clinically relevant bleed develops, HIT is diagnosed, or 28 
days after insertion of the CVC  
e: Daily. 
f: Starting from time permission form is signed until 30 hours after the last dose of enoxaparin in the trial. 
g: Within 48 hours of enrollment and at least weekly ± 2 days, thereafter.  
h: If clinically indicated as determined by the site PI.  
i: Collected <24 hours after insertion of CVC (and before enoxaparin is administered for subjects in the 
treatment arm); D1), 24±6 hours after D1 (or together with the blood draw for the anti-Xa activity for 
subjects in the treatment arm; D2), 4 days after insertion of CVC (if the child is still in the study at that 
time; D3), and at the end of the study period (D4). 
 
 
 


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493. 
 
 
 


48 
Version 5 August 22, 2017 
ACKNOWLEDGMENT OF THE INVESTIGATORS 
 
 
 
 
PROTOCOL TITLE: Prevention of central venous catheter-associated thrombosis in 
critically ill children: A multicenter phase 2b trial. 
 
 
Version Date: V5 August 22, 2017 
 
 
Acknowledgement of the Investigator: 
 
1.) I have read this protocol and agree that the study is ethical 
 
2.) I agree to conduct the study as outlined and in accordance with 
all applicable regulations and guidelines 
 
3.) I agree to maintain the confidentiality of all information received 
or developed in connection with this protocol 
 
 
 
 
 
 
Signature of Investigator:                                                                     Date: 
 
 
 
Name of Investigator (Printed or Typed) 
 
 
 
 
 


49 
Version 5 August 22, 2017 
 
APPENDIX I 
 
Infants and Children 0 to 2 Years of Age 
Weight-for-length 95th Percentiles, 45 cm to 110 cm 
 
Length (cm) 
Male (kg) 
Female (kg) 
81 
12.23 
11.98 
82 
12.45 
12.23 
83 
12.69 
12.49 
84 
12.94 
12.76 
85 
13.20 
13.04 
86 
13.47 
13.33 
87 
13.75 
13.62 
88 
14.02 
13.92 
89 
14.30 
14.21 
90 
14.57 
14.50 
91 
14.83 
14.79 
92 
15.10 
15.08 
93 
15.37 
15.37 
94 
15.64 
15.67 
95 
15.91 
15.96 
96 
16.19 
16.26 
97 
16.48 
16.57 
98 
16.78 
16.88 
99 
17.09 
17.19 
100 
17.41 
17.52 
101 
17.74 
17.86 
102 
18.09 
18.21 
103 
18.44 
18.58 
104 
18.80 
18.96 
105 
19.17 
19.34 
106 
19.55 
19.75 
107 
19.95 
20.16 
108 
20.35 
20.60 
109 
20.76 
21.04 
110 
21.18 
21.50 
Length (cm) 
Male (kg) 
Female (kg) 
45 
2.85 
2.87 
46 
3.04 
3.07 
47 
3.23 
3.26 
48 
3.43 
3.47 
49 
3.64 
3.68 
50 
3.87 
3.91 


50 
Version 5 August 22, 2017 
 
 
 
 
 
 
 
 
 
 
Adopted from: Centers for Disease Control and 
Prevention, National Center for Health Statistics, 
2010 
(http://www.cdc.gov/growthcharts/html
_charts/wtleninf.htm) 
 
 
Male and Female 2-20 Years Old 
Data Table of 95th Percentile BMI Value 
for Age 
 
Body Mass Index, or BMI, is calculated 
using the following formula: 
BMI = Weight (in kilograms)/Height (in 
meters)2 
 
 
51 
4.11 
4.16 
52 
4.36 
4.42 
53 
4.64 
4.70 
54 
4.94 
5.00 
55 
5.26 
5.31 
56 
5.58 
5.62 
57 
5.91 
5.93 
58 
6.25 
6.25 
59 
6.57 
6.55 
60 
6.90 
6.86 
61 
7.20 
7.15 
62 
7.50 
7.44 
63 
7.79 
7.72 
64 
8.07 
8.00 
65 
8.35 
8.26 
66 
8.62 
8.53 
67 
8.89 
8.78 
68 
9.15 
9.03 
69 
9.41 
9.28 
70 
9.68 
9.52 
71 
9.94 
9.75 
72 
10.19 
9.99 
73 
10.45 
10.21 
74 
10.69 
10.44 
75 
10.93 
10.66 
76 
11.16 
10.87 
77 
11.39 
11.08 
78 
11.60 
11.29 
79 
11.81 
11.51 
80 
12.02 
11.74 
Age 
Male (BMI) 
Female (BMI) 
2 
19.34 
19.11 
2.5 
18.67 
18.58 
3 
18.24 
18.25 
3.5 
17.97 
18.08 
4 
17.84 
18.03 
4.5 
17.83 
18.09 
5 
17.94 
18.26 
5.5 
18.14 
18.51 
6 
18.41 
18.84 
6.5 
18.76 
19.23 
7 
19.15 
19.68 
7.5 
19.59 
20.17 
8 
20.07 
20.70 
8.5 
20.57 
21.25 
9 
21.09 
21.82 
9.5 
21.62 
22.40 
10 
22.15 
22.98 
10.5 
22.69 
23.57 
11 
23.21 
24.14 


51 
Version 5 August 22, 2017 
 
 
 
 
 
 
 
 
Adopted from: Centers for Disease Control and 
Prevention, National Center for Health Statistics, 2001 
(http://www.cdc.gov/growthch
arts/html_charts/bmiagerev.htm) 
 
 
 
 
 
11.5 
23.73 
24.71 
12 
24.23 
25.26 
Age 
Male (BMI) 
Female (BMI) 
12.5 
24.71 
25.79 
13 
25.18 
26.30 
13.5 
25.62 
26.79 
14 
26.05 
27.26 
14.5 
26.45 
27.70 
15 
26.84 
28.12 
15.5 
27.21 
28.53 
16 
27.56 
28.91 
16.5 
27.91 
29.28 
17 
28.26 
29.63 
17.5 
28.60 
29.98 
18 
28.96 
30.33 
18.5 
29.33 
30.67 
19 
29.73 
31.03 
19.5 
30.16 
31.40 
20 
30.59 
31.76 


52 
Version 5 August 22, 2017 
APPENDIX II 
 


53 
Version 5 August 22, 2017 
APPENDIX III  
 


54 
Version 5 August 22, 2017 


55 
Version 5 August 22, 2017 


56 
Version 5 August 22, 2017 


57 
Version 5 August 22, 2017 


58 
Version 5 August 22, 2017 
 


59 
Version 5 August 22, 2017 
 

ICF_000.pdf: 
 
 
1
INFORMED CONSENT FORM 
 
 
Title: Prevention of central venous catheter-associated thrombosis in critically 
ill children: A multicenter phase 2b trial. 
 
NCT Number: 03003390 
 
Date: August 25, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
2
 
COMPOUND AUTHORIZATION AND PARENTAL PERMISSION FOR PARTICIPATION 
IN A RESEARCH PROJECT 
310 FR. 3a (2016-1) 
 
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL 
 
Study Title: Prevention of catheter-associated deep venous thrombosis in critically ill children 
Principal Investigator: E. Vincent S. Faustino, MD, MHS 
Funding Source: National Institutes of Health 
 
Invitation to Participate and Description of Project 
We are inviting your child to participate in a research study. The research study will see if giving a 
blood thinner called enoxaparin soon after a child has a central venous catheter (CVC) inserted will 
prevent blood clots from developing. Your child has been asked to participate because he/she has a 
CVC. The use of these catheters in sick children are associated with blood clots. Blood clots can 
cause swelling in the arms and legs. When there is a blood clot, it makes it harder for the people 
taking care of your child to use the CVC. Blood clots may cause infections. When blood clots form, it 
can go to the lungs, cause stroke, or lead to longer stays in the intensive care unit or even death. 
 
We do not know if blood thinners, particularly enoxaparin, can decrease the chances of getting blood 
clots in children with CVC. We are doing this study to find out if this drug helps prevent blood clots. 
 
In order to decide whether or not you wish your child to be a part of this research study you should 
know enough about its risks and benefits to make an informed decision. This permission form gives 
you detailed information about the study, which a member of the research team will discuss with you.  
This discussion should go over all parts of this research: the purpose and nature of the research study, 
the procedures that will be performed, the risks of the study drug, possible benefits, possible 
alternative treatments, your child’s rights as a participant and other information about the research 
study. You should take whatever time you need to discuss the research study with your child’s doctor 
and family. The decision to allow your child to participate or not is yours. Once you understand the 
study, you will be asked if you wish for your child to participate; if so, you will be asked to sign and 
date this form. If you do not sign this permission form, your child cannot take part in this study. 
 
If you choose to allow your child to participate, you will be told of any significant new findings that 
develop during the time your child is in the study that may affect your willingness to allow your child 
to continue to participate. 
 
Purpose 
 
The purpose of this study is to find out if giving children a blood thinner called enoxaparin, shortly 
after getting a CVC, will prevent blood clots from happening.  Even though doctors give this drug to 
children, we are not sure if it works. 
 
The study drug that will be used in this research study, enoxaparin, is investigational in children. 
This means it has not been approved for use by the public by the United States Food and Drug 
Administration (FDA) in children. The safety and whether it produces positive results in children is 
not known even though enoxaparin is used in clinical practice; which means that some doctors give 
enoxaparin to children. 
 


 
 
3
Enoxaparin is approved for use in adults by the FDA for the prevention of deep vein thrombosis 
(DVT), which may lead to pulmonary embolism (a blood clot in the artery in the lungs). Enoxaparin 
is also used to prevent blood clots in the leg in adult patients who are on bedrest or who are having 
hip replacement, knee replacement, or stomach surgery. It works by stopping the body from 
producing clots. 
 
In this study, we will enroll 100 children in 6 children’s hospitals (pediatric ICUs) across the country. 
It is expected that about 15 children will be enrolled in the research study at Yale University, Yale 
New Haven Children’s Hospital. 
 
Study Procedures 
 
If you agree to allow your child to participate in this research study, your child will be randomly 
assigned to the treatment group or the control group but a computer system. If your child is assigned 
to the treatment group, the following tests and procedures will be done in the Pediatric Intensive 
Care Unit (PICU): 
 
• 
Enoxaparin: Your child will have injections of enoxaparin 2 times a day (every 12 hours or 
so). These injections will be in your child’s thigh or abdomen (depending on your child’s 
age) under the skin until the end of your child’s participation in the study. 
 
• 
Anti-Xa Testing: Your child’s blood will be checked using a test called anti-Xa after the 
third time they get enoxaparin (3rd dose) to make sure the correct amount is being given. 
Your child’s doctor may change the dose of enoxaparin so that your child is getting the 
dose that they need. Blood (1/2 teaspoon) will be taken from the CVC for this test. 
 
The following tests and procedures will be done if you agree to allow your child to participate 
regardless of treatment group assignment: 
 
Ultrasound: Your child will have an ultrasound over the location where CVC is inserted. The 
ultrasound is being done for research purposes only and is not part of your child’s clinical care. This 
will be done once at only one the following time points, whichever comes first. 
 
o After the CVC is removed, OR 
o Before your child is discharged from the PICU, OR 
o If your child’s doctor detects a blood clot, OR 
o If your child’s doctor decides to start blood thinners, OR 
o If your child develops a bleed that is causing other health problems, OR 
o If your child’s platelet count drops because of enoxaparin, OR 
o At 28 days after insertion of the CVC. 
 
• 
Blood Draws: We will draw about 5.4 mL of blood at 4 different times (4 teaspoons total for 
the entire study) during the study. The blood will be drawn for research purposes only. This 
will happen on the day of enrollment (when your child starts being in the study), 1 day after 
that, 4 days after insertion of the CVC and at the end of the study period. Blood will be drawn 
from the CVC or another catheter that is already inserted. Your child will not need to have a 
needle stuck in them to get this blood. 
 
• 
Urine collection: We will collect 2-5 mL of urine at 4 different times (1.5- 4 teaspoons total 
for the entire study). The urine will be collected for research purposes only. This will happen 
at the same times that the blood for research is collected (see above). 


 
 
4
 
Your child will be in the study until the CVC is removed.  Your child could be in the study for 
up to 28 days. 
 
If any of the following things happen, your child will be removed from the study because these 
medical problems will stop us from knowing if the study drug is working. 
 
• 
He/she is discharged from the PICU 
• 
He/she is diagnosed with a blood clot in the vein from the CVC 
• 
He/she starts another mediation that helps prevent or to treat blood clots 
• 
He/she is bleeding and it is causing other health problems 
• 
His/her platelet count drops because of enoxaparin 
• 
28 days after the CVC is inserted 
 
Your child will no longer be in the study if any of the events listed above occur. Your child will 
be followed for side effects for 30 hours after the last dose of enoxaparin is given. 
 
Potential Risks 
 
While in this study, your child may have side effects.  Expected side effects are listed here. In 
addition to the risks listed below, there may be risks that are currently unknown. If significant new 
information becomes known to us during the time your child is on the study, we will tell you so you 
can decide if your child should stay in the study.  Possible side effects that your child may 
experience during this study will be fully explained to you by the study staff. Please ask as many 
questions as you want so that you can understand the possible side effects of your child’s treatment 
before you decide whether you want to allow him/her to be in this study. Please ask the study doctor 
or the study staff to explain any information or words that are not clear to you. 
 
Risks associated with enoxaparin (the drug we are studying) 
 
If your child is assigned to the treatment group, s/he will be given enoxaparin. Enoxaparin is a blood 
thinner commonly used in adults and children. Because it is a blood thinner, there is a possibility that 
your child may have some bleeding associated with the use of the drug. Based on the information 
that we have right now, less than 3 out of 100 sick children receiving enoxaparin had significant 
bleeding, which is the same in sick children who are not receiving any blood thinners. We try to 
lower the risk of bleeding by enrolling only those children that have lower tendency to bleed. We are 
also checking drug levels to make sure that bleeding is not likely to happen.  
 
In addition to an increased risk of bleeding, there is an increased risk of thrombocytopenia which 
means low platelets in the blood which help blood clot and stops bleeding, anemia (low healthy red 
blood cells or hemoglobin), elevation of serum aminotransferase (which could mean the liver is not 
functioning well), diarrhea, and nausea.  
 
Enoxaparin will be given as injections to the thighs or abdomen depending on your child’s age twice 
a day. There may be some pain involved with the injection. We will do our best to minimize pain 
from the injection. There is also a very small chance that your child will have anemia from the blood 
draw or other reaction to the drug. 
 
Other Risks 
 


 
 
5
The following risks are associated with participation in the study regardless of treatment assignment. 
 
Blood Collection 
The risks of drawing blood from your child through a catheter may include light-headedness and 
fainting. Approximately 5.4 mL of blood will be taken four times (a total of 4 teaspoons for the entire 
study) during your child’s participation for research purposes only. More will be taken as part of the 
routine care of your child. 
 
Ultrasound 
There might also be some discomfort to your child during the ultrasound procedure. We will do 
everything possible to reduce discomfort. There may be a slight pressure in the area when the 
ultrasound probe is passed over your child’s body. 
 
Loss of Privacy and Confidentiality 
There is also a potential for loss of privacy and confidentiality. To lower this risk, we will assign your 
child a study number. All data collected for the study will be identified by this number, not your 
child’s name or other information that could be linked to your child. 
 
For more information about risks and side effects, you can ask the researcher during your visits or 
contact their office at 203-785-4651 
 
Benefits 
 
If you agree to allow your child to take part in this research study, we cannot guarantee that your 
child will receive any good results or benefits. However, there is a potential that your child will 
directly benefit from the study. S/he may have less risk of developing blood clots in the blood vessel 
where the catheter was inserted if s/he is assigned to the treatment group. This may result in shorter 
stay in the hospital. We hope the information learned from this research study may benefit other 
children at risk of blood clots in the future. The information your child will provide in this study will 
be used to design a bigger study with more children to determine whether enoxaparin can decrease 
the risk of blood clots from CVC in sick children. 
 
Economic Considerations 
 
You and your child will not be paid for taking part in this study. Tests and procedures that are done 
for your child’s regular care (whether he/she is on this study or not) are called “standard of care”. 
There will be no charge to you or your insurance provider for tests or procedures that are not standard 
of care, done only for research purposes. You and your insurance provider will not have to pay for the 
study drug enoxaparin, or the ultrasound. All other tests and procedures will be charged to you or your 
insurance provider in the usual way because they are standard care for your child’s condition. This 
may include other tests and procedures not listed in this consent if your child’s doctor feels it is 
necessary for his/her care, such as additional laboratory tests. 
 
 
Alternatives 
 
Blood thinners are currently the only potential treatment to prevent blood clots. 
Another alternative is to provide no blood thinner or no treatment to prevent clots. 


 
 
6
If you decide not to allow your child participate in the study, your doctor will decide if your child will 
receive blood thinners which will have nothing to do with the study.  Currently there are no blood 
thinners approved for children to prevent blood clots from happening. 
 
Talk to your doctor about your choices before you decide if your child will take part in this study. 
 
Confidentiality and Authorization to collect, use and disclose Protected Health Information 
 
For purposes of this study, Yale University, Yale-New Haven Hospital, and Dr. Faustino will use 
medical information collected or created as part of the study, such as medical records and test results, 
which identifies your child by name or in another way. Your permission to allow your child to 
participate in the study means you agree that Yale University, Yale-New Haven Hospital, and Dr. 
Faustino may obtain your child’s medical information that they request for study purposes from your 
child’s doctors and other health care providers from the past or during your child’s participation in 
the study. The study doctor may need this information to watch, review and report on the safety of 
the study drug. 
 
The protected health information that will be collected in this study includes: demographics (name, 
date of birth), medical history, physical examinations, routine lab tests, your child’s medications 
(past and present), ultrasound scan results, blood and urine sample results and records about the 
study drug that your child received. 
 
Any identifiable information (information that has your child’s name on it) that is obtained in 
connection with this study will remain confidential and will be disclosed only with your permission or 
as permitted by U.S. or State law.  Examples of information that we are legally required to disclose 
include abuse of a child or elderly person, or certain reportable diseases such as HIV or hepatitis. 
When the results of the research are published or discussed in conferences, no information will be 
included that would reveal your child’s identity unless your specific permission for this activity is 
obtained. 
 
We understand that information about your child obtained in connection with your child’s health is 
personal, and we are committed to protecting the privacy of that information.  If you decide to allow 
your child to be in this study, the study staff will get information that identifies your child and his/her 
protected health information.  This may include information that might directly identify your child, 
such as his/her name, date of birth, and medical record number. This information will be de- identified 
prior to providing it to Yale University, meaning we will replace your child’s identifying information 
with a code that does not directly identify him/her. The study doctor will keep a link that identifies 
your child to his/her coded information, and this link will be kept secure and available only to the 
Principal Investigator or selected members of the study team. Any information that can identify your 
child will remain confidential. 
 
The records for this trial will be stored in locked cabinets and/or offices and password protected 
computers. It is anticipated that records containing the information that links your child to his/her 
coded information will be maintained indefinitely, as there are no plans at this time to destroy these 
records at the end of the study. 
 
Information about your child’s study participation will be entered into his/her Electronic Medical 
Record (EMR). Once placed in the EMR, these results are accessible to all of your child’s providers 
who participate in the EMR system. Information within your child’s EMR may also be shared with 


 
 
7
others who are appropriate to have access to your child’s EMR (e.g., health insurance company, 
disability provider.) 
 
Information about your child and his/her health which might identify he/she may be used by or given 
to: 
 
• The U.S. Department of Health and Human Services (DHHS) agencies and other government 
agencies in the United States and in foreign countries that watch over the study 
• Representatives from Yale University and Yale New Haven Hospital 
• Representatives from the Yale Human Research Protection Program, (the Institutional 
Review Board that reviews, approves, and monitors research on human subjects), who are 
responsible for ensuring research compliance. These individuals are required to keep all 
information confidential. 
• Representatives from the Yale Center for Clinical Investigation Quality Assurance may 
inspect study records during internal auditing procedures. However, these individuals are 
required to keep all information confidential. 
• Your child’s providers who are participants in the Electronic Medical Record (EMR) system 
• Individuals at Yale who are responsible for the financial oversight of research including 
billings and payments 
• The study doctor Vincent Faustino and the Yale University study team 
• The study funder (National Institutes of Health) 
• The U.S. Food and Drug Administration (FDA). This is done so that the FDA can review 
information about the drug being used in this research. The information may also be used 
to meet the reporting requirements of drug regulatory agencies. 
• Governmental agencies to whom certain diseases (reportable diseases) must be reported 
• Health care providers who provide services to your child in connection with this study. 
• Laboratories and other individuals and organizations that analyze your child’s health 
information in connection with this study, according to the study plan. 
• Data and Safety Monitoring Boards and others authorized to monitor the conduct of the 
Study 
• The people you have named as emergency contacts (if any) and the study team has not 
been able to reach you 
 
By signing this form, you authorize the use and/or disclosure of the information described above for 
this research study. The purpose for the uses and disclosures you are authorizing is to ensure that the 
information relating to this research is available to all parties who may need it for research purposes. 
 
The study sponsor Yale University, people who work with the sponsor on the study, and government 
agencies and other groups that watch over research studies like this one may look at all your child’s 
health information.  Regulatory authorities may also require that the study doctor turn over to them 
copies of all your child’s health information to make sure the study has been done the right way.  
They also want to make sure that your child’s health information has been collected the right way, or 
for other reasons that are allowed under the law. 
 
All health care providers subject to HIPAA (Health Insurance Portability and Accountability Act) are 
required to protect the privacy of your child’s information. The research staff at Yale University is 
required to comply with HIPAA and to ensure the confidentiality of your information.  Some of the 
individuals or agencies listed above may not be subject to HIPAA and therefore may not be required 
to provide the same type of confidentiality protection. They could use or disclose your child’s 
information in ways not mentioned in this form.  Federal law does not protect your child against this, 


 
 
8
but the laws of your state may provide additional protection. However, to better protect your child’s 
health information, agreements are in place with these individuals and/or companies that require that 
they keep your information confidential. 
 
Authorized representatives of the FDA may need to review records of individual subjects. People 
from the FDA or other Health and Human Services agencies may see your child’s name, but they 
are bound by rules of confidentiality not to reveal your child’s identity to others. 
 
The funder of this study, The NIH may see the research information we collect about your child if they 
come to monitor the conduct of this research study. This includes any persons that work for or are hired 
by the NIH. Researchers may also send the NIH your child’s health information during the study or at 
the end of the study. When Yale University researchers send information about your child to the NIH, 
they will not send information that directly identifies him/her such as your child’s name. 
 
You have the right to review and copy your child’s health information in your child’s medical record 
in accordance with institutional medical records policies.  You may also, under data protection laws, 
have the right to ask that any mistakes in your child’s study-related health information be corrected. 
However, you will not be allowed to look at or copy your child’s study related information until after 
the research is completed. This is because we want to wait until the study is over before we decide if 
the study drug worked well. 
 
This authorization to use and disclose your child’s health information collected during your 
participation in this study will never expire. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify your child.  At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
Your daughter will be asked to have a pregnancy test before starting this study. Only your daughter 
will be told the results. If she is pregnant, we will also advise her to get care for her pregnancy and to 
get the support of an adult.  If your daughter is under age 13 and has a positive pregnancy test, we will 
report the pregnancy to the Department of Children and Families. 
 
In Case of Injury 
 
If your child is injured while on study, seek treatment and contact the study doctor as soon as you 
are able. 
 
Yale University does not provide funds for the treatment of research-related injury. If your child is 
injured as a result of his/her participation in this study, treatment will be provided.  You or your 
child’s insurance carrier will be expected to pay the costs of this treatment.  No additional financial 
compensation for injury is available. 
 
You do not give up any of your legal rights by signing this form. 
 
Voluntary Participation and Withdrawal 
 
Participation in this study is voluntary. You are free to choose not to allow your child to take part in 
this research study.  Refusing to allow your child to take part in this research study will not lead to 
penalty or loss of benefits to which your child is otherwise entitled (such as his/her health care outside 


 
 
9
the study, the payment for his/her health care, and his/her health care benefits). However, your child 
will not be able to enroll in this research study and will not receive study procedures as a study 
participant if you do not sign this permission form and allow use of your child’s information as part of 
this study. 
 
Withdrawing from the Study: 
 
If you decide to allow your child to participate in this research study, you are free to stop and 
withdraw your permission at any time. To withdraw your child from the study, you can call a 
member of the research team at any time and tell them that you no longer want your child to take 
part. They will make sure that proper procedures are followed to stop the study. 
 
Withdrawing from the study will involve no penalty or loss of benefits to which you or your child are 
otherwise entitled. It will not harm your relationship with your child’s doctors or with Yale 
University. We would still treat your child with standard therapy or, at your request, refer you to a 
clinic or doctor who can offer this treatment. 
 
You may request that the Sponsor destroy your child’s blood and urine samples by contacting your 
study site.  As long as it is possible to identify your child’s samples (i.e., the samples have not been 
anonymized or the study site has not destroyed the key that links your child’s name to the study ID), 
then the Sponsor will destroy the sample.  However, if any analysis or research has already been 
performed on the samples, the Study Sponsor does not have to destroy the results of this analysis or 
research. If you request destruction of your child’s sample(s), your child will not lose any benefits, 
medical treatment or legal rights to which he/she are otherwise entitled. 
 
If you choose not to give your permission by not signing this document, or if you cancel your 
permission later, then your child will not be eligible to participate in this study and will not receive 
any treatment provided as part of the study. Unless and until you do cancel the permission, it will 
remain valid and effective. 
 
Withdrawing Your Authorization to Use and Disclose Your Child’s Health Information: 
 
You may withdraw or take away your permission to use and disclose your child’s health information 
at any time. You do this by telling the study staff or by sending written notice to the study doctor Dr. 
Vincent Faustino P.O. Box 208064 New Haven, CT 06520-8064. If you withdraw your permission, 
your child will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying your child will be 
collected after that date.  Information that has already been collected may still be used and given to 
others as permitted in this document until the end of the research study, as necessary to insure the 
integrity of the study and/or study oversight. 
 
Questions 
 
We have used some technical terms in this form.  Please feel free to ask about anything you don't 
understand and to consider this research and the permission form carefully – as long as you feel is 
necessary – before you make a decision. 
 
Biomarker Research 
 


 
 
10
A biomarker is a biological substance from your body, the cells of your body, that is useful for 
measuring or predicting a disease or your child’s response to the study medicine. We will perform 
research on your child’s samples to see if there is a way to predict how children respond to treatment 
with the study drug enoxaparin. 
 
Below is a list of bio specimen samples that we will collect in this study: 
 
Blood: We will draw about 5.4 mL of blood at 4 different times (4 teaspoons total for the entire 
study). Blood will be drawn from a catheter that is already inserted. Your child will not need to have 
a needle stuck in them to get this blood. 
 
• The day of enrollment (when your child starts being in the study) 
• 1 day after that 
• 4 days after insertion of the catheter 
• At the end of the study 
 
At any one of the time points specified above, additional 0.5 mL of blood will be drawn. 
 
Urine: We will collect 2-5 mL of urine at 4 different times (1.5- 4 teaspoons total for the entire 
study). This will happen at the same times that the blood for research is collected (see above) 
 
These samples are intended for research purposes only. These blood samples will be sent to and stored 
at research Laboratories at Yale University under the direction of Dr. E. Vincent Faustino and Saint 
Louis’s Children’s Hospital under the direction of Dr. Phillip Spinella. Both of these doctors are 
Investigators on this study. 
 
The urine samples will be sent to and stored at Yale University. 
 
Optional Future Storage/Genetic Testing of your Child’s Specimens 
 
You are invited to allow these blood and urine samples (called specimens) and related information to 
be stored (banked) for future research. This may help researchers in the future learn more about how 
to prevent blood clots from developing in children with CVC. 
 
The storage of the blood and urine samples is optional: This means that the choice to allow us to 
store these samples is up to you. You may choose not to let us store and use your child’s samples, 
and his/her care will not be affected by this decision. Your child will still be able to participate in this 
study if you do not agree to allow these samples to be stored for future use. 
 
If you decide that your child’s samples can be kept for future research, you may change your mind at 
any time. To withdraw your child’s samples from the study, you can call a member of the research 
team or you may write to the Principal Investigator using the contact information on page one of this 
form at any time and tell them you do not want your child’s samples used any longer. 
Your child’s samples will be destroyed if it is still possible to identify them. 
 
When your child’s specimens and information are stored, we are careful to try to protect his/her 
identity from discovery by others.  Your child’s samples and information will receive a unique code. 
Other researchers will only receive coded samples and information, and will not be able to link the 
code to your child.  Strict security safeguards are in place to reduce the chance of misuse or 
unplanned release of information. 


 
 
11
 
Using your child’s specimens for research will probably not help him/her. We do hope the research 
results will help other children in the future. 
 
There is a risk that your child’s information could be misused. The chance of this happening is very 
small. We have protections in place to lower this risk. There can also be a risk in uncovering genetic 
information. New health information about inherited traits that might affect you or your blood 
relatives could be found during a research study. Very rarely, health or genetic information could be 
misused by employers, health insurance companies, and others. There is a federal law called the 
Genetic Information Nondiscrimination Act (GINA) that, in general, makes it illegal for health 
insurance companies, group health plans, and most employers (except those with fewer than 15 
employees) to discriminate against your child based on his/her genetic information. However, it  does 
not protect him/her against discrimination by companies that sell life insurance, disability insurance, 
or long-term care insurance in the future. 
 
Your child’s specimens and information will only be used for research and will not be sold. There is 
a possibility that this research may lead to development of products that will be commercialized. If 
this happens, there is no plan to share any financial gain with you or your family or child. 
 
Research results will not be returned to you or your child’s doctor.  If research results are published, 
your child’s name and other personal information will not be given. 
 
Please indicate your choice below by checking yes or no: 
□ Yes, I agree to allow my child’s blood and urine samples and information to be stored and 
used for future, unspecified research of any kind. 
 
□ No, I do not agree to allow my child’s blood and urine samples and information to be stored 
and used for future research. 


 
 
HIC 2000020253 
 
 
 
Page 12 of 12 
Authorization and Permission 
 
I have read (or someone has read to me) this form and have decided to allow my child to 
participate in the project as described above.  The study, the details of my child’s involvement, 
risks inconveniences have been explained. My signature also indicates that I have received a 
copy of this permission form. 
 
By signing this form, I give permission to the researchers to use and give out information about 
my child for the purposes described in this form.  By signing this permission form, I have not 
given up any of the legal rights that my child otherwise would have as a subject in a research 
study. By refusing to give permission, I understand that my child will not be able to participate 
in this research. 
 
 
 
 
 
Name of Child (print name) 
 
 
 
Parent Name (print name) 
 
 
  
 
Parent Signature 
Date 
 
  
 
 
  
  
Signature of Person Obtaining Permission 
 
Date 
 
 
If after you have signed this form you have any questions about your privacy rights, please 
contact the Yale University Privacy Officer at (203) 432-5919. 
 
If you have further questions about this project or if you have a research-related problem, you 
may contact Dr. Faustino at (203) 785-4651. 
 
If you would like to talk with someone other than the researchers to discuss problems, concerns, 
and questions you may have concerning this research, or to discuss your rights as a research 
subject, you may contact the Yale Human Investigation Committee at (203) 785-4688.