Clinical trial NCT04360824
Conditions: COVID 19 Associated Coagulopathy
Sponsor: University of Iowa
Start date: 2020-05-06; Completion date: 2021-04-16
Enrollment: 176 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This prospective, randomized, open-label, multi-center interventional study is designed to compare the safety and efficacy of two LMWH dosing protocols in patients admitted to the University of Iowa Hospitals with COVID-19 who meet the modified ISTH Overt DIC criteria score ≥3. Patients will be randomized to standard prophylactic dose LMWH (standard of care arm) or intermediate-dose LMWH (intervention arm).

Detailed description:
Potentially eligible patients will be identified by a healthcare professional per institutional policy on privacy. The healthcare professional will assess the eligibility of the patient by performing a chart review which will include laboratory results and weight as measured on admission to the hospital. After obtaining verbal consent from the patient to be contacted for the study, a member of the research staff will approach the patient to be part of the study. The research staff will obtain informed consent from the patient/LAR before collecting any data and performing any procedures.

5.2 Trial interventions

As standard of care, hospitalized patients with confirmed COVID-19 will be monitored for coagulopathy. Daily blood tests for platelet count, prothrombin time, D-Dimer, and fibrinogen and weekly thromboelastography will be obtained, and a daily Modified ISTH Overt DIC score will be calculated (Exhibit 1). Only patients meeting all inclusion and exclusion criteria will be asked to participate in the trial. Patients will be randomized to one of two arms:

1. Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI \<30 kg/m2; 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2).
2. Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI \<30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30 kg/m2), with doses rounded up to the nearest dose syringe in hospitalized patients with laboratory confirmed SARS CoV-2 infection.

5.3 Dose Modifications

1. Enoxaparin will be held if platelets decrease to \<25,000/mm3. Enoxaparin will resume once platelets increase to ≥25,000/ mm3.
2. Enoxaparin will be held if fibrinogen is \<50 mg/dL. Enoxaparin will resume once fibrinogen increases to ≥50 mg/dL.
3. Enoxaparin will be held if estimated Creatinine clearance \< 15 ml/min calculated by the modified Cockcroft and Gault formula and resumed once the Creatinine Clearance is ≥15 ml/min.
4. Enoxaparin will be held if there is a clinical suspicion for heparin induced thrombocytopenia.
5. Enoxaparin dose will be reduced by 25% if Creatinine Clearance ≥15 and \<30 ml/min calculated by the modified Cockcroft and Gault formula and increased once the estimated Creatinine Clearance is ≥30 ml/min in both the arms.

All participating patients will continue the assigned doses of enoxaparin until hospital discharge or until a clinical event occurs requiring either discontinuation of anticoagulation therapy or full therapeutic dose anticoagulation therapy.

Arms: arm 1: 1\) Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI \<30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30kg/m2). arm 2: 2\) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI\<30 kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2).
Interventions: intervention 1: Intermediate dose thromboprophylaxis intervention 2: Standard of Care thromboprophylaxis
Intervention descriptions: intervention 1: 2\) Patients randomized to the intervention arm will receive intermediate-dose enoxaparin (1 mg/kg Subcutaneously daily if BMI\<30kg/m2 or 0.5 mg/kg Subcutaneously twice daily if BMI ≥ 30kg/m2). intervention 2: Patients randomized to the standard of care arm will receive standard prophylactic dose enoxaparin (40 mg subcutaneously daily if BMI \<30kg/m2 and 30 mg subcutaneously twice daily or 40 mg subcutaneously twice daily if BMI ≥ 30 kg/m2).

Protocol documents:
Prot_SAP_000.pdf: 
pg. 1 
 
Protocol Title: COVID-19-associated coagulopathy: Safety and efficacy of prophylactic 
anticoagulation therapy in hospitalized adults with COVID-19 
 
Version 1.0 
April 8, 2020 
 
 
Investigators: 
Usha Perepu, MBBS, Principal Investigator 
Isaac Chambers, MD 
Steven Lentz, MD, PhD 
Sanjana Dayal, PhD 
Grerk Sutamtewagul, MD 
 
Table of Contents 
1. Background and scientific rationale 
2. Objectives 
3. Study design 
4. Selection of subjects 
5. Study procedures and evaluations 
6. Randomization 
7. Assessment of Scientific Objectives 
8. Withdrawal or Termination 
9. Study Management 
10. Statistical analysis and considerations 
 
 
 
 
 


pg. 2 
 
1. Background and scientific rationale 
Infection with the novel coronavirus SARS-CoV-2, first identified in Wuhan, China in late 
2019, has become a global pandemic affecting over 209 countries and territories. The 
illness caused by SARS-CoV-2 is classified as COVID-19. As of April 8, 2020, the U.S. has 
by far the largest number of total cases (400,549) with a mortality rate of 3.4%. Higher 
mortality rates of over 5% have been seen in other countries. Although many patients 
may have only mild upper respiratory symptoms, some COVID-19 patients become 
severely ill with respiratory failure with risk of progression to multiple organ failure and 
development of a systemic coagulopathy with features similar to disseminated 
intravascular coagulation (DIC).1 The pathophysiology of COVID-19-associated 
coagulopathy appears to be complex and multifactorial, involving both cellular and 
plasmatic elements of the hemostatic system. Development of coagulopathy has been 
suggested to be a predictor of mortality in patients with COVID-19.2 The primary 
treatment of DIC is focused on treating the underlying pathology; which for COVID-19 is 
currently limited to supportive therapy and experimental therapeutics. Treatment with 
low-molecular weight heparin (LMWH) in prophylactic doses was associated with better 
outcomes in severe cases of COVID-19 meeting ISTH criteria for DIC in a retrospective 
analysis.1,2 The International Society of Thrombosis and Hemostasis (ISTH) has published 
an interim guidance document recommending thromboprophylaxis with LMWH for all 
hospitalized patients with COVID-19.3 However, it is not known if patients with 
coagulopathy from COVID-19 benefit from higher levels of prophylactic anticoagulation 
therapy. Presently no data exist regarding the relative safety or efficacy of intermediate-
dose versus low-dose prophylactic LMWH. 
 
This prospective, randomized, open-label, single-center interventional study is designed 
to compare the safety and efficacy of two LMWH dosing protocols in patients admitted 
to the University of Iowa Hospitals with COVID-19 who meet the modified ISTH Overt 
DIC criteria score ≥3. Patients will be randomized to low-dose LMWH (standard of care 
arm) or intermediate-dose LMWH (intervention arm).  
 
2. Objectives 
 
2.1 The primary objective of the study is to compare all-cause mortality of hospitalized 
patients with COVID-19 coagulopathy treated with low-dose versus intermediate-dose 
LMWH at 30 days. 
2.2 The secondary objectives are to determine whether the use of low-dose versus 
intermediate-dose LMWH has an impact on major bleeding, arterial thrombosis, venous 
thrombosis, ICU admission, or transfusion of blood products. 
2.3 The exploratory objectives are to determine the effects of SARS-CoV-2 infection on 
laboratory coagulation parameters to better understand the mechanism of COVID-19 
coagulopathy. 
 


pg. 3 
 
3. Study design 
3.1. Design 
This is a single center, randomized, open-label study comparing low-dose enoxaparin 
(40 mg SC daily or 30 mg SC twice daily if BMI ≥40; standard of care arm) versus 
intermediate-dose enoxaparin (1 mg/kg SC daily or 0.5 mg/kg SC twice daily if BMI≥40; 
intervention arm) in hospitalized patients with laboratory-confirmed SARS-CoV-2 
infection. 
3.2. Rationale for enoxaparin dosing 
Severe infection with SARS-CoV-2 is commonly complicated with coagulopathy. 
Prophylactic anticoagulation therapy was associated with decreased mortality in a 
retrospective analysis of Chinese patients with COVID-19 associated coagulopathy.2 
Pharmacologic thromboprophylaxis is standard of care for patients admitted to the 
hospital with severe respiratory illness and is recommended by the ISTH guidance 
document for hospitalized patients with COVID-19.3 Patients with a BMI ≥ 40 
randomized to the standard of care arm will receive low-dose prophylaxis with LMWH 
but will be adjusted for weight per University of Iowa institutional recommendations.4 
The relative safety and efficacy of low-dose prophylactic LMWH versus higher doses of 
LMWH is unknown. Due to potential bleeding risks with full therapeutic dose 
anticoagulation, the intervention arm in this study will be intermediate-dose of LMWH.  
 
4. Selection of subjects 
4.1 Inclusion criteria 
Subjects must meet all the inclusion criteria to participate in this study. 
• 
Laboratory confirmed SARS-CoV-2 infection 
• 
Age ≥18 years 
• 
Requires hospital admission for further clinical management 
• 
Modified ISTH Overt DIC score ≥ 3 
 
4.2 Exclusion criteria 
Subjects meeting any of the exclusion criteria at baseline screening will be excluded. 
• 
Indication for full therapeutic-dose anticoagulation 
• 
Acute venous thromboembolism (deep vein thrombosis or pulmonary 
embolism) within prior 3 months 
• 
Acute cardiovascular event within prior 3 months 
• 
Acute stroke (ischemic or hemorrhagic) within prior 3 months 
• 
Active major bleeding 
• 
Severe thrombocytopenia (<25,000/mm3) 
• 
Increased risk of bleeding, as assessed by the investigator 
• 
Acute or chronic renal insufficiency with glomerular filtration rate (GFR) < 30 
ml/min calculated by the modified Cockcroft and Gault formula 
• 
Weight < 40 kg or > 150 kg 
• 
Known allergies to ingredients contained in enoxaparin 


pg. 4 
 
 
5. Study procedures and evaluations 
5.1 Screening and enrollment 
Potentially eligible patients will be identified by a healthcare professional per 
institutional policy on privacy. The healthcare professional will assess the eligibility of 
the patient by performing a chart review which will include laboratory results and 
weight as measured on admission to the hospital. After obtaining verbal consent from 
the patient to be contacted for the study, a member of the research staff will approach 
the patient to be part of the study. The research staff will obtain informed consent from 
the patient/LAR before collecting any data and performing any procedures. 
5.2 Trial interventions 
As standard of care, hospitalized patients with confirmed COVID-19 will be monitored 
for coagulopathy. Daily blood tests for platelet count, prothrombin time, D-Dimer, and 
fibrinogen and weekly thromboelastography will be obtained, and a daily Modified ISTH 
Overt DIC score will be calculated (Exhibit 1). Only patients meeting all inclusion and 
exclusion criteria will be asked to participate in the trial. Patients will be randomized to 
one of two arms: 
1) Patients randomized to the standard of care arm will receive low-dose enoxaparin 
(40 mg subcutaneously daily if BMI <40 and 30 mg subcutaneously twice daily if BMI 
≥ 40). 
2) Patients randomized to the intervention arm will receive intermediate-dose 
enoxaparin (1 mg/kg Subcutaneously daily or 0.5 mg/kg Subcutaneously twice daily 
if BMI ≥ 40). 
5.3 Dose Modifications 
1) Enoxaparin will be held if platelets decrease to <25,000/mm3. Enoxaparin will 
resume once platelets increase to ≥25,000/ mm3. 
2) Enoxaparin will be held if fibrinogen is <50 mg/dL. Enoxaparin will resume once 
fibrinogen increases to ≥50 mg/dL.  
3) Enoxaparin will be help if glomerular filtration rate (GFR) < 30 ml/min calculated by 
the modified Cockcroft and Gault formula and resumed once the GFR is ≥30 ml/min. 
 
All participating patients will continue the assigned doses of enoxaparin until hospital 
discharge or until a clinical event occurs requiring either discontinuation of 
anticoagulation therapy or full therapeutic dose anticoagulation therapy. 
6. Randomization 
Randomization to treatment arm will be allocated through a centralized randomization system 
in a 1:1 ratio for the standard of care versus intervention arms (low-dose versus intermediate-
dose enoxaparin, respectively). The randomization process will be initiated by the study 
personnel who will access the web-based system and enter the patient’s unique identifier, 
confirmation of eligibility and informed consent. 


pg. 5 
 
 
7. Assessment of Scientific Objectives 
7.1 Study Outcome Measures 
This study will track clinical events of interest 
7.1.1 
All-cause mortality at 30 days from enrollment date 
1) In-hospital mortality will be determined by chart review 
2)  Out-of-hospital mortality will be determined by chart review or via 
telephone encounter by a trial investigator  
7.1.2 
Venous thrombotic events 
1) Symptomatic DVT 
2) Pelvic DVT or inferior vena cava DVT 
3) Superior vena cava thrombosis (SVC syndrome) 
4) Pulmonary embolism 
5) Cerebral venous thrombosis 
6) Retinal vein thrombosis 
7) Mesenteric venous thrombosis 
8) Adrenal hemorrhage/adrenal vein thrombosis 
9) Renal vein thrombosis 
10) Line-related venous thrombosis 
7.1.3 
Arterial thrombotic events 
1) Acute limb arterial thrombosis, including arterial limb gangrene 
2) Ischemic stroke (defined as any residual neurologic deficits at 24 
hours) 
3) Transient ischemic attack (defined as no residual deficits at 24 
hours) 
4) Acute (unstable) coronary syndrome 
5) Myocardial infarction 
6) Aortic thrombosis 
7) Spinal cord infarction 
8) Mesenteric artery thrombosis 
9) Renal artery thrombosis 
10) Hemodialysis graft (or fistula) occlusion 
7.1.4 
Bleeding events 
1) Major Bleeding 
a. Bleeding resulting in a decrease in hemoglobin of 2 g/dL or 
more over a 24-hour period 
b. Bleeding leading to a transfusion of 2 or more units of 
packed red blood cells 
c. Bleeding that occurs in a critical site (intracranial, 
intraspinal, intraocular, pericardial, intra-articular other 
than the operative site, intramuscular with compartment 
syndrome or retroperitoneal) 


pg. 6 
 
d. Bleeding that leads to death 
2) Minor Bleeding 
a. Bleeding event that does not meet any of the criteria 
required for the event to be classified as a major event  
7.1.5 
Admission to the intensive-care unit  
7.1.6 
Acute renal failure 
7.1.7 
Transfusion of blood products 
1) Transfusion of blood products including packed red blood cells, 
platelets, cryoprecipitate and fresh frozen plasma will be 
documented and recorded 
7.1.8 
Laboratory Assessments 
1) Daily labs will be obtained including complete blood count with 
differential, prothrombin time, partial thromboplastin time, D-
dimer, fibrinogen, lactate dehydrogenase, C-reactive protein, 
ferritin, aspartate aminotransferase, alanine aminotransferase, 
alkaline phosphatase, and serum creatinine 
2) Thromboelastography (TEG) will be obtained within 24 hours of 
enrollment and weekly thereafter  
3) Blood samples for exploratory laboratory tests will be obtained 
within 24 hours of enrollment and weekly thereafter. Exploratory 
tests will include thrombin generation, cell free DNA, and PAI-1.  
 
 
8. Withdrawal or Termination 
Any participant who wishes to withdraw from the study may do so at any time. If a participant 
chooses to withdraw from the study, no new data about that participant will be collected for 
study purposes. A participant may also withdraw authorization for the researchers to use his or 
her data that has already been collected (other than data needed to keep track of the 
withdrawal, including demographic data), but the participant must do this in writing to the site 
principal investigator. 
The study may be terminated at any time by the Principal Investigator if it is deemed 
continuation of the protocol will not yield statistically or scientifically useful data. 
 
9. Study Management 
It is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations. The IRB should approve the consent form and protocol. In 
obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s) and should adhere to Good Clinical Practice (GCP) and to 
ethical principles that have their origin in the Declaration of Helsinki. Before recruitment and 
enrollment onto this study, the patient will be given a full explanation of the study and will be 


pg. 7 
 
given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by the FDA Regulations and local or state regulations. Once 
this essential information has been provided to the patient and the investigator is assured that 
the patient understands the implications of participating in the study, the patient will be asked 
to give consent to participate in the study by signing an IRB-approved consent form. Prior to a 
patient’s participation in the trial, the written informed consent form should be signed and 
personally dated by the patient or the patient’s legally acceptable representative, and by the 
person who conducted the informed consent discussion. 
 
 
10. Statistical analysis and considerations 
The null hypothesis is that intermediate-dose LMWH (intervention arm) will have a mortality rate 
that is not less than low-dose LMWH (standard of care arm). A sample size of 82 patients to each 
arm of the study are needed to have 80% power when testing a difference of 20% (40% vs 20% for 
the two arms). Mean with SD and frequencies for all variables will be reported for each arm. A chi-
square test will be conducted to test the mortality difference between the two arms. 
 
 
 
 
Exhibit 1 
Modified ISTH Overt DIC Score 
Laboratory Results 
Points 
Platelet Count 
 
> 100,000/µL 
0 
< 100,00/µL and ≥50,000 /µL 
1 
< 50,000 /µL 
2 
D-Dimer  
 
No increase, ≤0.50 mcg/mL 
0 
Moderate increase, >0.50 and <3.00 mcg/mL 
2 
Strong increase, ≥3.00 mcg/mL 
3 
Prothrombin time 
 
Prolonged < 3 sec 
0 
Prolonged 3 to 5 sec 
1 
Prolonged ≥ 6 sec  
2 
Fibrinogen level 
 
> 100 mg/dL 
0 
< 100 mg/dL 
1 
 
 
Interpretation of Score  
 


pg. 8 
 
If≥ 3: compatible with COVID-19-associated coagulopathy 
If< 3: not suggestive of COVID-19-associated coagulopathy 
  
 
 
References 
 
1. 
Guan W-j, Ni Z-y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. New 
England Journal of Medicine. 2020. 
2. 
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor 
prognosis in patients with novel coronavirus pneumonia. Journal of Thrombosis and 
Haemostasis. 2020;18(4):844-847. 
3. 
Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of 
coagulopathy in COVID-19. Journal of Thrombosis and Haemostasis.n/a(n/a). 
4. 
Lentz SR. Thrombosis in the setting of obesity or inflammatory bowel disease. Hematology. 
2016;2016(1):180-187.