Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity

The primary safety endpoint is assessed as the cumulative incidence of adverse events directly associated with TPE during the study period as determined by clinical judgment of ICU team providing direct patient care and the study PI.

Time frame: Up to Day 28

Population: This analysis includes participants in the TPE study arm.

Plasma viscosity is measured in centipoise (cP). The normal range is 1.4 - 1.8 cP and measurements above this range indicate increased viscosity.

Time frame: Day 1 (within 24 hours prior to TPE), Day 4 (within 24 hours of last TPE)

The aPTT test is a measurement of blood clotting time. Normal values for aPTT are around 30 to 40 seconds. Higher aPTT values can indicate a bleeding risk.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

The normal range for albumin is 3.4 to 5.4 g/dL of blood. High albumin may indicate acute infection while low albumin can indicate malnutrition or liver disease.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

The anti-factor Xa assay measures plasma heparin and is useful with monitoring anticoagulation therapy. Interpretation of the resulting values depends on the anticoagulation medication used as well as the dosing schedule and indication. Patients not taking heparin should have an anti-Xa value of 0 units per milliliter (U/mL).

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

For adults, normal values for total bilirubin are around 1.2 mg/dL of blood. High bilirubin indicates that the liver is not functioning well.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

The normal range for BUN is 7 to 20 milligrams per deciliter (mg/dL) of blood. A high BUN value indicates that kidneys are not functioning well.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

Body temperature will be assessed in degrees Celsius.

Time frame: Days 7, 14, 21, and 28

Population: Body temperature was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

The clinical status of participants was assessed using a single item modified from the World Health Organization (WHO) ordinal clinical severity scale for COVID. The instrument was customized for this study to evaluate thrombotic/bleeding events. In this 12-point ordinal scale, a score of 1 indicates no evidence of infection and the severity of the clinical status increases as the number of necessary interventions increases to the final score of 12, which is death. All patients were included at every timepoint recorded, with terminal scores carried over from the measure before for those that expired or fully recovered.

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

A normal value for CRP (with a standard test) is less than 10 milligrams per liter (mg/L) of blood. CRP increases with inflammation, which could be attributed to an infection, chronic inflammatory disease or heart disease.

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

Population: This analysis includes participants who had CRP assessed at the indicated time point.

The normal range for creatinine is 0.84 to 1.21 mg/dL of blood. High serum creatinine indicates that kidneys are not functioning well.

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

Population: This analysis includes participants who had creatinine assessed at the indicated time point.

The number of participants dying from any cause is reported as a cumulative measures of mortality.

Time frame: Up to Day 28

The number of bleeding and thromboembolic complications will be compared between study arms. This endpoint is a composite outcome including any acute bleeding requiring transfusion support, venous thrombosis (deep vein thrombosis or pulmonary embolism), arterial clots (myocardial infarction, stroke, limb ischemia), renal replacement therapy or catheter line related clots. The values reported are cumulative.

Time frame: Up to Day 28

The D-dimer blood test is a method of screening for deep vein thrombosis or pulmonary embolism. A normal D-dimer value is less than 0.50 micrograms per milliliter (mcg/mL) of blood. High levels of D-dimer can occur when a patient has a major blood clot, infection, or liver disease.

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

Population: This analysis includes participants who had D-dimer at the indicated time point.

Diastolic blood pressure will be assessed in millimeters of mercury (mm Hg).

Time frame: Days 7, 14, 21, and 28

Population: Blood pressure was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

The number of participants in each study arm discharged to home or to a long-term acute care (LTAC) hospital, versus palliative care or death.

Time frame: Up to Day 48

The number of days spent hospitalized after study enrollment is presented here. All patients are included in calculating the reported mean, including those whose hospitalization ended due to death.

Time frame: Up to Day 48

The number of days spent in the ICU after study enrollment is presented here. All patients are included in calculating the reported mean, including those whose ICU stay ended due to death.

Time frame: Up to Day 48

Fibrinogen is a protein that helps with the formation of blood clots. For adults, the normal range of fibrinogen is 200 to 400 mg/dL. Fibrinogen can be increased in patients with liver, kidney, or inflammatory diseases. The risk of developing a thromboembolism is increased with chronically high levels of fibrinogen.

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

Population: This analysis includes participants who had fibrinogen assessed at the indicated time point.

Heart rate will be assessed as beats per minute.

Time frame: Days 7, 14, 21, and 28

Population: Heart rate was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

A measure of hematocrit is the volume of red blood cells in the total blood volume. Normal hematocrit for males is 40 to 54% and a normal measurement for females is 36 to 48%

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

Hemoglobin is measured in grams per deciliter (grams/dL). A normal Hb count for males is 13.2 to 16.6 grams/dL and a normal count for females is 11.6 to 15 grams/dL. A patient has anemia when their hemoglobin is low.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

A normal value for IL-6 is 1.8 picograms per milliliter (pg/mL) or less. IL-6 is increased in patients with infections or chronic inflammation.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

An INR of around 1.1 is considered normal. Lower INR can means that blood is clotting faster than desired while higher INR indicates that blood is clotting slower than normal.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

MVP is a measurement of platelet size. Platelet size tends to be increased when platelet count is high. Typical platelet volume is 9.4 to 12.3 femtoliters (fL).

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

Whether or not breathing assistance from an RRT is needed will be compared between study arms.

Time frame: Days 7, 14, 21, and 28

Population: Need for treatment from an RRT was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

The PaO2/FiO2 ratio is decreased with hypoxia. A value of less than 200 indicates acute respiratory distress syndrome (ARDS).

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

Population: This analysis includes participants with available arterial blood gas (ABG) values.

A normal platelet is 150,000 to 450,000 platelets per microliter of blood. An excess of platelets in the blood can be caused by inflammation or infection.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

PEEP during ventilator use is measured in centimeters of water (cmH2O) and is the pressure in the lungs above atmospheric pressure, at the end of an exhalation. Higher PEEP (10 cmH2O or greater) may be associated with improved mortality, compared with PEEP below 10 cmH2O.

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

Population: This analysis includes participants who were assessed for PEEP at the indicated time point.

Prothrombin time is a measurement of the time it takes (in seconds) for blood to clot. A normal value is 10 to 14 seconds.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

Respiratory rate will be assessed as breaths per minute.

Time frame: Days 7, 14, 21, and 28

Population: Respiratory rate was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

The Sequential Organ Failure Assessment (SOFA) score is a method of predicting mortality that is based on the degree of dysfunction of six organ systems (respiratory, nervous, cardiovascular, liver, coagulation, and kidneys). Each organ system is scored between 0 and 4, where 0 indicates normal function and 4 indicates a high degree of dysfunction. Total scores range from 0 to 24. A score of 0-6 is associated with a mortality rate of less than 10% while a score between 16 and 24 is associated with a greater than 90% mortality rate.

Time frame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28

Population: This analysis includes participants who had a SOFA score assessment at the indicated time point.

Systolic blood pressure will be assessed in millimeters of mercury (mm Hg).

Time frame: Days 7, 14, 21, and 28

Population: Blood pressure was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

Time to treatment failure will be assessed in days and is defined as plasma viscosity \> 3.5 cP and/or the participant is offered TPE outside of trial by primary clinical team.

Time frame: Up to Day 28

Population: This analysis includes participants experiencing treatment failure.

The normal range for total protein is 6.0 to 8.3 g/dL of blood. High levels of total protein can occur with inflammation or infection while low levels may indicate kidney or liver problems, or malnutrition.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.

Whether or not breathing assistance from vasopressors is needed will be compared between study arms.

Time frame: Days 7, 14, 21, and 28

Population: Vasopressor requirements were not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

The number of days participants are on a ventilator, among participants who were ever on a ventilator after study enrollment.

Time frame: Up to Day 28

Population: This analysis includes participants who were on a ventilator; two participants in the TPE arm were never on a ventilator.

The oxygen percent delivered with a ventilator that is needed to maintain blood oxygen levels will be compared between study arms.

Time frame: Days 7, 14, 21, and 28

Population: FiO2 was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

Ventilatory ratio will be documented. The formula for the ventilatory is \[minute ventilation (ml/min) × PaCO2 (mm Hg)\]/(predicted body weight × 100 × 37.5).

Time frame: Days 7, 14, 21, and 28

Population: Information for calculating the ventilatory ratio was not collected in an effort to reduce redundancy and workload for clinicians as more relevant/direct measures were already being collected.

The normal range for WBC is 3,400 to 6,600 cells per microliter (cells/mL) of blood. A high WBC occurs when inflammation or infection is present.

Time frame: Days 7, 14, 21, and 28

Population: Information for this outcome was not collected for any participants. Limited laboratory data was available for clinical parameters ordered by the patients' healthcare providers as part of routine clinical care and later abstracted by study team members by chart review. This analyte was not abstracted by the study team for any patient given realization that too few points were available for analysis to generate meaningful data for interpretation.