Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity

Study Overview
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Brief Summary
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Many patients with Coronavirus Disease 2019 (COVID-19) have atypical blood clots. These blood clots can occur in either veins or arteries and be large, like in stroke or heart attack, or very tiny, called microthrombi. Some patients with COVID-19 even have blood clots despite being on anti-clotting medications. Blood with increased viscosity does not flow through the body normally, in the same way that syrup, a highly viscous liquid, and water, a minimally viscous liquid, flow differently. The researchers believe that hyperviscosity may contribute to blood clots and organ damage seen in patients with severe COVID-19. Plasma exchange removes a patient's plasma, which contains the large sticky factors that the researchers believe are increasing viscosity, and replaces it with plasma from healthy donors. In addition to providing important information about plasma exchange as a treatment in COVID-19 for patients, this study will provide data to justify resource and staffing decisions. This study will enroll 20 participants who are critically ill from COVID-19. Participants will be randomized to receive therapeutic plasma exchange (TPE) or standard of care (SOC).

Detailed Description
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Critically ill COVID-19 patients have high rates of complications, including respiratory failure, renal impairment, and a coagulopathic state that may exacerbate these conditions and contribute to additional end organ injury. Consistent with a fundamentally distinct nature of COVID-19-associated disease, our preliminary studies demonstrate that patients with COVID-19 exhibit an increase in plasma viscosity. Furthermore, the researchers have found that plasma viscosity strongly correlates with sequential organ failure assessment (SOFA) scores, a mortality prediction score used in the intensive care unit (ICU), in COVID-19 infected patients. These results strongly suggest that altered blood flow secondary to hyperviscosity may contribute to end organ injury and therefore morbidity and mortality in the most critically ill COVID-19 patients. More detailed analysis of the potential etiology of COVID-19-associated plasma hyperviscosity has demonstrated that these patients also have significantly elevated levels of the plasma protein fibrinogen. Increased fibrinogen levels, which may be either entirely responsible for or at least contribute to hyperviscosity in these patients, may be the primary mediator of refractory hypercoagulability in this patient population. Thus, hyperviscosity induced by hyperfibrinogenemia may be a critical driver of morbidity and mortality in patients with COVID-19. Therapeutic plasma exchange (TPE) is the only procedure known to directly and rapidly decrease plasma viscosity, suggesting that TPE may improve patient outcomes in critically ill patients with COVID-19 by decreasing plasma viscosity and thereby enhancing blood flow. However, as a procedure, extensive implementation of TPE would require significant devotion of hospital resources, including apheresis machines and the staff needed to successfully conduct these procedures. The procedures alone require staff to have prolonged interactions with critically ill COVID-19 patients, placing them at a potentially increased risk for contracting COVID-19. It is therefore essential that clear and unequivocal data be generated in order to accurately assess the risk and benefits of this procedure for both patients and staff. Such data will also aid in determining the necessary resources that may be needed to successfully conduct TPE for this patient population. Participants will be randomized in a 1:1 ratio to receive TPE or SOC. Participants in the TPE study arm will receive two treatments of TPE with frozen plasma on sequential days. Plasma viscosity will be measured before TPE (Day 1) and following the second TPE treatment (Day 3 or 4). Participants in the SOC study arm will also have their plasma viscosity assessed on Days 1 and 3. Participants will be followed for the duration of their hospital stay.

Official Title
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Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity

Conditions
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COVID-19

Intervention / Treatment
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* Biological: Therapeutic plasma exchange (TPE)
* Other: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Patients admitted to the ICU at Emory University Hospital, Emory University Hospital Midtown, or Emory Saint Joseph's Hospital Evidence of COVID-19 infection documented by a laboratory test either by one of the following: A diagnostic test (e.g., nasopharyngeal swab, tracheal aspirate, other) Positive serological test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies Medical records from outside institution Plasma viscosity >2.3 and <3.5 centipoise (cp) or Fibrinogen >800 mg/dL Exclusion Criteria: Patients with plasma viscosity > 3.5 cp Moribund patients that the ICU clinical team expects to die within 24 hours Patients with any condition that, in the opinion of the clinical team or investigator, could increase the subject's risk by participating in the study or confound the outcome of the study Patients participating in another clinical trial that prohibits the use of TPE Pregnant women Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic plasma exchange (TPE)<br>Participants with COVID-19-associated hyperviscosity randomized to receive therapeutic plasma exchange (TPE). | Biological: Therapeutic plasma exchange (TPE)<br>* Participants will receive two treatments of TPE with frozen plasma (FP) replacement on two sequential days (Day 2 and Day 3). All procedures will be performed by the apheresis staff at the hospital sites, following institutional standard operating procedures. FP will be obtained from American Red Cross or LifeSouth Community Blood centers.<br>|
| Active Comparator: Standard of care<br>Participants with COVID-19-associated hyperviscosity randomized to receive standard of care treatment. | Other: Standard of care<br>* Participants will continue to receive standard of care and be closely monitored by ICU team for any change in clinical status, and any adverse events directly related to study intervention will be reported to the study investigator.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Viscosity | Plasma viscosity is measured in centipoise (cP). The normal range is 1.4 - 1.8 cP and measurements above this range indicate increased viscosity. | Day 1 (within 24 hours prior to TPE), Day 4 (within 24 hours of last TPE) | 
| Cumulative Incidence of Adverse Events | 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. | Up to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative All Cause Mortality | The number of participants dying from any cause is reported as a cumulative measures of mortality. | Up to Day 28 | 
| Cumulative Count of Bleeding and Thromboembolic Complications | 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. | Up to Day 28 | 
| Time to Treatment Failure | 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. | Up to Day 28 | 
| Duration of ICU Stay | 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. | Up to Day 48 | 
| Duration of Hospital Stay | 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. | Up to Day 48 | 
| Discharge Disposition | 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. | Up to Day 48 | 
| Clinical Status Score | 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. | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 
| Body Temperature | Body temperature will be assessed in degrees Celsius. | Days 7, 14, 21, and 28 | 
| Systolic Blood Pressure | Systolic blood pressure will be assessed in millimeters of mercury (mm Hg). | Days 7, 14, 21, and 28 | 
| Diastolic Blood Pressure | Diastolic blood pressure will be assessed in millimeters of mercury (mm Hg). | Days 7, 14, 21, and 28 | 
| Heart Rate | Heart rate will be assessed as beats per minute. | Days 7, 14, 21, and 28 | 
| Respiratory Rate | Respiratory rate will be assessed as breaths per minute. | Days 7, 14, 21, and 28 | 
| Ventilator Days | The number of days participants are on a ventilator, among participants who were ever on a ventilator after study enrollment. | Up to Day 28 | 
| Ventilator Oxygen Percent (FiO2) | The oxygen percent delivered with a ventilator that is needed to maintain blood oxygen levels will be compared between study arms. | Days 7, 14, 21, and 28 | 
| Positive End-Expiratory Pressure (PEEP) | 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. | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 
| Vasopressor Requirements | Whether or not breathing assistance from vasopressors is needed will be compared between study arms. | Days 7, 14, 21, and 28 | 
| Need for Treatment From a Registered Respiratory Therapist (RRT) | Whether or not breathing assistance from an RRT is needed will be compared between study arms. | Days 7, 14, 21, and 28 | 
| Sequential Organ Failure Assessment (SOFA) Score | 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. | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 
| Partial Pressure of Arterial Oxygen (PaO2)/Percentage of Inspired Oxygen (FiO2) Ratio | The PaO2/FiO2 ratio is decreased with hypoxia. A value of less than 200 indicates acute respiratory distress syndrome (ARDS). | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 
| Ventilatory Ratio | Ventilatory ratio will be documented. The formula for the ventilatory is [minute ventilation (ml/min) × PaCO2 (mm Hg)]/(predicted body weight × 100 × 37.5). | Days 7, 14, 21, and 28 | 
| White Blood Count (WBC) | 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. | Days 7, 14, 21, and 28 | 
| Hemoglobin (Hb) | 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. | Days 7, 14, 21, and 28 | 
| Hematocrit (Hct) | 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% | Days 7, 14, 21, and 28 | 
| Platelet Count | 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. | Days 7, 14, 21, and 28 | 
| Mean Platelet Volume (MVP) | 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). | Days 7, 14, 21, and 28 | 
| Blood Urea Nitrogen (BUN) | 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. | Days 7, 14, 21, and 28 | 
| Creatinine | 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. | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 
| Bilirubin | 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. | Days 7, 14, 21, and 28 | 
| Total Protein | 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. | Days 7, 14, 21, and 28 | 
| Albumin | 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. | Days 7, 14, 21, and 28 | 
| C-reactive Protein (CRP) | 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. | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 
| Interleukin 6 (IL-6) | 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. | Days 7, 14, 21, and 28 | 
| Prothrombin Time (PT) | Prothrombin time is a measurement of the time it takes (in seconds) for blood to clot. A normal value is 10 to 14 seconds. | Days 7, 14, 21, and 28 | 
| International Normalized Ratio (INR) | 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. | Days 7, 14, 21, and 28 | 
| Activated Partial Thromboplastin Time (aPTT) | 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. | Days 7, 14, 21, and 28 | 
| Anti-factor Xa (Anti-Xa) | 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). | Days 7, 14, 21, and 28 | 
| Fibrinogen | 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. | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 
| D-dimer | 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. | Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperviscosity