Intermediate or Prophylactic-Dose Anticoagulation for Venous or Arterial Thromboembolism in Severe COVID-19: A Cluster Based Randomized Selection Trial (IMPROVE-COVID)
Phase: PHASE4
Conditions: COVID-19, Venous Thromboses, Arterial Thrombosis
Sponsor: Columbia University

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Protocol Outline 
Protocol Title: 
Intermediate or Prophylactic-Dose Anticoagulation for Venous or 
Arterial Thromboembolism in Severe COVID-19: A Cluster Based 
Randomized Selection Trial (IMPROVE-COVID) 
Protocol Version: 
V2 
Protocol Date: 
12/30/20 
Principal 
Investigator: 
Sahil A. Parikh, MD 
Biostatistics Core: 
Shing Lee, PhD (Biostatistician) 
Cheng-Shiun Leu, PhD (Biostatistician) 
Study Chairman: 
Ajay J. Kirtane, MD, SM 
Background and 
Significance 
/Preliminary 
Studies 
Hemostatic, biomarker, and inflammatory changes are common in severe 
manifestations of coronavirus disease 2019 (COVID-19) (1-3). Such 
factors, as well as the bedridden status and critical illness may constitute 
a prothrombotic milieu, predisposing to venous and arterial thrombosis. 
However, the optimal antithrombotic regimen for patients with COVID-19, 
especially those with severe disease, remains uncertain and is currently 
an area of active clinical interest (4-6). Prophylactic-dose anticoagulation 
is generally recommended for acutely ill hospitalized patients. However, 
given the hemostatic abnormalities of severe COVID-19 illness, it is 
unknown whether more intensive anticoagulation is preferred to reduce 
the risk of thrombotic events, potentially mitigating microvascular and 
macrovascular thrombi and even disseminated intravascular coagulation 
(DIC). Further, the risks of therapeutic dose anticoagulation must be 
weighed against the bleeding risks inherent to this approach. To address 
this critical gap in knowledge in an area of clinical equipoise, we plan to 
conduct a cluster-randomized trial in patients admitted to a large volume 
academic medical center to select the best anticoagulation intervention. 
NCT04367831

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Study Aims and 
Objectives 
To assess the impact of intermediate-dose anticoagulation compared with 
prophylactic anticoagulation of critically ill patients with COVID-19 with 
regards to the composite primary endpoint of being alive and without 
clinically-relevant venous or arterial thrombotic events at discharge from 
the ICU (without transfer to palliative care unit/hospice) or at ICU duration  
(if ICU stay lasted 30 days or longer). 
 
Clinically relevant venous or arterial thrombotic events will all be 
adjudicated and are defined as any of the following: 
• 
Confirmed or treated deep venous thrombosis or pulmonary 
embolism 
• 
Type I myocardial infarction (MI) as confirmed by a combination of 
biomarkers, electrocardiogram and angiogram 
• 
New ischemic stroke 
• 
Acute limb ischemia 
• 
Actionable line thrombosis requiring escalation of anticoagulation 
or removal or replacement of the line 
• 
CVVH Filter thrombosis requiring escalation of anticoagulation 
• 
Other thrombotic events requiring anticoagulation (e.g., 
intracardiac thrombosis)  
Secondary Aims: 
1. To determine the impact of intermediate-dose anticoagulation 
compared with prophylactic anticoagulation on the individual 
components of the primary outcome in the ICU. 
2. To determine the impact of intermediate-dose anticoagulation 
compared with prophylactic anticoagulation on ICU length of stay. 
3. To determine the impact of intermediate-dose anticoagulation 
compared with prophylactic anticoagulation on rates of acute kidney 
injury and renal recovery in the ICU. 
4. To determine the safety of intermediate-dose anticoagulation 
compared with prophylactic anticoagulation with respect to major 
bleeding (assessed by BARC criteria, also explored by ISTH and TIMI 
criteria) in the ICU. 
5. To determine the impact of intermediate-dose anticoagulation 
compared with prophylactic anticoagulation on the individual 
components of the primary outcome until hospital discharge 
6. To determine the impact of intermediate-dose anticoagulation 
compared with prophylactic anticoagulation on hospital length of stay. 
 
Design 
To avoid bias in statistical inference due to bias in sampling, only the first 
60 patients will be included in this set of analysis. Details explain why 
bias occurs and how it will affect the statistical inference can also be 
found in the supplemental appendix. We will use the data from these 60 
patients to generate the proportions of patients with the events specified 
as primary and secondary outcomes. We will also report the descriptive 
statistics (mean, median, interquartile range) for the time to ICU 
discharge. Graphical display of the data will be done as well. To compare 
the intervention effect between the two study groups on the primary and 
secondary outcomes, we will use generalized linear model with identity 
link function for continuous variables and logit link function for 

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dichotomous variables following the intent-to-treat principle. Covariates in 
these models include intervention group indicator, ICU indicators, and the 
potential confounding factors. The pre-spectified potential confounders 
are age, sex, weight, estimated glomerular filtration rate (eGFR), 
concomitant treatment with an IL-6 inhibitor, and concomitant treatment 
with corticosteroids. Generalized estimating equations methodology will 
be employed to account for the within-ICU correlation for subject 
assignment to the same ICU area. The key parameter of interest is the 
regression coefficient corresponding to the intervention group indicator 
which is the mean difference for continuous outcomes and log-odds ratio 
for dichotomous outcomes and it represents intervention effect of 
intermediate-dose anticoagulation compared with that of prophylactic 
anticoagulation. To report the trial findings, we will present the mean 
difference and odds ratio when appropriate and their corresponding p-
values and 95% confidence intervals. Several pre-specified sensitivity 
analyses will be conducted: (1) excluding the patients who undergo 
CRRT during the study period; (2) excluding patients who experienced 
deviation in anticoagulation from randomized treatment arm; (3) 
analyzing the patients as the treatment they actually received. Additional 
sensitivity analysis will also be conducted to include covariates found 
imbalanced between the two intervention groups. 
Intervention 
/Comparator 
Intervention arm: intermediate-dose anticoagulation 
• 
If stable eGFR ≥ 30 mL/min: enoxaparin 1mg/kg SC daily or 
unfractionated heparin infusion at 10 units/kg/hour with goal anti-Xa 
0.1-0.3 U/mL.1 
• 
If eGFR <30 mL/min or acute kidney injury (as defined below) or 
CRRT: Unfractionated heparin infusion at 10 units/kg/hour (minimum 
500 units/hour if CRRT) with goal anti-Xa 0.1-0.3 U/mL.2 
 
Control arm: prophylaxis  
Prophylactic dose anticoagulation (per CUIMC Guidelines): 
• 
If eGFR ≥30 mL/min (stable kidney function):  
o BMI < 40 kg/m2: Enoxaparin 40 mg SC daily  
o BMI 40 – 50 kg/m2: Enoxaparin 40 mg SC q12h 
o BMI > 50 kg/m2: Enoxaparin 60 mg SC q12h 
•  If eGFR < 30 mL/min or acute kidney injury:  
o 50-120 kg: Unfractionated heparin 5000 units SC q8h  
o > 120 kg: Unfractionated heparin 7500 units SC q8h 
If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour  

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Primary Endpoint 
Primary outcome: Composite of being alive and without clinically-relevant 
venous or arterial thrombotic events at discharge from ICU (without 
transfer to another palliative care unit/hospice) or at (if ICU duration 
lasted 30 days or longer). 
Clinically relevant venous or arterial thrombotic events will all be 
adjudicated and are defined as any of the following: 
• 
Confirmed or treated deep venous thrombosis or pulmonary 
embolism 
• 
Type I myocardial infarction (MI) as confirmed by a combination of 
biomarkers, electrocardiogram and angiogram 
• 
New ischemic stroke 
• 
Acute limb ischemia 
• 
Actionable line thrombosis requiring escalation of anticoagulation 
or removal or replacement of the line 
• 
CVVH Filter thrombosis requiring escalation of anticoagulation 
• 
Other thrombotic events requiring anticoagulation (e.g., 
intracardiac thrombosis) 
Secondary 
Endpoints 
1. Composite of being alive and without clinically-relevant venous or 
arterial thrombotic events at discharge from the hospital (without 
transfer to a palliative care unit/hospice) or at 30 days (if hospital stay 
lasted 30 days or longer) 
2. Individual components of the primary outcome in the ICU 
3. ICU length of stay 
4. Need for renal replacement therapy 
5. Major bleeding (assessed by BARC criteria, also explored by ISTH 
and TIMI criteria)  
6. Individual components of the primary outcome during entire 
hospitalization. 
7. Hospital length of stay 
Estimated Sample 
Size 
Up to 150 subjects (to be determined by sequential randomized selection 
design) 
1This dose generally does not require routine monitoring of anti-Xa activity, but may be monitored by the 
primary team outside this study to assess for effectiveness and dose adjusted in consultation with pharmacist 
2To be monitored at least 8 hours after the initiation of the infusion or any dose change. 
 
***Patients with improving kidney function or new AKI can be switched from one agent to the other within the 
same intervention group*** 
Acute kidney injury defined as:  
• 
Increase in SCr by ≥ 0.4 mg/dL within 48 hours; or 
• 
Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 
days; or 
• 
Urine volume <40 mL/h for 6 hours 
 
 

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I. 
Study Population 
Patient Inclusion 
Criteria 
• 
Age>18 years of age 
• 
Confirmed diagnosis of COVID-19 by RT-PCR 
• 
New admission to eligible CUIMC ICUs within 5 days  
o Transfer from nonparticipating to participating ICU is eligible if 
otherwise meets eligibility criteria. 
o Patients not on therapeutic anticoagulation and who were 
already admitted to participating ICU within 5 days of trial 
initiation are additionally eligible. 
Patient Exclusion 
Criteria 
• 
Weight under 50kg 
• 
Contraindication to anticoagulation in the opinion of the treating clinician 
including 
o overt bleeding  
o platelet count <50,000 
o BARC major bleeding in the past 30 days 
o GI bleeding within 3 months  
o history of intracranial hemorrhage 
o Ischemic stroke within the past 2 weeks 
o craniotomy/major neurosurgery within the past 30 days 
o cardiothoracic surgery within the past 30 days 
o intra-abdominal surgery within 30 days prior to enrollment 
o Head or spinal trauma in the last months  
o History of uncorrected cerebral aneurysm or arteriovenous 
malformation AVM 

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II. 
Study Procedures 
a. Screening procedures 
b. Randomization 
c. Study intervention 
d. Study Assessments and Activities 
o Intracranial malignancy 
o Presence of an epidural or spinal catheter 
o Recent major surgery within the last 14 days 
o Decrease in hemoglobin >3 g/dL over the last 24 hours 
o Allergic reaction to anticoagulants (e.g. Heparin Induced 
Thrombocytopenia) as documented in the electronic health 
records. Extracorporeal membrane oxygenation (ECMO) 
support or other mechanical circulatory support. 
• 
Severe chronic liver dysfunction (history of portosystemic HTN, 
esophageal varices, or Child-Pugh class C or above or similar MELD 
scores), abnormality in liver function tests (AST, ALT, bilirubin) 5 times 
greater than upper normal limit. 
• 
History of cirrhosis 
• 
A history of congenital bleeding diatheses or anatomical anomaly that 
predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic 
telangiectasia) 
• 
Treating physician preference for therapeutic anticoagulation 
• 
Enrollment in other concurrent trials related to anticoagulant or 
antiplatelet therapy 
• 
Existing treatment with therapeutic anticoagulation during the previous 
7 days of hospitalization prior to ICU admission (e.g. for VTE, atrial 
fibrillation, mechanical valve, etc). 
• 
CMO orders prior to enrollment. 
Screening 
procedures 
All patients in participating CUIMC ICUs will be screened by the study team. 
Study eligibility criteria (described above) will be implemented to identify the 
modified intention-to-treat cohort. 
Randomization 
procedures 
Patients, when eligible, will be enrolled to the study at the “first-come-first-
serve” basis. All the participating ICUs can have 2 possible “room type”: 
negative pressure rooms and non-negative pressure rooms. Each of the 
participating ICUs will be divided into either two or four clusters as follows. 
Any ICU with only one room type (i.e., it only has negative pressure rooms 
or only has non-negative pressure rooms) will be divided into 2 clusters. For 
ICUs that contain both room types (i.e., it has negative pressure rooms and 
non-negative pressure rooms), we will divide that ICU into 4 clusters with 
two clusters for each room type.  Two clusters within each ICU and each 
room type will then be randomized to either of the study arms. . Enrolled 
patients will receive the treatment according to the cluster of ICU they are 
assigned. Post-randomization pairing scheme will be employed to form the 
pairs if the stopping criterion is not reached at the time that first 60 outcomes 
have been observed. As the hospital administration changed the room type 
to accommodate the decrease of COVID patients (e.g., some negative 

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pressure rooms were changed to non-negative pressure rooms), we 
currently recruitment included more patients in the prophylactic dose group 
than those of the intermediate dose group.  At the recommendation of the 
DSMB, in each ICU and each room type, we will randomize “intermediate 
dose rooms” and “prophylactic dose rooms” in a 3:1 ratio until we reach 
enrollment of 30 patients for one group and we will then only assign patients 
to the other group until we achieve the recruitment of 30 patients that group 
as well. After we recruit 30 patients for each arm, the ratio of the rooms will 
be changed back to 1:1 (intermediate vs. prophylactic) for the subsequent 
recruitment. 
 
Study 
intervention 
• 
Each cluster will be randomized to one of the two antithrombotic 
regimens: prophylactic-dose or intermediate dose as described above 
The choice of agents will be dependent upon the renal function (at the 
time of enrollment and every subsequent day). 
• 
At the onset of study enrollment, clusters including patients admitted 
within the past 5 days will be randomized. 
• 
Patients who meet eligibility by screening team will be enrolled.Patient is 
considered enrolled after a co-investigator has confirmed all 
inclusion/exclusion criteria have been met.  Assessment of 
appropriateness of anticoagulation dose will occur daily based on the 
renal function, progressive thrombocytopenia or anemia, or development 
of another indication for anticoagulation such as new-onset atrial 
fibrillation,  
• 
Patients’ treatment course will be followed from randomization to hospital 
discharge or 30 days, whichever happens earlier. 
• 
Patients will continue with randomization therapy until discharged from 
the ICU, except in the setting of an adverse event attributed to 
anticoagulation, developing an event requiring therapeutic 
anticoagulation, or change in code status to comfort measures. 
• 
Patients transferred between participating ICUs will remain in the 
treatment arm assigned at initial randomization. Recommendation will be 
to continue study treatment if patient transferred to ICUs not participating 
in the present trial. If the study treatment is changed by the primary 
treating team in the second ICU, then patient will be evaluated by 
intention to treat principle. 
 
Intervention arm: intermediate-dose anticoagulation 
• 
If stable eGFR ≥ 30 mL/min: enoxaparin 1mg/kg SC daily1 
• 
If eGFR <30 mL/min or acute kidney injury (as defined below) or CRRT: 
Unfractionated heparin infusion at 10 units/kg/hour (minimum 500 
units/hour if CRRT) with goal anti-Xa 0.1-0.3 U/mL2 
 
Control arm: Prophylactic dose anticoagulation (per CUIMC Guidelines): 
• 
If eGFR ≥30 mL/min (stable kidney function):  
o BMI < 40 kg/m2: Enoxaparin 40 mg SC daily 
o BMI 40 – 50 kg/m2: Enoxaparin 40 mg SC q12h 
o BMI > 50 kg/m2: Enoxaparin 60 mg SC q12h 
•  If eGFR < 30 mL/min or acute kidney injury: •  If eGFR < 30 mL/min or 
acute kidney injury:  

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III. 
Endpoint  Definition 
 
a) Endpoint  Reporting Requirements 
Safety surveillance and reporting starts as soon as the patient is enrolled  in the clinical 
investigation and will continue until the subject is deceased, the subject concludes participation in 
the clinical investigation or the subject withdraws from the clinical investigation. 
Endpoint data will be collected throughout the time period defined above and will be entered on 
a CRF.  
 
For the purposes of this investigation the following are reportable endpoints: 
Death 
 
Deep venous thrombosis  
 
 
Diagnosed on duplex ultrasonography including 
upper (internal jugular, subclavian, 
axillary/brachial) and lower extremity (iliac, 
femoral/popliteal, gastrocnemius, peroneal, 
posterior tibial) thrombosis  
 
Pulmonary embolism  
 
Diagnosed on CT angiography, V/Q scan, or 
invasive pulmonary angiography  
 
Type I myocardial infarction  
 
 
Detection of a rise and/or fall of cTn values with 
at least one value above the 99th percentile URL 
and at least one of the following:: symptoms of 
ischemia, new or presumed new significant ST-
segment–T wave (ST–T) changes or new left 
bundle branch block (LBBB); development of 
o 50-120 kg: Unfractionated heparin 5000 units SC q8h  
o > 120 kg: Unfractionated heparin 7500 units SC q8h 
• 
If CRRT: Unfractionated heparin infusion pre-filter at 500 units/hour 
Study 
assessment and 
activities 
All anticoagulation medications are standard of care according to 
discussions between clinician leadership in multiple disciplines and review of 
treatment protocols from institutions in the region and internationally. 
Anticoagulants will be ordered through the hospital pharmacy. 
 
Patient receiving any anticoagulation are at risk for development of 
hemorrhage, thrombocytopenia, and in rare cases (overall rate of 0.2%) 
heparin induced thrombocytopenia (7). Patients who have a bleeding event 
may have cessation of the administered drug per clinical standard of care, 
and in some cases may require transfusion of blood products, and additional 
testing and therapy to identify and treat the source of bleeding. Patients who 
develop a thrombotic event may have intensification of anticoagulation per 
clinical standard of care. 
We will collect all clinical, laboratory and imaging data generated per 
standard of care throughout the patient’s hospitalization.   Primary and 
Secondary endpoints will be assessed at ICU discharge, hospital discharge 
and 30 days if the patient is still hospitalized. 
 

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pathological Q waves on the ECG; imaging 
evidence of new loss of viable myocardium or 
new regional wall motion abnormality; 
identification of an intracoronary thrombus by 
angiography or autopsy 
Ischemic stroke  
 
 
Neurological dysfunction caused by focal 
cerebral, spinal, or retinal infarction based on 
pathological, imaging, or other objective 
evidence of cerebral, spinal cord, or retinal focal 
ischemic injury in a defined vascular distribution; 
or 2. clinical evidence of cerebral, spinal cord, or 
retinal focal ischemic injury based on symptoms 
persisting ≥24 hours or until death, and other 
etiologies excluded. Exclude hemorrhagic 
infarction.  
 
Acute limb ischemia  
 
Sudden decrease in limb perfusion that threatens 
limb viability with confirmed arterial obstruction 
based on duplex ultrasonography or invasive 
peripheral angiography  
 
Actionable line thrombosis   
 
 
Arterial or central venous catheter thrombosis 
that results in removal or replacement of 
catheter or initiation of therapeutic 
anticoagulation. Excludes use of indwelling tPA.  
 
CVVH filter thrombosis  
 
 
Filter thrombosis requiring exchange in order to 
resume continuous veno-venous hemofiltration 
(CVVH) or resulting in cessation of CVVH  
 
Other thrombotic events requiring 
anticoagulation  
 
 
For example atrial fibrillation, left ventricular 
thrombus, right ventricular thrombus, etc. 
Acute kidney injury  
 
 
KDIGO criteria: 1. Increase in sCr ≥0.3 mg/dL 
(≥26.5 μmol/L) within 48 hours; or 2. Increase in 
sCr ≥1.5 times baseline, which is known or 
presumed to have occurred within the prior 7 
days; or 3. Urine volume <0.5 mL/kg/h for 6 
hours.  
 
Serious bleeding  
 
 
• 
BARC 3 or 5 bleeding (3: decrease in the 
hemoglobin of >3 g per deciliter, any 
transfusion, cardiac tamponade, or 
intracranial or ocular involvement; 5: 
fatal)  
 

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• 
ISTH major bleeding: 1: Fatal bleeding, 
and/or 2. Symptomatic bleeding in a 
critical area or organ, such as intracranial, 
intraspinal, intraocular, retroperitoneal, 
intraarticular or pericardial, or 
intramuscular with compartment 
syndrome, and/or 3. Bleeding causing a 
fall in hemoglobin level of 2 g/dL (1.24 
mmol/L) or more, or leading to 
transfusion of two or more units of whole 
blood or red cells.  
 
• 
TIMI major bleeding: Any intracranial 
bleeding (excluding microhemorrhages 
≤10 mm evident only on gradient-echo 
MRI), or Clinically overt signs of 
hemorrhage associated with a drop in 
hemoglobin of ≥5 g/dL, or Fatal bleeding 
(bleeding that directly results in death 
within 7 d 
 
IV. 
Event Adjudication 
A clinical events committee will be formed for adjudication of clinical endpoints. Suspected 
components of the primary endpoint as well as the secondary endpoints, including the bleeding 
endpoint as documented in case report forms will be adjudicated based on pre-defined clinical 
definitions of venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, 
clinically-actionable line thrombosis, and major bleeding. All suspected events will be independently 
reviewed by two physicians blinded to randomized group assignment. If there is disagreement on 
whether an endpoint event has occurred, the case will be reviewed by the clinical events committee 
for adjudication. 
 
V. 
Safety Monitoring Plan 
All events outlined above will be reported to the Clincial Events Committee (CEC) and Data and 
Safety Monitoring Board (DSMB) and reviewed on a regular basis. The DSMB may request 
additional information as needed. Based on safety data, the DSMB may recommend to the Study 
Chairman to stop or otherwise modify the study. The Study Chairman will make the final decision 
after weighing the recommendation of the DSMB whether the study should then be stopped, 
modified or continued without change. The DSMB procedures will be described in the DSMB 
Charter.  
 
 
VI. 
Risk/Benefit Analysis 
Include research related risks and potential benefits (if any). 
 
There is equipoise for the antithrombotic treatment intensity in patients with severe COVID-19. The 
table below summarizes the potential benefits and risks of intermediate-dose vs. prophylactic dose 
anticoagulation. 

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Potential benefits of 
intermediate-dose 
vs. prophylactic 
dose anticoagulation  
• 
Potential for reduced risk of thrombotic complications (including 
VTE, MI, stroke, and line thrombosis) 
• 
Potential for improving the recovery from need from 
mechanical ventilation. 
• 
Potential for reducing the risk of DIC. 
• 
Potential for reducing the risk of renal failure. 
• 
Potential for reducing mortality as a result of reducing the 
above components. 
Potential risks of 
intermediate-dose 
vs. prophylactic 
dose anticoagulation 
• 
Increased risk of bleeding, including major bleeding 
• 
Heparin induced thrombocytopenia 
 
 

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VIII. 
Study Design and Analysis Plan (include timing and primary and secondary 
endpoint analysis) 
 
In order to assess event rates and appropriately adjust study measures as part of adaptive trial 
design, a blinded interim analysis at the combined event rate of both study arms will be performed. 
Once the trial is completed, analysis will be performed by intention to treat.  
 
General Design 
This is a cluster randomized-controlled clinical selection trial of interventions for anticoagulation for 
COVID-19 patients in the ICU. ICU subunits will be randomly assigned to give patients intermediate 
(higher) dose or prophylactic (lower) dose of anticoagulation. The primary goal of the trial is to 
select the best intervention with a high probability of correct selection if one intervention is truly 
superior by a pre-specified effect size. Up to 100 patients (with expected sample sizes between 69-
75 patients for the most likely scenarios) will be enrolled in the study, using a novel sequential 
design. Each time an outcome is observed for a patient, those outcomes are added to a running 
tally of successes for each intervention. There is a pre-specified criterion in terms of the success 
tallies for selecting arm as evidence of apparent superiority accumulates. With this sequential 
procedure, the preferred intervention can be selected during the ongoing enrollment as soon as the 
pre-specified selection criteria are met, and further enrollment will cease. To ensure that there will 
be some unbiased estimates of the proportion of patients with a good outcome available for each 
intervention arm, the selection criteria will not be applied until 60 patients have been observed. This 
novel approach based on the Levin-Robbins-Leu family of sequential selection procedures [18-23]. 
 
Study Implementation 
The identification of a preferred treatment will be done using an innovative sequential selection 
procedure, which will substantially reduce the number of patients in comparison to a hypothesis test 
procedure. The data will be examined each time a pair of patients completes follow-up after 60 
patients have been observed.  
 
The goal of the procedure is to make a correct selection with high probability. The procedure follows 
the preference zone / indifference zone approach, wherein we require the selection procedure to 
guarantee a probability of at least 90% correct selection (of the truly best intervention), assuming 
that one is truly superior to the other by a pre-specified amount. This pre-specification defines a 
region in the parameter space called the preference zone. If the best intervention does not exceed 
the next best by the pre-specified amount, the success probabilities are said to lie in the 
indifference zone, where we shall be indifferent to the fact that the probability of correct selection 
may be less than 90%. For this trial, the preference zone consists of all parameter vectors (p1, p2) of 
success probabilities where the odds ratio comparing the largest to the next largest is greater than 
or equal to 2.15 (p1=0.35, p2=0.20). 
 
The selection procedure is specified by the sampling rule, the stopping rule, and the terminal 
decision rule, as follows.  
 
Sampling rule: Patients, when eligible, will be enrolled to the study at the “first-come-first-serve” 
basis. All the participating ICUs can have 2 possible “room type”: negative pressure rooms and non-
negative pressure rooms. Each of the participating ICUs will be divided into either two or four 
clusters as follows. Any ICU with only one room type (i.e., it only has negative pressure rooms or 
only has non-negative pressure rooms) will be divided into 2 clusters. For ICUs that contain both 
room types (i.e., it has negative pressure rooms and non-negative pressure rooms), we will divide 
that ICU into 4 clusters with two clusters for each room type.  Two clusters within each ICU and 
each room type will then be randomized to either of the study arms. . Enrolled patients will receive 

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the treatment according to the cluster of ICU they are assigned. Post-randomization pairing scheme 
will be employed to form the pairs if the stopping criterion is not reached at the time that first 60 
outcomes have been observed. As the hospital administration changed the room type to 
accommodate the decrease of COVID patients (e.g., some negative pressure rooms were changed 
to non-negative pressure rooms), we currently recruitment included more patients in the 
prophylactic dose group than those of the intermediate dose group.  Pending the approval of 
DSMB, in each ICU and each room type, we will randomize “intermediate dose rooms” and 
“prophylactic dose rooms” in a 3:1 ratio until we reach enrollment of 30 patients for one group and 
we will then only assign patients to the other group until we achieve the recruitment of 30 patients 
that group as well. After we recruit 30 patients for each arm, the ratio of the rooms will be changed 
back to 1:1 (intermediate vs. prophylactic) for the subsequent recruitment. 
 
Success tallies: 
Each time the follow-up for each patient in a pair is complete and a “good” or “poor” outcome is 
determined for each based on the composite primary outcome, the pair becomes “observed” and is 
available for sequential monitoring by adding to a running tally of the “good” outcomes for each 
intervention. These success tallies are used for the stopping rule. 
 
Stopping and Decision rule: The criterion for stopping is a difference of 4 or more between the 
talliesif this occurs at or before 60 patients’ outcomes have been observed. At that time, 
intervention with the largest success tally is selected as the preferred intervention. However, we will 
not stop the procedure and make a decision before the outcomes of the first 60 patients have 
become available. In addition, if the criterion for stopping has not been reached at or before 100 
outcomes have been observed, the trial will stop by truncation with a maximum of 100 patients. At 
that time, intervention with the largest success tally is selected as the preferred intervention. If there 
are ties for the largest success tally at time of truncation, we will select the intervention according to 
other considerations (safety, better secondary outcomes, etc.). 
 
Incomplete pairs: 
If at the time of stopping there are partially filled or partially observed pairs of patients that have 
been randomized and have started their intervention, we will allow each patient in each such pair to 
complete their follow-up even if the arm to which they were randomized is eliminated.  
 
Operating characteristics: In Appendix, we calculate the operating characteristics for various 
scenarios via simulation study with 100,000 replications. Operating characteristics include the 
probability of correction, the expected total number of patients, the expected total number of 
patients with bad outcome, the probability that the trial will be truncated before reaching the criterion 
for stopping, the probability of reaching a decision after exactly 60 patients (30 in each arm), the 
probability of correct selection after exactly 60 patients (30 in each arm), and the conditional 
probability that correct selection is made given that exactly 60 patients (30 in each arm). Scenarios 
discussed cover the parameters in the preference zone, in the indifference zone, and the null case 
(i.e., p1=p2). 
 
Analysis of the Primary Endpoint with the Full Sample 
In general, a selection procedure, unlike a hypothesis test procedure, is not specifically designed to 
provide a p-value below a conventional level of significance. Indeed, we will not be declaring any 
differences statistically significant, as that is explicitly not the goal of the present selection trial, i.e., 
we are explicitly not interested in testing the null hypothesis of no differences between the 
interventions. Instead, because the adaptive sequential selection procedure can be described as a 
procedure that samples until there is a pre-specified weight of evidence for making correct 
selections, assuming there is a minimum true degree of superiority as measured by the design odds 

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ratio, we will quote the likelihood ratio (LR) measure of weight of evidence in various ways. Details 
regarding how the LR was calculated and examples to illustrate their interpretations can be found in 
the supplemental appendix.   
 
Endpoint Evaluation 
All patients will be evaluable for ischemic outcomes and bleeding from the time of their first 
treatment with the anticoagulant.  
 
Analysis of Primary Endpoint and Secondary Endpoints for the first 60 patients 
To avoid bias in statistical inference due to bias in sampling, only the first 60 patients will be 
included in this set of analysis. Details explain why bias occurs and how it will affect the statistical 
inference can also be found in the supplemental appendix. We will use the data from these 60 
patients to generate the proportions of patients with the events specified as primary and secondary 
outcomes. We will also report the descriptive statistics (mean, median, interquartile range) for the 
time to ICU discharge. Graphical display of the data will be done as well. To compare the 
intervention effect between the two study groups on the primary and secondary outcomes, we will 
use generalized linear model with identity link function for continuous variables and logit link 
function for dichotomous variables following the intent-to-treat principle. Covariates in these models 
include intervention group indicator, ICU indicators, and the potential confounding factors. The pre-
spectified potential confounders are age, sex, weight, estimated glomerular filtration rate (eGFR), 
concomitant treatment with an IL-6 inhibitor, and concomitant treatment with corticosteroids. 
Generalized estimating equations methodology will be employed to account for the within-ICU 
correlation for subject assignment to the same ICU area. The key parameter of interest is the 
regression coefficient corresponding to the intervention group indicator which is the mean difference 
for continuous outcomes and log-odds ratio for dichotomous outcomes and it represents 
intervention effect of intermediate-dose anticoagulation compared with that of prophylactic 
anticoagulation. To report the trial findings, we will present the mean difference and odds ratio when 
appropriate and their corresponding p-values and 95% confidence intervals. Several pre-specified 
sensitivity analyses will be conducted: (1) excluding the patients who undergo CRRT during the 
study period; (2) excluding patients who experienced deviation in anticoagulation from randomized 
treatment arm; (3) analyzing the patients as the treatment they actually received. Additional 
sensitivity analysis will also be conducted to include covariates found imbalanced between the two 
intervention groups. 
 
Operating characteristics of the Study Design 
The stopping criterion of a lead of at least 4 between largest and smallest success tallies was 
chosen to achieve a probability of correct selection of at least 90% for any true success probabilities 
lying in the preference zone characterized by an odds ratio of 2.15 or greater between the true 
success probabilities of the two interventions. For example, true success probabilities of 0.35 and 
0.20 with an odds ratio of 2.15 is lying on the boundary between the preference and indifference 
zones. For any such configuration with {p1/(1− p1)}/{p2/(1− p2)} = 2.15, the selection procedure will 
result in a correct selection with at least 90% probability. Table 1 shows the operating 
characteristics of the selection procedure under various scenarios of true success probability 
configurations for the two arms. 
 
 

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TABLE 1 
Operating characteristics of the selection procedure 
Scenario 1. p1=0.35, p2=0.20, criterion for stopping is a difference of 4 between the tallies, 
truncation at 100 patients, minimum # of patients before possible selection=60 
ET 
EF 
PCS 
P[truncation] 
P[T=T0] 
P[T=T0,CS ] 
P[CS|T=T0] 
68.4 
49.6 
95.1% 
10.2% 
62.6% 
61.6% 
98.4% 
 
Scenario 2. p1=0.30, p2=0.20, criterion for stopping is a difference of 4 between the tallies, 
truncation at 100 patients, minimum # of patients before possible selection=60 
ET 
EF 
PCS 
P[truncation] 
P[T=T0] 
P[T=T0,CS ] 
P[CS|T=T0] 
74.0 
55.5.4 
87.1% 
21.5% 
46.6% 
44.0% 
94.5% 
 
Scenario 3. p1=0.20, p2=0.20, criterion for stopping is a difference of 4 between the tallies, 
truncation at 100 patients, minimum # of patients before possible selection=60 
ET 
EF 
PCS 
P[truncation] 
P[T=T0] 
P[T=T0,CS ] 
P[CS|T=T0] 
83.0 
66.4 
50.2% 
43.5% 
25.7% 
12.9% 
50.2% 
ET is the expected total number of patients 
EF is the expected total number of patients with bad outcome 
PCS is the probability of correct selection  
P[truncation] is the probability that the trial will be truncated before reaching the criterion for 
stopping 
P[T=T0] is the probability of reaching a decision after exactly 60 patients (30 in each arm) 
P[T=T0, CS] is the probability of correct selection after exactly 60 patients (30 in each arm) 
P[CS|T=T0] is the conditional probability that correct selection is made given that exactly 60 patients 
(30 in each arm) 
 
The first scenario corresponds to the abovementioned design alternative which we believe is 
minimal clinically meaningful and worthwhile. The second scenario describe the operating 
characteristics of the selection procedure inside the indifference zone, assuming smaller differences 
in the success rates for the two interventions. The third scenario illustrates a case where there is no 
true difference in the rates for the two arms.  
 
In scenarios 1 and 2 where there is a superior arm, the design chooses the superior arm over 87% 
of the time across these scenarios with average sample sizes between 68.4 and 74.0. Under the 
design alternative, there is 82.5% probability that we will stop the trial with 30 patients per arm. The 
probability of having to truncate the study ranges from 3.5% to 10.6%, with the lowest probability for 
our design alternative. The probability of selecting the superior arm at exactly 100 patients are 
enrolled is between 63.7% and 81.9% in these scenarios, which explains the need to continue 
enrollment to ensure that the correct dose is selected with high probability. Nevertheless, the 
conditional probability that correct selection is made given that exactly 100 patients have been 
randomized is very high (between 96.4% and 99.2%). 
 
In scenario 3, there is no difference between the two arms. Thus, the design randomly selects one 
of them with a probability of 0.50. However, given that they are all the same, it is acceptable to 
select any of them and thus the probability of selecting an acceptable intervention is 100%. 
Because there is no superior intervention in this scenario, evidence of an apparent advantage 
accumulates more slowly than under other scenarios and thus the procedure incurs a larger 
average sample size and probability of truncation.  
 
 
 

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Formula to Calculate the Likelihood Ratio and its Interpretations 
At the end of the trial, we will calculate the likelihood of the success tallies. This likelihood is given 
by  
)
(
)
(
)
(
)
(
)
1
(
)
1
(
)
,
|
,
(
)
(
)
(
n
j
n
j
n
i
n
i
X
n
j
X
j
X
n
i
X
i
n
j
n
i
j
i
p
p
p
p
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X
p
p
L
−
−
−
−
=
, 
where 
)
(n
i
X
and 
)
(n
j
X
 are the observed success tallies for the selected and not selected intervention 
and where pi and pj are the respective true success probabilities. We will also calculate the 
likelihood of the observed success tallies under the assumption that we erred in our selection and 
that the true success probabilities are those for the two interventions transposed, namely, 
)
,
|
,
(
)
(
)
(
n
j
n
i
i
j
X
X
p
p
L
. The likelihood ratio LR is the ratio of these two likelihoods. It can be shown 
that LR, equals the true odds ratio raised to the fourth power, 
 
4
)
(
)
(
)
(
)
(
)
1(
)
1(
)
,
|
,
(
)
,
|
,
(






−
−
=
=
j
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p
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p
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X
X
p
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LR
, 
 
in the case where the trial ends meeting the selection criterion. In the case of truncation, the 
exponent 4 is replaced by 
)
(
)
(
n
j
n
i
X
X
−
. We will evaluate LR at the maximum likelihood estimates of 
pi and pj, which are the adjusted sample proportions 
)1
(
)
5.0
(
)
(
+
+
n
X n
i
 and 
)1
(
)
5.0
(
)
(
+
+
n
X n
j
. 
The values of success tallies used in LR are those used in the selection criteria, i.e., without data 
from incomplete pairs. However, for the values of pi and pj used in LR, we will use the 
corresponding sample proportions using all of the available outcome data including data from 
incomplete pairs. The LR may offer strong evidence of correct selection (if LR>10) or only weak 
evidence, and the LR weight of evidence will be taken account of in evaluating whether or not to 
mount a subsequent phase 3 trial.  
 
For instance, suppose we stop after 60 patients. If the difference between the two groups’ success 
tallies is exactly equal to 4 (the minimum given the design), the likelihood ratio (LR) in favor of 
having selected the truly better treatment as opposed to having made a mistaken selection equals 
the odds ratio (OR) raised to the 4th power. Thus, at the design alternative p1=0.35, p2=0.20, the LR 
would be 21.5. This is usually considered “very strong” evidence. Likelihood ratios in excess of 8 or 
10 are generally considered to be moderate to strong evidence [Royall R. Statistical Evidence: A 
likelihood paradigm. 1997 Chapman and Hall/CRC ]. For comparison, the usual “significant at 
p<0.05” corresponds to a LR of only 6.8 in large samples. Furthermore, if the design alternative 
holds, it is highly probable the difference between success tallies will be greater than 4. For 
example, if the tallies are 11 (about 30×0.35) and 6 (=30×0.20), the LR under the design alternative 
is much larger (46), very strong evidence in favor of a correct selection. 
 
To address the weight of evidence in favor of the maximum likelihood estimate (mle) being the true 
parameters as opposed to the null hypothesis p1=p2 being the true parameters, the generalized LR 
is 11.2 for the case T=60, X1=20, X2=10, which would again be moderate to strong evidence. On 
the other hand, if X1=14, X2=10, LR=1.55, very weak evidence against the null hypothesis. 
Assuming the trial does not stop at T=60, the above LR’s will be assessed with the data at the time 
of selection at the observed mle’s for weight of evidence in favor of correct selection and for weight 
of evidence against the null hypothesis. The assessments will be repeated when all data have been 
observed, including overrun data coming in after the time of selection. 
 

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Minimizing Selection Bias 
While the primary aim for the study is to select the best intervention from the 2 candidates, we are 
also interested in conducting point estimation and hypothesis test for the primary and secondary 
outcomes when appropriate and to conduct such analysis, only the first 30 pairs of patients can be 
included. This is because we will not enroll any additional patients if decision can be made based 
on the data from the first 30 pair of patients. In other words, the enrollment of 31st pair of patients 
and thereafter will not be necessary unless we don’t have sufficient evidence (i.e., the difference in 
number of “good” outcomes is less than 4) to demonstrate one intervention is better than the other 
from the outcomes obtained from the first 30 pairs. Therefore, when we have to continue sampling 
(after the first 30 pairs) until a winner appears and use the entire sample to construct the analysis, 
two consequences will occur: (1) from point estimation standpoint, the probability of “good” outcome 
for the winner will be over-estimated (and for the loser will be under-estimated); and (2) from 
hypothesis testing standpoint, as sampling plan “enforces” the data to support the alternative 
hypothesis, bias then introduced against the null.  
 
Nevertheless, to prevent any bias due to sampling, we propose to recruit the first 30 pairs without 
any look and/or comparison of their primary and secondary efficacy outcomes (unless the early 
stopping is required from the recommendation of DSMB due to safety concern). In such case, the 
recruitment of first 30 pairs of patients is independent of their outcome as we usually do for any 
fixed sample size design. Thus, conducting point estimation (together with a 95% confidence 
interval) and hypothesis testing with those 60 patients is entirely appropriate (i.e., can be done 
unbiasedly).  
 
 
 
 

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VII. 
References 
 
 
1. 
Lippi G, Favaloro EJ. D-dimer is associated with severity of coronavirus disease 2019 
(COVID-19): a pooled analysis. Thromb Haemost In press. 
2. 
Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin 
Chem Lab Med 2020. 
3. 
Lippi G, Plebani M, Michael Henry B. Thrombocytopenia is associated with severe 
coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clin Chim Acta 2020. 
4. 
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. 
5. 
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor 
prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020. 
6. 
Crackower MA, Sarao R, Oudit GY et al. Angiotensin-converting enzyme 2 is an essential 
regulator of heart function. Nature 2002;417:822-8. 
7. 
Smythe MA, Koerber JM, Mattson JC. The incidence of recognized heparin-induced 
thrombocytopenia in a large, tertiary care teaching hospital. Chest 2007;131:1644-9.