Clinical trial NCT04354155
Conditions: Infection Viral Thromboses, Venous COVID-19
Sponsor: Johns Hopkins All Children's Hospital
Start date: 2020-06-02; Completion date: 2021-06-04
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety, dose-requirements, and exploratory efficacy of twice-daily subcutaneous enoxaparin as venous thromboembolism prophylaxis in children (birth to 18 years) hospitalized with signs and/or symptoms of SARS-CoV-2 infection (i.e., COVID-19).

Detailed description:

Arms: arm 1: Twice-daily low-dose enoxaparin thromboprophylaxis (starting dose, 0.5 mg/kg subcutaneously q12 hours, adjusted to achieve a 4 hour post-dose anti-factor Xa level of 0.20-0.49 anti-Xa U/mL)
Interventions: intervention 1: Enoxaparin Prefilled Syringe [Lovenox]
Intervention descriptions: intervention 1: Twice-daily low-dose enoxaparin thromboprophylaxis (starting dose, 0.5 m/gkg subcutaneously q12 hours, adjusted to achieve a 4 hour post-dose anti-factor Xa level of 0.20-0.49 anti-Xa U/mL)

Protocol documents:
Prot_000.pdf: 
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COVID-19 Anticoagulation in Children - 
Thromboprophylaxis (COVAC-TP) Trial 
Protocol ID: COVAC-TP 
eIRB #: IRB00247991 
National Clinical Trial (NCT) Identified Number:  NCT04354155 
Overall (National) Principal Investigator: Anthony Sochet, MD, MSc 
Funded by: Johns Hopkins All Children's Hospital Foundation Inc. 
 
Historical Protocol Versions 
Original/Version 1/Date: 05/12/2020 
Amendment/Version 2/Version Date: 05/21/2020 
Amendment/Version 3/Version Date: 07/02/2020 
Amendment/Version 4/Version Date: 02/01/2021 
Amendment/Version 5/Version Date: 03/08/2021 
 
 


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Table of Contents 
I. 
HYPOTHESES AND SPECIFIC AIMS/PURPOSE ...............................................................................3 
A. 
Statement of Purpose ............................................................................................................3 
B. 
Principal Aims and Hypotheses ...............................................................................................3 
II. 
BACKGROUND AND SIGNIFICANCE .............................................................................................4 
III. 
PRELIMINARY STUDIES/PROGRESS REPORT: ...........................................................................5 
IV. 
RESEARCH METHODS: SUMMARY OF STUDY RATIONALE ........................................................6 
A. 
Primary Outcome: ..................................................................................................................6 
B. 
Secondary Outcome(s): ..........................................................................................................6 
C. 
Endpoint Adjudication: ..........................................................................................................6 
D. 
Summary of Research methods and Study Design ...................................................................6 
E. 
Description of Population to be Enrolled ................................................................................8 
1. 
Target Enrollment ..............................................................................................................8 
2. 
Inclusion Criteria .............................................................................................................. 10 
3. 
Exclusion Criteria ............................................................................................................. 11 
F. 
Description and Justification of Procedures, Measures, and Data Collection Tools: ................ 11 
G. 
Potential Scientific Problems: ............................................................................................... 14 
H. 
Data Analysis Plan: ............................................................................................................... 15 
I. 
Data Management and Security ........................................................................................... 16 
J. 
Data Safety and Monitoring Plan .......................................................................................... 16 
1. 
DSMP Summary ............................................................................................................... 16 
2. 
Protocol Stopping Criteria ................................................................................................ 17 
3. 
AE/SAE Reporting Plan ..................................................................................................... 18 
4. 
Deviation Reporting Guidelines ........................................................................................ 20 
5. 
Unanticipated Problem Reporting Guidelines ................................................................... 21 
K. 
Human Subject Research Considerations .............................................................................. 21 
1. 
Risks to Study Participants ............................................................................................... 21 
2. 
Alternative Treatments Considered .................................................................................. 21 
3. 
Adequacy of Protection Against Risks ............................................................................... 22 
4. 
Special Consent/Assent Plan ............................................................................................ 22 
5. 
Potential Benefits ............................................................................................................ 22 
6. 
Incentives or Rewards Offered for Participation ................................................................ 22 
L. 
Summary of Knowledge to be Gained: .................................................................................. 23 
V. 
REFERENCES............................................................................................................................. 24 
VI. 
APPENDICES......................................................................................................................... 26 
A. 
Appendix 1. Planned participating centers and site investigators........................................... 26 
     B.  
Appendix 2. Clinical coordinating center description. 
 
 


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I. 
HYPOTHESES AND SPECIFIC AIMS/PURPOSE 
 
A. 
Statement of Purpose 
 
The purpose of this study is to evaluate the safety, dose-requirements, and exploratory 
efficacy of twice-daily subcutaneous enoxaparin as in-hospital venous thromboembolism 
(VTE) prophylaxis in children (birth to 18 years) hospitalized with signs and/or symptoms 
of SARS-CoV-2 infection (i.e., COVID-19) including COVID-19 multisystem inflammatory 
syndrome (CMIS) 
 
B. 
Principal Aims and Hypotheses 
 
Specific Aim 1: To investigate the safety of in-hospital thromboprophylaxis with twice-
daily low-dose enoxaparin thromboprophylaxis (starting dose, 0.5 m/gkg subcutaneously 
q12 hours, adjusted to achieve a 4 hour post-dose anti-factor Xa level of 0.20-0.49 anti-
Xa U/mL) in children hospitalized with COVID-19 related-illnesses, as measured by the 
cumulative incidence of ISTH-defined [10] clinically-relevant bleeding (primary endpoint).  
 
Hypothesis 1: The observed cumulative incidence of ISTH-defined clinically-
relevant bleeding is ≤2.6% (upper limit of 90% confidence interval: ≤11.8%) among 
children with COVID-19 who receive in-hospital thromboprophylaxis with twice-
daily low-dose enoxaparin.   
 
Specific Aim 2: To determine the median twice-daily enoxaparin dose, as measured in 
mg/kg, required to achieve a 4 hour post-dose anti-factor Xa level of 0.20-0.49 anti-Xa 
U/mL in children hospitalized with COVID-19 related-illnesses, and to compare dose-
requirements by age group (birth to <1 year old, 1-<6 years old, 6-<13 years old, and 13-
<18 years old).  
 
Hypothesis 2: Median dose-requirement for anti-Xa-targeted thromboprophylaxis 
with twice-daily enoxaparin, as measured in mg/kg, in children hospitalized with 
COVID-19 are associated with age, with younger age groups requiring higher 
doses. 
 
Specific Aim 3 (Exploratory): To investigate, on an exploratory basis, the efficacy of in-
hospital thromboprophylaxis with twice-daily enoxaparin in children hospitalized with 
COVID-19, as measured by the proportion of serial D-dimer levels obtained at 
standardized time points that are <2 times the upper limit of normal (<2x ULN) values for 
age (Aim 3a; surrogate marker of efficacy), the cumulative incidence of radiologically-
confirmed HA-VTE (Aim 3b; clinical efficacy), and the median duration of in-hospital 
increased respiratory support (new requirement for high-flow nasal cannula, non-invasive 
ventilation, and/or mechanical ventilation, relative to any at-home baseline requirement; 
Aims 3c, clinical efficacy). 
 
 
 


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II. 
BACKGROUND AND SIGNIFICANCE 
 
VTE is a serious condition in children associated with significant morbidity. Adverse VTE 
outcomes include VTE-related mortality, recurrent VTE, and development of chronic 
venous insufficiency following deep venous thrombosis (post-thrombotic syndrome). 
Given these adverse outcomes, as well as recent recognition of VTE as the second 
leading cause of preventable harm in hospitalized children (after central line associated 
blood stream infections; CLABSI) [1], a national patient safety initiative in the U.S., 
supported by the Children’s Hospitals Association Solutions for Patient Safety network, 
has been undertaken to reduce the incidence of hospital‐associated VTE (HA‐VTE) in 
children. While pharmacological thromboprophylaxis with various anticoagulants 
(including low molecular weight heparins and the direct oral anticoagulants) has been 
shown to be safe and effective in hospitalized adults, both safety and efficacy among 
hospitalized children have yet to be fully established.  
 
In order to optimize benefit‐risk ratio for target populations in future trials of anticoagulant 
thromboprophylaxis in hospitalized children, the PI and colleagues have developed risk 
models for HA-VTE in several important hospitalized pediatric populations, including non-
critically ill children, critically-ill children without underlying cardiac disease, and critically-
ill children following cardiac surgery or cardiac catheter-based therapeutic intervention 
[2–5]. These models share common features of central venous catheterization, severe 
infection or systemic inflammatory state, and anticipated length of stay (LOS) >3 days as 
statistically-significant, independent risk factors for HA-VTE in hospitalized children. In 
the absence of efficacy and safety data from pediatric trials, clinicians across the U.S., 
Canada, Europe and many other countries/regions have, in recent years, used low-dose 
low molecular weight heparins (LMWH; most often, enoxaparin) as primary 
thromboprophylaxis in hospitalized children who exhibit these and/or other high-risk 
features for the development of in-hospital VTE.    
 
A novel coronavirus, SARS-CoV-2, is responsible for a rapidly spreading pandemic that 
has reached 160 countries, causing infection in over 500,000 individuals, and 25,000 
deaths, as of April 1, 2020. The SARS-CoV-2 illness, known as COVID-19, exhibits a 
range of disease severity, from asymptomatic infection to respiratory failure, multi-organ 
failure, and death. Among hospitalized patients, COVID-19 is characterized by atypical 
pulmonary infiltrates and a severe inflammatory response with which marked coagulation 
activation, as evidenced by marked elevation in plasma D-dimer levels. A recent 
retrospective analysis from China demonstrated reduced mortality and reduced LOS 
among hospitalized patients (primarily adults) with COVID-19 and markedly-elevated D-
dimers who received anticoagulation (predominantly, LMWH) [6]. Accordingly, the 
International Society on Thrombosis and Haemostasis (ISTH) has recently recommended 
prophylactic anticoagulation be strongly considered in patients hospitalized for COVID-
19 [7]. Similarly, the American Society of Hematology has recommended that “all patients 
hospitalized with COVID-19 should receive pharmacologic thromboprophylaxis” and 
recommend participation in “well-designed clinical trials and/or epidemiologic studies 
when they become available.” [8] Children with COVID-19 have also presented with 


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CMIS, a Kawasaki-disease-like illness, presenting with severe systemic inflammatory 
disease affecting multiple systems beyond the respiratory system. [9]  
Hospitalization of children infected with SARS-CoV-2 have increased across many 
children’s hospitals in the U.S. with nearly 1% of the infected pediatric population 
anticipated to develop acute respiratory distress syndrome [10]. Many children 
hospitalized with COVID-19 are exhibiting markedly elevated D-dimer levels [11] much 
as has been observed in hospitalized adults, and it is expected that these children will 
similarly exhibit a heightened VTE risk. Based on this urgent and time-sensitive clinical 
need, and given that anticoagulant prophylaxis against HA-VTE in children is used 
selectively in routine care at children’s hospitals across the U.S. but is not yet supported 
by safety data from multicenter clinical trials, the objective of this proposal is to rapidly 
conduct a phase 2 multicenter trial of low-dose enoxaparin thromboprophylaxis in children 
newly-hospitalized with COVID-19. The study proposed herein will leverage an existing 
network and clinical coordinating center (CCC) infrastructure of the NIH NHLBI U01 
Prospective Multi-Center Evaluation of the Duration of Therapy for Thrombosis in 
Children (Kids-DOTT). 
 
This proposal is significant in that it addresses a critical need for establishing safety of 
prophylactic anticoagulation in hospitalized children who are at heightened risk for HA-
VTE. Furthermore, this proposal is innovative, in that it seeks to establish first multicenter 
evidence on safety of prophylactic anticoagulation for the prevention of HA-VTE in 
children, with a focus on the especially-heightened VTE risk population of pediatric 
patients hospitalized with COVID-19 related-illnesses. The work under this supplement is 
a logical extension of the parent award, and will provide complementary knowledge to the 
findings derived from the Kids-DOTT trial, addressing a critical gap in knowledge in the 
pediatric VTE field. The proposed trial addresses the same problem as the parent award 
(i.e., VTE in children) and employs the same therapeutic agents (i.e., conventional 
anticoagulants, which have consisted of the LMWH enoxaparin in >95% of patients). 
 
III. 
PRELIMINARY STUDIES/PROGRESS REPORT: 
 
Based on a PubMed search on 13April2020, no prior studies of safety, dose-requirement, 
and/or efficacy of twice-daily enoxaparin thromboprophylaxis in hospitalized children, with 
or without COVID-19, have been published. Based on clinicaltrials.gov and 
eudract.ema.europa.eu search on 13April2020, no such studies have been registered on 
clinicaltrials.gov or with EudraCT in Europe.   
 
 
 


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IV. RESEARCH METHODS: SUMMARY OF STUDY 
RATIONALE 
 
A. 
Primary Outcome 
 
PRIMARY SAFETY:  Occurrence of clinically-relevant (i.e., major plus clinically relevant 
non-major [CRNM]) bleeding within 30 days. 
 
Based upon International Society on Thrombosis and Haemostasis (ISTH) Scientific and 
Standardization Committee standardized definitions for pediatric trials [12], “Major 
bleeding” will be characterized by bleeding satisfying any one of the following criteria: 
1) fatal; 2) clinically overt and associated with a decrease in hemoglobin of at least 2 g/dL 
in a 24 hour period; 3) clinically overt and for which blood product is administered; 
4) retroperitoneal, pulmonary, or involving the central nervous system; 5) requiring 
surgical intervention in an operating suite. 
 
“CRNM bleeding” definition includes any bleeding that does not fulfill the above criteria 
but fulfills one of the following: 1) Bleeding requiring medical or surgical intervention to 
restore hemostasis; 2) Bleeding for which medical attention is sought. 
 
B. 
Secondary Outcome(s) 
 
DOSE REQUIREMENT: Median twice-daily enoxaparin dose, as measured in mg/kg, 
required to achieve a 4 hour post-dose anti-factor Xa level of 0.20-0.49 anti-Xa U/mL. 
 
EXPLORATORY EFFICACY: Proportion of plasma D-dimer levels <2x ULN; cumulative 
incidence of VTE; and duration of assisted ventilation. 
 
C. 
Endpoint Adjudication 
The primary safety outcome (clinically-relevant bleeding) and exploratory clinical efficacy 
outcome of recurrent VTE, as well as all death events, will be centrally adjudicated via an 
independent Clinical Endpoint Adjudication Committee (CEAC), using a standardized 
process delineated in the CEAC charter. Upon reporting of these outcome events, de-
identified information on pertinent history, physical exam findings, imaging studies, 
laboratory studies, and other pertinent information from the medical record corresponding 
to these outcome events (clinically-relevant bleeds) will be submitted by the study team 
at participating sites for review by the clinical experts on the committee. 
D. 
Summary of Research Methods and Study Design 
 
The study design is a phase 2, single-arm, open-label, non-randomized clinical trial 
conducted among the Kids-DOTT Investigators Group, at 12-15 of the Kids-DOTT 
participating centers. The list of participating Kids-DOTT centers (including primary and 
alternate/supplemental sites) is shown in Appendix 1. Study activity at each site will be 


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overseen by either a pediatric hematologist, pediatric intensivist, or pediatric hospitalist 
as the site principal investigator, in close collaboration with sub-investigators from the 
other two aforementioned specialties.   
 
The Clinical Coordinating Center (CCC) and Data Coordinating Center (DCC) for this non-
blinded, non-randomized phase 2 trial are at Johns Hopkins All Children’s Hospital 
(JHACH; St. Petersburg, FL), led by Johns Hopkins University School of Medicine faculty 
based on that campus (Appendix 2. CCC). Coordinating center personnel have extensive 
experience in the conduct of numerous large collaborative clinical trials, with specific 
expertise in pediatric phase 1-3 trials. CCC and DCC key personnel include: 
 
Overall (National) Principal Investigator:  
Anthony Sochet, MD, MSc 
Steering Committee Chair:  
 
 
Neil Goldenberg, MD, PhD 
Clinical Endpoint Adjudication Ctte Chair:  
Robert Sidonio, MD 
Data and Safety Monitoring Board Chair:  
Sarah O’Brien, MD, MPH 
Medical Safety Officer:  
 
 
 
Neil Goldenberg, MD, PhD 
Multi-Site Project Managers:  
 
 
Fatima Tariq, MS (CCC) 
 
 
 
 
 
 
 
Nuredin Joehar, MBA-IT (DCC) 
Lead Biostatistician:  
 
 
 
Ernest Amankwah, PhD 
Biorepository Manager: 
 
 
 
Billy Schleif, MS, MT 
 
Anticoagulant (low-dose enoxaparin) thromboprophylaxis dosing regimen is as follows for 
inpatient use only: 
 
• Enoxaparin starting dose 0.5 mg/kg (max starting dose: 60 mg) subcutaneously 
q12 hours, adjusted to achieve a 4 hour post-dose anti-factor Xa level of 0.20-0.49 
anti-Xa U/mL after the 1st or 2nd dose. 
 
o For anti-Xa values <0.20 U/mL, the enoxaparin dose will be increased by 
10-20%, and a 4 hour post-dose anti-Xa level will be obtained after the 1st 
or 2nd dose at the new dosing regimen. 
 
o For anti-Xa values ≥0.5 U/mL, the enoxaparin dose will be decreased by 
10-20%, and a 4 hour post-dose anti-Xa level will be obtained after the 1st 
or 2nd dose at the new dosing regimen.  
 
The Schedule of Assessments is shown in Table 1. SAE monitoring and safety laboratory 
monitoring occurs on days 1-3, and on days 7 and 14 if the patient is still hospitalized. 
For all participants, pertinent clinical data will be captured as follows: results of 
coagulation and thrombophilia testing; nature of any major or clinically-relevant non-major 
bleeding episodes (as defined in Section IV B, above) during the anticoagulant therapy 
period (with detail as to amount of any related blood transfusion and/or any other 
intervention required—see also Data and Safety Monitoring Plan section); and nature of 
any new onset VTE (with detail as to signs/symptoms and anatomic site). PDFs of the 
REDCap electronic case report forms (eCRFs), as well as SAE report forms, are provided 
in the Manual of Operations. All SAEs and enoxaparin regimen adherence will be tracked 


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throughout hospitalization, and SAEs will continue to be tracked through 30 days post-
enrollment.  
 
Children will complete their participation in the trial at the 30 days (+/- 2 days) post-
enrollment end-of-study telephone visit.  As noted previously, the primary safety endpoint 
collection also occurs at the 30 days (+/- 2 days). 
 
E. 
Description of Population to be Enrolled 
 
1. 
Target Enrollment 
The target accrual is based on the primary endpoint (safety). The safety population is 
defined as all patients who received at least one dose of the enoxaparin regimen. In order 
to achieve adequate power and precision for determination of safety in the primary 
analysis (see also section G, below), the target enrollment is 38 evaluable children, from 
among a total of 12-15 participating sites. Participants who do not received at least one 
dose of the enoxaparin regimen (i.e. early termination, withdrawal of consent) will be 
replaced.  Anticipating an 85% retention rate, we will enroll up to 45 participants. Both 
males and females of all races and ethnic groups are eligible for this study.  
 
 


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Table 1. Schedule of Assessments. 
 
Assessment 
Screening 
(Within 72 
hours of 
hospital 
admission)  
Enrollm
ent  
Day 0 
Day 1 
Day 2 
Day 3 * 
Day 7 * 
Day 14 * 
Day 30  
(+/- 2 
days) 
Informed consent 
 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
Full H&P 
X 
 
 
 
 
 
 
 
Focused H&P 
 
 
X 
X 
X 
X 
X 
 
Weight 
X 
 
 
 
 
 
 
 
CBC with platelet count 
X 
 
 
 
X 
X 
X 
 
PT and aPTT 1 
X 
 
 
 
X 
X 
X 
 
Fibrinogen 1 
X 
 
 
 
X 
X 
X 
 
Serum creatinine 
X 
 
 
 
X 
X 
X 
 
Urine pregnancy screen1 
X 
 
 
 
 
 
 
 
Research blood specimen2 
 
 
X 
X 
X 
X 
X 
X 
 
Anti-factor Xa level 1,3 
 
 
X 
+/- X 
 
 
 
 
SAE Monitoring 
 
 
X 
X 
X 
X 
X 
X 
Bleeding event (based on 
focused interim H&P) 
 
 
X 
X 
X 
X 
X 
X 
VTE event (based on 
focused interim H&P, 
with radiological 
confirmation when 
suspected clinically) 
 
 
X 
X 
 
X 
 
X 
X 
X 
Telephone visit 4 
 
 
 
 
 
 
 
X 
 
1 Obtained for research purposes if not already being obtained clinically. 
2 For participants <20kg: (1) 3ml blue top tube and (1) 4mL CPT Tube (7mL total). For participants ≥20kg, (1) 3mL blue top tube and (2) 4mL 
CPT tubes (11mL total). Research blood collection is for central research lab testing of D-dimer, Clot Formation and Lysis (CloFAL) assay, IL-6, 
and anti-SARS-CoV-2 IgG, as well as banking plasma, DNA isolated from the buffy coat, and peripheral blood mononuclear cells (PBMCs)for 
future research. 
3 Obtained at 4 hours after 1st or 2nd dose of enoxaparin, at initial dosage (mg/kg) and any subsequent change in dosage. 
4 Focused, scripted assessment of symptoms of potential concern for bleeding events, VTE events, and SAEs. Refer to Manual of Operations. 
* If still hospitalized. 
 
Abbreviations: H&P, history and physical exam; CBC, complete blood count; PT, prothrombin time; aPTT, partial thromboplastin time; SAE, 
serious adverse events; VTE, venous thromboembolism; CT, computed tomography. 
 
 
 


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2. 
Inclusion Criteria 
 
 
Inclusion Criteria for COVID-19 Infected Patients: 
 
1. Children (birth to <18 years of age) 
2. Positive nucleic acid test, antigen testing, or antibody testing for SARS-CoV-2 
within the past 7 days  
3. Hospitalized <72 hours post-admission  
4. One or more signs and/or symptoms of COVID-19 illness within the past 72 hours, 
as follows:  
i.) 
Cough  
ii.) 
Fever (oral temperature >100.4°F/38°C)  
iii.) 
Chest pain  
iv.) 
Shortness of breath  
v.) 
Myalgia 
vi.) 
Acute unexplained loss of smell or taste 
vii.) 
New/increased supplemental oxygen requirement 
viii.) 
Acute respiratory failure requiring non-invasive or invasive ventilation 
ix.) 
Encephalitis 
5. Clinical suspicion that the above symptoms are related to COVID-19 infection and 
not an alternative etiology. 
 
Inclusion Criteria for CMIS Patients Who Do Not Already Meet the Above Criteria 
for COVID-Infected Patients: 
 
1. Children (birth to <18 years of age) 
2. Signs and symptoms of COVID-19 Multi-System Inflammatory Syndrome (CMIS) 
including: 
i.) 
fever ≥ 3 days;  
ii.) 
Two or more of the following: 
a) Rash of bilateral non-purulent conjunctivitis or muco-cutaneous 
inflammation (oral, hands, or feet), 
b) Hypotension or shock, 
c) Features of myocardial dysfunction, pericarditis, valvulitis, or 
coronary abnormalities (including ECHO findings or elevated 
troponin/NT-proBNP), 
d) Evidence of coagulopathy (by PT, PTT, or d-Dimer) 
e) Acute gastrointestinal problems (diarrhea, vomiting, abdominal 
pain) 
iii.) 
Elevated markers of inflammation (erythrocyte sedimentation rate, C-
reactive protein, or pro-calcitonin);  
iv.) 
No other obvious microbial cause of inflammation, including bacterial 
sepsis, staphylococcal or streptococcal shock syndrome;  
v.) 
Known exposure to a SARS-CoV-2 positive case, as documented by 
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3. 
Exclusion Criteria (for both COVID-19 and CMIS) 
 
1) Patient’s expected length of hospitalization is < 2 days 
2) Receiving therapeutic dosing of anticoagulation (NOTE: pre-enrollment 
prophylactic enoxaparin administration is not an exclusion criterion) 
3) Receiving ASA dosing > 5 mg/kg/day 
4) Clinical-relevant bleeding (see criteria under Primary Outcome, below) within the 
past 72 hours 
5) Platelet count <50,000/µL within the past 24 hours 
6) Prothrombin time (PT) ≥2 seconds above the upper limit of age-appropriate local 
reference range within 24 hours prior to enrollment, unless PT was <2 seconds 
above upper limit within 24 hours prior to start of anticoagulation for routine 
clinical care OR unless a PT mixing study at either of these time points indicates 
the absence of a coagulation factor deficiency* 
7) Activated partial thromboplastin time (aPTT) ≥4 seconds above the upper limit of 
age-appropriate local reference range within 24 hours prior to enrollment, unless 
PTT was <4 seconds above upper limit within 24 hours prior to start of 
anticoagulation for routine clinical care OR unless a PTT mixing study at either of 
these time points indicates the absence of a coagulation factor deficiency * 
8) Fibrinogen level <75 mg/dL 
9) Severe renal impairment, as defined by estimated glomerular filtration rate 
(eGFR) <31 mL/min/1.73 m2, as calculated by the Schwartz formula 
10) Parent or legally authorized representative unwilling to provide informed consent 
for patient participation.  
 
*NOTE: A PT-based or PTT-based mixing study indicates the absence of a coagulation 
factor deficiency if the originally-prolonged clotting time in the assay does not correct to 
within the age-appropriate local reference range upon the addition of pooled normal 
plasma to patient plasma in a 1:1 ratio.  
NOTE regarding pregnancy and eligibility: 
A patient that is pregnant while enrolled in this study will remain eligible for this study. 
F. 
Description and Justification of Procedures, Measures, and 
Data Collection Tools: 
There will be minimal laboratory assays, examinations, or other procedures performed 
solely for the purposes of this study and not currently part of best/standard clinical care.   
The first is an additional 11 mL blood specimen (7mL in participants <20kg) obtained at 
visits on post-enrollment days 1 and 2 (and days 3, 7, and 14 if still hospitalized) for 
protocol-specified research laboratory investigations (D-dimer, IL-6, anti-SARS-CoV-2 
IgG/IgM, and CloFAL assay) and future unspecified research (i.e., banking of plasma, 
DNA isolated from the buffy coat, and isolated PBMCs). These biospecimens will be 
stored in the Johns Hopkins All Children’s Pediatric Biorepository at the Clinical 
Coordinating Center. All biospecimen storage tubes are pre-labeled with a unique 2D 


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barcode, with the association between the barcode and the participant’s unique study ID 
maintained in the Biorepository’s secure, web-based, password-protected Lab 
Information Management System (LIMS) maintained behind the information technology 
firewall at Johns Hopkins All Children’s Hospital. Biospecimens will be used to identify 
and validate putative prognostic biomarkers in pediatric venous thrombosis and COVID-
19-related illness. The genetic investigations will involve candidate genes, a genome-
wide association study (GWAS), and whole genome sequencing approaches in 
deoxyribonucleic acid. The Johns Hopkins All Children’s Pediatric Biorepository uses a 
secure database to store all data related to the samples, behind the institutional firewall. 
Following completion of the protocol-specified aims, external requests for specimens in 
the COVAC-TP trial biobank will be vetted and made available through the National 
Institutes of Health (NIH), in accordance with NIH policies on data and biospecimen 
sharing. The second procedure will be obtaining a contrast enhanced computed 
tomography scan of the chest within 24 hours preceding discharge from the hospital (if 
not already obtained clinically during hospitalization) to assess for pulmonary emboli. 
Throughout their study participation, up to and including visit 6, patients will be assessed 
for bleeding and VTE events by their inpatient medical provider team with any SAEs being 
documented in the case report forms (supported by source documentation in the patient’s 
electronic medical record) and reported to the Medical Safety Officer (MSO)  as described 
in Section J.2.  The MSO will perform an independent determination of each SAE that 
has been locally determined by the responsible site PI, regarding relatedness to study 
intervention. If EITHER determination is that the SAE is “related”, the SAE will be reported 
to the DSMB chair. The DSMB will then assess whether any action is needed, depending 
on the nature of the SAE. Adverse events (and symptoms of concern for possible VTE or 
clinically-relevant bleeding) will be further assessed at a long-term follow up visit 30 days 
(+/- days) after enrollment via telephone call from a study team member.  
Screening/Within 72 hours of hospital admission (Day 0) 
• Informed consent 
• Enrollment 
• Full medical history and physical exam 
• Weight 
• Initial plasma laboratory evaluation including the following (obtained as research 
purposes if not already obtained clinically 
o Complete blood cell count with platelet count 
o PT and aPTT 
o Fibrinogen 
o Serum creatinine 
o Urine pregnancy screening (beta-HCG) 
• Research blood specimen collection 
 
 


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Day 1 after enrollment (as inpatient) 
• Interval focused interim history and physical with assessment for serious 
adverse events, bleeding event, and/or VTE event by inpatient medical provider 
• Anti-factor Xa level 
• Research blood specimen 
Day 2 after enrollment (as inpatient) 
• Interval focused interim history and physical with assessment for serious 
adverse events, bleeding event, and/or VTE event by inpatient medical provider 
• Anti-factor Xa level (if enoxaparin dose sub- or supratherapeutic) 
• Research blood specimen 
Day 3 after enrollment (if still hospitalized) 
• Interval focused interim history and physical with assessment for serious 
adverse events, bleeding event, and/or VTE event by inpatient medical provider 
• Repeat plasma laboratory evaluation including the following (obtained as 
research purposes if not already obtained clinically) 
o Complete blood cell count with platelet count 
o PT and aPTT 
o Fibrinogen 
o Serum creatinine 
• Research blood specimen 
Day 7 after enrollment (if still hospitalized) 
• Interval focused interim history and physical with assessment for serious 
adverse events, bleeding event, and/or VTE event by inpatient medical provider 
• Repeat plasma laboratory evaluation including the following (obtained as 
research purposes if not already obtained clinically) 
o Complete blood cell count with platelet count 
o PT and aPTT 
o Fibrinogen 
o Serum creatinine 
• Research blood specimen 
 
 


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Day 14 after enrollment (if still hospitalized) 
• Interval focused interim history and physical with assessment for serious 
adverse events, bleeding event, and/or VTE event by inpatient medical provider 
• Repeat plasma laboratory evaluation including the following (obtained as 
research purposes if not already obtained clinically) 
o Complete blood cell count with platelet count 
o PT and aPTT 
o Fibrinogen 
o Serum creatinine 
• Research blood specimen 
30 days (+/- 2 days) after enrollment 
Patient will be assessed for SAEs, bleeding events, and VTE events via telephone call 
with a study team member using a standardized screening script. 
Off-Study Criteria:  
1. In the investigator’s opinion, it is in the participant’s best interest to discontinue 
participation.  
2. Study discontinuation by sponsor, IRB, or other regulatory body.  
3. Lost to follow-up: Participants will not be deemed lost to follow-up until they have 
had no successful contact by the end of the 30-day visit window. Sites must 
document all attempts to contact the participant.  
G. 
Potential Scientific Problems: 
Although this study involves relatively minimal intervention relative to standard care for 
hospitalized children with potentially severe respiratory viral infections, the main potential 
problems and challenges involve maintaining adequate personal protection from the 
exposure and transmission of SARS-CoV-2 (the cause of COVID-19 disease).  
Accordingly, all interactions with participants will take place as part of each site’s standard 
of care for patients with COVID-19.  Clinical assessments and the procurement of biologic 
specimens will be obtained concurrent with routine clinical procedures so to limit the 
consumption of limited personal protective equipment.  In order to reduce exposure of 
study personnel to patients positive for SARS-CoV-2 and reduce the consumption of PPE, 
informed consent will be obtained in accordance with FDA regulations (21 CFR 50.27(a)) 
that allow each site to obtain informed consent if the appropriate technology is available 
or utilizing the following steps: 
1) An unsigned consent form will be provided to the parent/legal guardian by a 
health care worker that has already entered the patient’s room 
2) In the event direct communication with the parent/legal guardian and patient is 
not feasible or safe, the investigator (or designee) will arrange a three-way call 
or video conference with the parent/legal/guardian and impartial witness 


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3) Each site will utilize a standard practice to ensure all patients approached in a 
consistent fashion including: 
a) Identification of who is on the call 
b) Review of the informed consent with the parent/legal guardian and 
response to any questions they may have 
c) Confirmation by the witness that the patient’s questions have been 
answered 
d) Confirmation by the investigator that the parent/legal guardian is 
consenting for the patient to participate in the study 
If the informed consent document is obtained in person and cannot be removed from the 
patient’s room and included in the study records due to infection control processes, the 
following measures will be considered compliant with FDA regulations for informed 
consent: 
1) Attestations by the witness who participated in the call and by the investigator 
that the patient confirmed that they agreed to participate in the study and 
signed the informed consent; OR 
2) A photograph of the informed consent document with attestation by the person 
entering the photograph into the study record that states how that photograph 
was obtained and that it is a photograph of the informed consent signed by the 
patient. 
Other challenges stem from the multi-center nature of the study, including uniformity of 
data collection and anticoagulant management, and timely data entry into the EDC 
system. These challenges are overcome via the CCC and DCC structure and close 
oversight of the trial, the use of EDC system with standardized eCRFs, and the agreement 
of all participating centers to follow the protocol-defined enoxaparin thromboprophylaxis 
regimen, as being consistent with their local standard practice. These potential challenges 
did not materialize as substantive issues in the Kids-DOTT phase 3 multicenter trial 
conducted by the same investigator group. 
H. 
Data Analysis Plan: 
 
The statistical analysis plan was developed by the lead trial biostatistician. Subject 
demographics and characteristics at study entry will be summarized with counts and 
percentages for categorical variables, and with means, standard deviations, medians, and 
interquartile ranges (IQR) as appropriate, for numeric variables. Missing data will not be 
imputed. Analysis of the primary endpoint will be conducted on the safety population, 
which includes all subjects who receive at least one dose of enoxaparin. The primary 
endpoint, cumulative incidence of ISTH-defined [11] clinically-relevant bleeding events 
during hospitalization, will be calculated with the corresponding exact (Clopper-Pearson) 
90% confidence intervals (90%CIs). The precision of estimates for different cumulative 
incidences of clinically-relevant bleeds and corresponding 90% Cis are as follows: 0/38, 
0% (0-7.6)%; 1/38, 2.6% (0-11.8%); 2/38, 5.3% (0-15.7%). The secondary endpoint, 
twice-daily enoxaparin dose required to achieve target anti-Xa levels, will be summarized 


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with medians and IQRs for all the study participants combined and by age group. Medians 
will be compared across age groups, if there are adequate numbers in the groups, using 
the Kruskal-Wallis test and a post-hoc Bonferroni-adjusted Mann-Whitney U test, if 
needed. The tertiary endpoints (as outlined in Section IV.B) will be calculated as 
proportions and cumulative incidences with 90%CIs, and medians with IQRs. 
 
I. 
Data Management and Security 
At the Data Coordinating Center (DCC) level, data management and security are 
facilitated via a JHACH-hosted, web-based, secure, user-restricted, password-protected, 
Electronic Data Capture (EDC) system, REDCap. When combined with the Standard 
Operating Procedures of the COVAC-TP trial DCC at JHACH (sponsoring institution), 
REDCap fosters 21CFR part 11 adherence. Electronic case report form (eCRF) additions, 
modification of programmed data quality assurance alerts, and programming of reports 
within the EDC system is overseen by the DCC. Data export and transfers to the JHACH-
based lead biostatistician at the DCC are executed via a secure, user-restricted, 
password-protected server that resides behind the firewall at the Johns Hopkins 
University School of Medicine.  
At the participating site level, the EDC system is used by Principal Investigators (PIs) and 
their designees for participant enrollment, and data collection, and query resolution. Data 
collection in the EDC system includes protected health information (PHI), limited to date 
of birth and dates of events. In addition to using the EDC system, PIs at participating sites 
will maintain a local “COVAC-TP participant key” as a password-protected file on a secure 
shared drive behind the institutional firewall. This key will consist of each participant’s 
unique study ID code (centrally generated, via the EDC system) along with his/her 
Medical Record Number at the local medical institution. Any hard copy records containing 
PHI – including the regulatory binder for the trial as well as individual participant study 
binders -- will be kept in a locked file cabinet under the local PI’s direct oversight.  
At the CCC level, administrative access to the COVAC-TP instance in the EDC system is 
granted to the CCC project managers on a limited basis. Specifically, this user-restricted 
role is used for query generation, and has “view-only” access within the eCRFs.  
In addition, the Johns Hopkins All Children’s Pediatric Biorepository at the CCC, serving 
as the central biorepository for the trial, facilitates data management and security by 
means of a 21 CFR part-11-adherent web-based LIMs system (STARLIMSTM, Abbot 
Informatics), that affords password-protected, user-restricted access to Biorepository 
staff only, and consists of PHI-free data on specimen/derivative inventory and pre- 
analytical quality assurance.  
J. 
Data Safety and Monitoring Plan 
 
1. 
DSMP Summary 
An independent Data and Safety Monitoring Board (DSMB) consisting of a pediatric 
hematologist, a pediatric critical care or hospital medicine physician, and a PhD-level 


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biostatistician will be established and supported via the Pediatric Data Coordinating 
Center at Johns Hopkins All Children’s. The DSMB will convene at least quarterly 
throughout the trial, including interim analyses for safety monitoring, to review confidential 
and de-identified data. Criteria for halting enrollment pending further evaluation by the 
DSMB are shown in Table 2, below. At that time, the DMSB will consider a 
recommendation to terminate versus continue the trial, based on evaluation of most up-
to-date literature on the rate of clinically-relevant bleeding among children hospitalized 
with COVID-19 outside of the trial.  
A Medical Safety Officer (MSO) will function for additional safety oversite for the Overall 
PI, and to facilitate timely sponsor-level SAE review and communication with the DSMB. 
The MSO will perform an independent determination of each SAE that has been locally 
determined by the responsible site PI, regarding relatedness to study intervention. If 
EITHER determination is that the SAE is “related”, the SAE will be reported to the 
DSMB chair. Reporting timelines are provided in the Manual of Operations 
2. 
Protocol Stopping Criteria 
Following its review of the DSMB Report and any other relevant data at each meeting, 
the COVAC-TP independent DSMB will make recommendations to the Steering 
Committee and the NHLBI Office of the Director regarding termination vs. continuation of 
the phase 2 clinical trial as noted in Table 2. These recommendations by the DSMB will 
consider the stopping rules and cumulative SAE profile to date and other relevant safety 
findings in the study, as well as trial quality and enrollment metrics. In the case of 
persistently poor trial enrollment metrics, the DSMB may recommend termination of the 
trial for futility, versus continuation of the trial with protocol modifications.  
Reasons for early termination are as follow:  
• Evidence of safety concerns—although stopping rules have been established as 
a guide, this can occur at any point during the study, based on the DSMB’s review 
of cumulative data to date at scheduled or ad hoc DSMB meetings.  
• Determination of futility: Evidence of persistently poor trial enrollment metrics, 
which cannot be (or has not been) remedied via protocol modification or other 
appropriate corrective action.  
Table 2.  
Optimized Boundaries for Halting Enrollment (i.e., “Pause”)  
               Pending Further Evaluation by the DSMB.  
• 
 
• 
 
 
 
 
# Patients who Received 
Enoxaparin 
Thromboprophylaxis 
Pause if # of Patients with  
Clinically-Relevant Bleeding   
<10 
1 
10-<20 
2 
20-<30 
3 
30-<38 
4 


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3. 
SAE Reporting Plan 
SAEs will be collected from time of enrollment to the end of the 30 day study window.  
Diseases or conditions that were present prior to the time of randomization should not be 
counted as adverse events unless they increase in grade or severity during the timeframe 
described above.  
Adverse event: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
Serious adverse event: An adverse event is considered "serious" if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
• 
A congenital anomaly/birth defect  
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.  
All SAEs will be reported within 24 hours of knowledge of the event. Please refer to 
the Manual of Operations for SAE reporting forms and guidelines.  
Bleeding Events:  
• 
Major bleeds and clinically-relevant non-major (CRNM) bleeds will be considered 
SAEs of particular interest (if they occur during the AE reporting window).  
• 
Based upon ISTH standardized definitions for pediatric trials [10], “Major bleeding” 
will be characterized by bleeding satisfying any one of the following criteria: 1) fatal; 
2) clinically overt and associated with a decrease in hemoglobin of at least 2 g/dL 
in a 24 hour period; 3) clinically overt and for which blood product is administered; 
4) retroperitoneal, pulmonary, or involving the central nervous system; 5) requiring 
surgical intervention in an operating suite.  
• 
“CRNM bleeding” definition includes any bleeding that does not fulfill the above 
criteria but fulfills one of the following: 1) Bleeding requiring medical or surgical 
intervention to restore hemostasis, but not in an operating suite; 2) Bleeding for 
which medical attention is sought.  


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VTE events will be considered outcome events rather than SAEs, unless they otherwise 
fulfill the regulatory definition of an SAE (i.e., they will not fulfill the SAE criterion of 
investigator-defined “important medical events”).  
 
 


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Adjudication of clinically-relevant bleeding, VTE,  and death:  
The primary outcome on safety in regard to clinically-relevant bleeding, the tertiary 
outcome on clinical efficacy in regard to VTE events, and all death events will be centrally 
adjudicated via an independent, non-blinded Clinical Endpoint Adjudication Committee 
(CEAC) for this non-blinded, non-randomized phase 2 trial. Refer to the Manual of 
Operations for reporting forms and submission instructions. 
4. 
Deviation Reporting Guidelines 
A protocol deviation is defined as a variation from the protocol-directed conduct of a 
clinical trial. Any non- compliance with the study protocol, GCP, ICH guidelines, or a 
protocol-specific requirement is considered a protocol deviation. Protocol deviations will 
be entered into REDCap and reported to the site IRB per site policy. Deviations are 
reviewed in aggregate fashion at standing meetings of the COVAC-TP DSMB, via the 
DSMB report template. Any concerning trends can be further assessed via review of site-
specific deviation logs by the COVAC-TP DSMB, as warranted, and upon request.  
Major Protocol Deviations  
Major Protocol Deviations are defined as deviations that impact patient safety or the final 
outcome measures of the trial. Deviations that meet the defined criteria as Major Protocol 
Deviations will be reported within 5 days of identification of deviation to the CCC Project 
Manager and the site institutional review board (IRB) per local IRB policy.  
Major Protocol Deviations include, but are not limited to:  
1. Inappropriate enrollment; expired protocol*, violation of eligibility criteria or 
incomplete consent documentation  
2. Violation of any site specific IRB requirements (e.g. If sites IRB requires both 
parents to sign consent)  
3. Failure to report SAE in the 24 hour time period following knowledge of SAE*  
4. Failure to provide source documentation of a primary efficacy or safety outcome, 
as well as death event, for central adjudication by the Clinical Endpoint 
Adjudication Committee (CEAC).  
*items are identified as major protocol deviations, but do not disqualify participant’s data 
to be included in the per protocol analysis.  
Minor Protocol Deviations  
Minor Protocol Deviations are defined as deviations that do not impact patient safety or 
the final outcome measure of the trial, but do not follow study specified guidelines. All 
deviations that are not determined to be major deviations are to be recorded as minor 
deviations.  


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Minor Protocol Deviations include, but are not limited to:  
1. Missed visits or visits outside study windows (except Visits 4-6 if not hospitalized 
at time visit is scheduled)  
2. Missed laboratory samples or radiographic imaging that are not related to patient 
eligibility or study outcome (includes research specimens) 
 
5. 
Unanticipated Problem Reporting Guidelines 
Unanticipated problems encountered or uncovered by a participating site PI must be 
promptly reported to the Overall PI and the CCC Project Manager via email. Unanticipated 
problems must also be reported to the IRB or as per IRB policy.  
 
K. 
Human Subject Research Considerations 
 
1. 
Risks to Study Participants 
As discussed in the consent document, risks of bleeding in patients treated with 
anticoagulation are reduced by anticoagulant monitoring; nevertheless, the risk of major 
bleeding in patients given a standard therapeutic course of anticoagulation is 2% [13].  
Retrospective analysis of the Pediatric Health Information System (PHIS) revealed a 
combined minor and major bleeding rate of 5.6% in hospitalized children receiving 
thromboprophylaxis [14]. Such major bleeding includes bleeding in the brain or 
retroperitoneum, bleeding associated with a significant decline in hemoglobin in a 24-hour 
period, and bleeding requiring surgical intervention to establish hemostasis. These types 
of major bleeding can be life threatening. Minor bleeding episodes (those not described 
above, such as nosebleeds or bleeding from lacerations that do not require surgical 
intervention and do not result in a brisk drop in hemoglobin) are more frequently observed 
than major bleeding events. The rate of minor bleeding episodes has been difficult to 
quantify in pediatric and adult studies of VTE treatment (including standard-dose 
enoxaparin), but may be as high as 20% [13]. Minor bleeding episodes developed in 4% 
of 48 children receiving either VTE prophylaxis or acute VTE therapy. No additional 
adverse events were reported. Enoxaparin is used as first-line therapy for treatment 
dosing and  prophylaxis for VTE in pregnant women because it does not cross the 
placenta into fetal circulation [15]. Therefore, exposure to enoxaparin does not pose risk 
to the developing fetus.  
2. 
Alternative Treatments Considered 
An alternative to this research is to not participate and have the prophylaxis approaches 
against HA-VTE determined by the primary medical team, with consultation of a pediatric 
hematologist as deemed clinically appropriate.  


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3. 
Adequacy of Protection Against Risks 
With regard to risks of anticoagulation, participants in whom clinically-relevant bleeding 
develops in-patient (on enoxaparin prophylactic regimen) will receive appropriate medical 
attention, and those in whom bleeding develops as an outpatient (off enoxaparin 
prophylaxis) will be instructed to seek medical attention, as part of routine hospital 
discharge instructions, with re-enforcement by study personnel. However, it should be 
noted that this study involves standard prophylactic dosing of low-dose enoxaparin, and 
is therefore not anticipated to engender substantively greater bleeding risk than standard 
care, and is not expected to be associated with increased bleeding risk beyond 12 hours 
post-cessation of the in-patient low-dose enoxaparin regimen. With regard to participant 
confidentiality, participant identifiers will be highly limited (i.e., Health Insurance Portability 
and Accountability Act [HIPAA] “limited data set”) in the database, and a unique study 
code will be used in lieu of patient names. These data will be kept for as long as necessary 
to conduct this and any future research and to comply with legal obligations related to 
research. A copy of all consent forms, which will contain participant names, will be 
retained in a secure and locked file in the office of the local site principal investigator. A 
key will be securely stored separately at the local institution from all study documents that 
will link the participant name to the study code. The study will be conducted under the 
Declaration of Helsinki and International Conference on Harmonization guidelines.  
Non-English speaking families will be provided with an informed consent written in a 
language understandable to them and a translator provided. To the extent permissible by 
local IRB policy, a short form (in the patient’s native language) may be used in lieu of a 
fully translated informed consent form.  
4. 
Special Consent/Assent Plan 
As this study specifically addresses the pediatric population, assent must be obtained as 
per IRB policy. A subset of children will be unable to provide assent as a result of age, 
maturity, or severity of illness. These children qualify for a waiver of assent. The 
remainder of children will have assent without a signature obtained at the time of parental 
permission to both limit research staff exposure to COVID-19 to research staff. 
 
5. 
Potential Benefits 
No definite direct benefit to the participant is expected from this study. There is a possible 
direct benefit in the form of a decreased risk for development of VTE; however, no such 
benefit may be shown by the study.  
 
6. 
Incentives or Rewards Offered for Participation 
There will be no compensation for participation in this study.  


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L. 
Summary of Knowledge to be Gained: 
The knowledge gained from this study will advance our understanding of safety, dose-
finding and (on an exploratory basis) efficacy of twice-daily low-dose enoxaparin 
thromboprophylaxis in children hospitalized with COVID-19, and more generally, 
hospitalized children who are at increased risk of VTE. The tertiary aim, investigating the 
effect of thromboprophylaxis on respiratory-related outcomes and D-dimer, will contribute 
to the currently limited understanding of the pathophysiology of COVID-19 disease in 
children. 
 
 


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V. 
REFERENCES 
1.  
Goldenberg NA. Venous thromboembolism in children. Clin Adv Hematol Oncol. 2019; 
17(6):326–329.  
2.  
Branchford BR, Mourani P, Bajaj L, Manco-Johnson M, Wang M, Goldenberg NA. Risk 
factors for in-hospital venous thromboembolism in children: a case-control study 
employing diagnostic validation. Haematologica. 2012; 97(4):509–15.  
3.  
Atchison CM, Arlikar S, Amankwah E, et al. Development of a new risk score for hospital-
associated venous thromboembolism in noncritically ill children: findings from a large 
single-institutional case-control study. J Pediatr. 2014; 165(4):793–8.  
4.  
Arlikar SJ, Atchison CM, Amankwah EK, et al. Development of a new risk score for 
hospital-associated venous thromboembolism in critically-ill children not undergoing 
cardiothoracic surgery. Thromb Res. 2015; 136(4):717–22.  
5.  
Atchison CM, Amankwah E, Wilhelm J, et al. Risk factors for hospital-associated venous 
thromboembolism in critically ill children following cardiothoracic surgery or therapeutic 
cardiac catheterisation. Cardiol Young. 2018; 28(2):234–242.  
6.  
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with 
decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J 
Thromb Haemost. 2020; .  
7.  
Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management 
of coagulopathy in COVID-19. J Thromb Haemost. 2020; .  
8. 
American Society of Hematology. COVID-19 and VTE/Anticoagulation: Frequently asked 
questions. Accessed 04/18/2020 < https://www.hematology.org/covid-19/covid-19-and-
vte-anticoagulation>  
8.  
Kids-DOTT Investigators Group.  
9. 
Riphagen S, Gomez X, Gonzales-Martinez C, Wilkinson N, Theocharis P. 
Hyperinflammatory shock in children during COVID-19 pandemic. The Lancet. 2020;DOI: 
https://doi.org/10.1016/S0140-6736(20)31094-1. 
10.  
Cruz AT, Zeichner SL. COVID-19 in Children: Initial Characterization of the Pediatric 
Disease. Pediatrics. 2020; .  
11.  
Wang Z, Zhu F, Wang C, et al. Children hospitalized with severe COVID-19 in Wuhan. 
Pediatr Infect Dis J. 2020;39(7):e91-e94. 
12. 
Mitchell LG, Goldenberg NA, Male C, et al. Definition of clinical efficacy and safety 
outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in 
children. J Thromb Haemost. 2011; 9(9):1856–8.  
13.  
She J, Liu L, Liu W. COVID-19 epidemic: disease characteristics in children. J Med Virol. 
2020; .  
14.  
Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in China. Pediatrics. 
2020; .  
15.  
Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children: 
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th 
Edition). Chest. 2008; 133(6 Suppl):887S-968S.  
16.  
Amos LE, Silvey M, Hall M, Witmer CM, Carpenter SL. Primary thromboprophylaxis in 
hospitalized children: A multi-center retrospective analysis. Thromb Res. 2019; 176:1–7 


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17. 
Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, 
thrombophilia, antithrombotic therapy, and pregnancy, 9th ed: American College of Chest 
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012. 141(2 Suppl):e691S-
e736S. 
 
 


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VI. 
APPENDICES 
 
Appendix 1. Planned participating centers and site investigators. 
 
Primary Centers 
 
Site Name 
(Location) 
Affiliation 
PI /Sub-I(s) 
All Children’s Hospital Johns Hopkins 
Medicine (St. Petersburg, FL)  
Johns Hopkins University 
Sochet/Goldenberg/Morrison 
Children's Hospital of Los Angeles 
(Los Angeles, CA) 
Univ. of Southern California 
Jaffray/Kamerkar/Cowell 
Rady Children's Hospital 
(San Diego, CA) 
University of California San Diego 
Thornburg/Harvey/Fisher 
Children’s Medical Center of Dallas 
(Dallas, TX) 
University of Texas Southwestern 
Zia/McMichael/Linver 
Cohen Children’s Medical Center 
(New Hyde Park, NY) 
Hofstra University-Northshore Long 
Island Jewish 
Acharya/Bakar/Lau 
Boston Children’s Hospital 
(Boston, MA) 
Harvard University 
Kumar/Randolph 
Akron Children’s Hospital 
Northeast Ohio Medical University 
Fargo/McKee/Rajbhandari 
Children’s of Alabama 
University of Alabama Birmingham 
Wilson/Hallman/Molina 
Children’s Hospital of Atlanta 
Emory University 
Woods/Hebbar 
Children’s Hospital of Pittsburgh 
University of Pittsburgh 
Xavier/Aneha 
Children’s National Medical Center  
George Washington University 
Diab/Siems/Pavuluri 
 
 
  Alternate/Supplemental Centers 
 
Site Name 
(Location) 
Affiliation 
PI /Sub-I(s) 
Johns Hopkins Children’s Center  
(Baltimore, MD)  
Johns Hopkins University 
Lawrence/Kudchadkar 
Cincinnati Children's Hospital 
(Cincinnati, OH) 
University of Cincinnati 
Tarango/Chima/Jerardi 
Children’s Hospital of New Orleans 
(New Orleans, LA) 1 
Louisiana State University 
Godiwala/Palombo/Prasad 
Children’s Hospital of Michigan 
Wayne State University 
Rajpurkkar/Bauerfeld 
Lurie Children’s Hospital 
Northwestern University 
Bhat/Barhight/Harris 
 
 
 
 
 


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Appendix 2. Clinical Coordinating Center description of responsibilities. 
 
Johns Hopkins All Children’s Hospital will serve as the Clinical Coordinating Center for the study 
entitled “COVID-19 Anticoagulation in Children - Thromboprophylaxis (COVAC-TP) Trial”.  The 
Clinical Coordinating Center for Pediatric Multicenter Studies at JHACH provides Principal 
Investigators (PIs) with the infrastructure to successfully lead and conduct multicenter pediatric 
studies.  This is accomplished by leveraging the existing resources within the JHAC Clinical and 
Translational Research Organization (CTRO) and All Children’s Research Institute (ACRI) and 
applying them to the overall management and organization of a multicenter study.   
Led by a team of Project Managers (PMs), the CCC manages the project through each phase of 
the study lifecycle from start-up through close out and manuscript publication.   
• In collaboration with the PI, PMs develop and revise all study documents including the 
protocol, consent, and operations manuals and communicates any changes to the 
participating sites.    
• PMs assist the Principal Investigator (PI) in selecting highly-reliable sites with a proven 
track-record of accrual and compliance.   
• PMs maintain contact information for each site. 
• PMs maintain CCC IRB approvals and approved consents (local, single, or central) as well 
as on an ongoing basis the study’s overall Trial Master File (TMF) of regulatory 
documents.   
• PMs confirm that each participating center has an FWA on file with OHRP. 
• PMs provide training to site staff at initiation as well as ongoing through monthly 
conference calls and webinars as well as annual investigator meetings.    
• In collaboration with the PI and study biostatistician, the PM develops and tests Case 
Report Forms (CRFs). 
• In collaboration with the JHAC CTRO Regulatory Affairs/Quality Assurance Unit, PMs 
perform remote monitoring of participating site’s regulatory documentation and study 
data to ensure data accuracy, completeness and integrity. 
• PMs facilitate the reporting of problem events from participating sites. 
• Coordinates with the JHAC Pediatric Biorepository to design, prepare and ship kits for 
sample collection, receipt, and to coordinate return shipment, receipt and storage of 
biological samples, with accompanying sample tracking information.   
 
 
 

SAP_001.pdf: 
1 
 
 
 
Trial monitoring plan – NCT04354155 
 
STATISTICAL ANALYSIS PLAN 
 
 
SAP History: 
Version 
Number 
Version Date 
Summary of Revisions 
Made: 
1.00 
7-Apr-20 
Initial 
1.01 
14-Jul-21 
To present results by age and MISC 
status 
 
 
 
Data Coordinating Center for Pediatric Multicenter Studies 
Institute for Clinical and Translational Research  
601 5t h Street South, Suite 711 
St. Petersburg, FL 33701 
HopkinsAllChildrens.org 
PROJECT TITLE: 
 
 COVID-19 Anticoagulation in Children - 
Thromboprophylaxis (COVAC-TP) Trial 
PRINCIPAL INVESTIGATOR: 
 Anthony Sochet, MD, MPH  
DEPARTMENT/INSTITUTE: 
Clinical and Translational Research Institute 
INSTITUTION: 
Johns Hopkins All Children’s Hospital 
SAP DATE: 
July 14, 2021 
DATA SOURCE: 
Redcap 
PREPARED BY: 
Ernest Amankwah, PhD 


2 
 
 
 
Table of Contents 
1. STUDY OBJECTIVES .................................................................................................................................... 3 
1.1. SPECIFIC AIM 1 3 
1.2. SPECIFIC AIM 2 3 
1.3. SPECIFIC AIM 3 3 
2. STUDY DESIGN ........................................................................................................................................... 3 
2.2. TREATMENT GROUPS 
3 
2.3. STUDY POPULATION 
3 
Inclusion Criteria ................................................................................................................................... 3 
Exclusion Criteria ................................................................................................................................... 4 
2.4. EXPOSURE 
5 
2.5. SAMPLE SIZE 
5 
3. OUTCOME VARIABLES ............................................................................................................................... 5 
3.1. PRIMARY OUTCOME(S) 5 
Safety .................................................................................................................................................... 5 
3.2. SECONDARY OUTCOMES 5 
3.3. EXPLORATORY OUTCOMES 
5 
3.3. OTHER PARAMETERS 
5 
4. STATISTICAL METHODOLOGY ................................................................................................................... 6 
4.1. GENERAL METHODOLOGY 
6 
4.1.1. Population for analysis ................................................................................................................ 7 
4.1.2. Baseline data ............................................................................................................................... 7 
4.1.3. Distributional assumptions ......................................................................................................... 7 
4.1.4. Handling of missing data ............................................................................................................. 7 
4.1.5. Protocol violations and patient withdrawals .............................................................................. 7 
4.2. ANALYSIS OF THE PRIMARY OUTCOME 
7 
4.3. ANALYSIS OF THE SECONDARY OUTCOME 7 
4.4. ANALYSIS OF THE TERTIARY OUTCOMES 8 
4.5 STUDY POWER 
8 
 
 
 
 


3 
 
 
 
1. STUDY OBJECTIVES  
 
1.1. SPECIFIC AIM 1  
- To investigate the safety of in-hospital thromboprophylaxis with twice-daily low-dose enoxaparin 
thromboprophylaxis (starting dose, 0.5 m/gkg subcutaneously q12 hours, adjusted to achieve a 4 
hour post-dose anti-factor Xa level of 0.20-0.49 anti-Xa U/mL) in children hospitalized with 
COVID-19 related-illnesses, as measured by the cumulative incidence of ISTH-defined [10] 
clinically-relevant bleeding (primary endpoint). 
 
1.2. SPECIFIC AIM 2  
- To determine the median twice-daily enoxaparin dose, as measured in mg/kg, required to 
achieve a 4 hour post-dose anti-factor Xa level of 0.20-0.49 anti-Xa U/mL in children hospitalized 
with COVID-19 related-illnesses, and to compare dose-requirements by age group (birth to <1 
year old, 1-<6 years old, 6-<13 years old, and 13-<18 years old). 
 
1.3. SPECIFIC AIM 3  
- To investigate, on an exploratory basis, the efficacy of in-hospital thromboprophylaxis with twice-
daily enoxaparin in children hospitalized with COVID-19, as measured by the proportion of serial 
D-dimer levels obtained at standardized time points that are <2 times the upper limit of normal 
(<2x ULN) values for age (Aim 3a; surrogate marker of efficacy), the cumulative incidence of 
radiologically-confirmed HA-VTE (Aim 3b; clinical efficacy), and the median duration of in-hospital 
increased respiratory support (new requirement for high-flow nasal cannula, non-invasive 
ventilation, and/or mechanical ventilation, relative to any at-home baseline requirement; Aims 3c, 
clinical efficacy). 
 
2. STUDY DESIGN  
The study is a phase 2, single-arm, open-label, non-randomized clinical trial conducted at 12 centers in 
the US to evaluate the safety, dose-requirements, and exploratory efficacy of twice-daily subcutaneous 
enoxaparin as in-hospital venous thromboembolism (VTE) prophylaxis in children (birth to 18 years) 
hospitalized with signs and/or symptoms of SARS-CoV-2 infection (i.e., COVID-19) including COVID-19 
multisystem inflammatory syndrome (MISC)  
 
2.2. TREATMENT GROUPS 
One 
 
2.3. STUDY POPULATION  
Inclusion Criteria 
 
1. Children (birth to <18 years of age)  
2. Positive nucleic acid test, antigen testing, or antibody testing for SARS-CoV-2 within the past 
7 days  
3. Hospitalized <72 hours post-admission  
4. One or more signs and/or symptoms of COVID-19 illness within the past 72 hours, as follows: 
i.) Cough  


4 
 
 
 
ii.) Fever (oral temperature >100.4°F/38°C)  
iii.) Chest pain  
iv.) Shortness of breath  
v.) Myalgia  
vi.) Acute unexplained loss of smell or taste  
vii.) New/increased supplemental oxygen requirement  
viii.) Acute respiratory failure requiring non-invasive or invasive ventilation  
ix.) Encephalitis  
 
5. Clinical suspicion that the above symptoms are related to COVID-19 infection and not an 
alternative etiology.  
 
 Inclusion Criteria for MIS-C Patients Who Do Not Already Meet the Above Criteria for 
COVID-Infected Patients:  
1. 1. Children (birth to <18 years of age)  
2. 2. Signs and symptoms of COVID-19 Multi-System Inflammatory Syndrome (MIS-C) 
including: i.) fever ≥ 3 days;  
3. ii.) Two or more of the following: a) Rash of bilateral non-purulent conjunctivitis or muco-
cutaneous inflammation (oral, hands, or feet),  
4. b) Hypotension or shock,  
5. c) Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities 
(including ECHO findings or elevated troponin/NT-proBNP),  
6. d) Evidence of coagulopathy (by PT, PTT, or d-Dimer)  
7. e) Acute gastrointestinal problems (diarrhea, vomiting, abdominal pain)  
8.  
9. iii.) Elevated markers of inflammation (erythrocyte sedimentation rate, C-reactive protein, or 
pro-calcitonin);  
10. iv.) No other obvious microbial cause of inflammation, including bacterial sepsis, 
staphylococcal or streptococcal shock syndrome;  
11. v.) Known exposure to a SARS-CoV-2 positive case, as documented by clinical history 
 
 
Exclusion Criteria 
 
1) Patient’s expected length of hospitalization is < 2 days  
2) Receiving therapeutic dosing of anticoagulation (NOTE: pre-enrollment prophylactic 
enoxaparin administration is not an exclusion criterion)  
3) Receiving ASA dosing > 5 mg/kg/day  
4) Clinical-relevant bleeding (see criteria under Primary Outcome, below) within the past 72 
hours  
5) Platelet count <50,000/μL within the past 24 hours  
6) Prothrombin time (PT) ≥2 seconds above the upper limit of age-appropriate local reference 
range within the past 24 hours  
7) Activated partial thromboplastin time (aPTT) ≥4 seconds above the upper limit of age-
appropriate local reference range within the past 24 hours  
8) Fibrinogen level <75 mg/dL  
9) Severe renal impairment, as defined by estimated glomerular filtration rate (eGFR) <31 
mL/min/1.73 m2, as calculated by the Schwartz formula  


5 
 
 
 
10)Parent or legally authorized representative unwilling to provide informed consent for patient 
participation.  
  
2.4. EXPOSURE 
Enoxaparin dose 
 
2.5. SAMPLE SIZE  
The study enrolled 38 participants 
3. OUTCOME VARIABLES  
 
3.1. PRIMARY OUTCOME(S) 
Safety: Occurrence of clinically-relevant (i.e., major plus clinically relevant non-major [CRNM]) bleeding 
within 30 days. 
 
3.2. SECONDARY OUTCOMES  
Median twice-daily enoxaparin dose, as measured in mg/kg, required to achieve a 4 hour post-dose anti-
factor Xa level of 0.20-0.49 anti-Xa U/mL. 
 
 
3.3. EXPLORATORY OUTCOMES  
Proportion of plasma D-dimer levels <2x ULN; cumulative incidence of VTE; and duration of assisted 
ventilation (Mechanical ventilation, Non-invasive ventilation and Extracorporeal life support).  
 
3.3. OTHER PARAMETERS 
 
3.3.1 Demographic and clinical characteristics  
- Age, median years 
- Gender 
- Weight 
- BMI  
- Complete blood count 
     - White blood count 
     - Hemoglobin 
     -Platelet 


6 
 
 
 
-Coagulation 
    -Prothrombin time 
    -Partial thromboplastin time 
    -International normalized ratio 
    -Fibronogen 
    -D-dimer 
    -Creatinine 
 
3.3.2 Clinical measures  
  
-COVID-19-related medications 
   -Corticosteroids 
  -Nonsteroidal anti-inflammatory 
   -Intravenous immunoglobulin 
   -Remdesivir 
   -Azithromycin 
   -Anakinra 
  - Tocilizumab 
- Hospital course 
  - Length of stay 
   -Mortality 
   -Central venous catheterization 
- Discharged on thromboprophylaxis 
- Discharged on aspirin 
 
4. STATISTICAL METHODOLOGY  
 
4.1. GENERAL METHODOLOGY   
Data analysis for this study will be performed at the JHAC DCC-PMCS at study completion, 
once the database has been locked and the Statistical Analysis Plan has been finalized and 
approved by the study team.  


7 
 
 
 
 
4.1.1. Population for analysis  
The population will include all enrolled patients who: 1) had no protocol violations in eligibility 
criteria; 2) received at least one dose of enoxaparin; and 3) underwent primary outcome 
determination within 30 days of COVID diagnosis.  
 
 
4.1.2. Baseline data   
The flow of patients, including the overall eligible patients, excluded patients and patients in the analytic 
dataset will be presented in a Figure (Figure 1). We will present demographic and clinical characteristics 
for all patients and by age (<12 and >=12 years) and MISC status (Table 1). Continuous variables will be 
summarized as means with standard deviations or medians with observed range or interquartile range 
and compared between groups with independent t-test or Mann-Whitney U test as appropriate. 
Categorical variables will be summarized as counts with percentages and compared using the Chi-
squared test or Fishers exact test as appropriate. All statistical analyses will be performed with SAS v 9.4 
 
4.1.3. Distributional assumptions   
- The distribution of continuous variables will be evaluated for normality.  
  
4.1.4. Handling of missing data  
The analysis for all the Aims will be a complete case analysis. Missing data will not be imputed.  
 
4.1.5. Protocol violations and patient withdrawals 
All deviations / violations to the protocol (if applicable) will be summarized using counts and 
frequencies. Similarly, reasons for early withdrawal from the study will be summarized using counts and 
frequencies.  
  
4.2. ANALYSIS OF THE PRIMARY OUTCOME  
The primary endpoint, cumulative incidence of ISTH-defined clinically-relevant bleeding events during 
hospitalization, will be calculated with the corresponding exact (Clopper-Pearson) 90% confidence 
intervals (90%CIs) 
 
4.3. ANALYSIS OF THE SECONDARY OUTCOME 
The secondary endpoint, twice-daily enoxaparin dose required to achieve target anti-Xa levels, will be 
summarized with medians and IQRs for all the study participants combined and by age group and MISC 
status. Distributions will be compared across groups, if there are adequate numbers in the groups, using 
Mann-Whitney U test. 
  


8 
 
 
 
4.4. ANALYSIS OF THE TERTIARY OUTCOMES 
The tertiary outcomes will be calculated as proportions and cumulative incidences with 90%CIs, and 
medians with IQRs for all the study participants combined and by age group and MISC status 
 
4.5 STUDY POWER 
With a sample size of 38 patients in the safety population, the precision of estimates for various 
cumulative incidences of clinically-relevant bleeding (with corresponding 90% CIs) was as follows: 0/38, 
0% (0-7.6%); 1/38, 2.6% (0-11.8%); 2/38, 5.3% (0-15.7%).