Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity

Phase 4

Completed

• Conditions: COVID-19
• Interventions: Biological: Therapeutic plasma exchange (TPE); Other: Standard of care

• Registration Number: NCT04441996
• Lead Sponsor: Emory University

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2020-06-19
• Study First Submitted QC: 2020-06-19
• Study First Posted: 2020-06-22
• Study Start: 2020-07-17
• Primary Completion: 2021-03-18
• Study Completion: 2021-03-18
• Disposition First Submitted: 2021-12-08
• Results First Submitted: 2022-10-28
• Status Verified: 2022-11
• Results First Submitted QC: 2022-11-29
• Disposition First Submitted QC: 2022-11-29
• Last Update Submitted: 2022-11-29
• Results First Posted: 2022-12-21
• Disposition First Posted: 2022-12-21
• Last Update Posted: 2022-12-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 20

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Therapeutic plasma exchange (TPE)	Therapeutic plasma exchange (TPE)	Participants with COVID-19-associated hyperviscosity randomized to receive therapeutic plasma exchange (TPE).
Standard of care	Standard of care	Participants with COVID-19-associated hyperviscosity randomized to receive standard of care treatment.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (3)

Emory University Hospital Midtown; 🇺🇸 Atlanta, Georgia, United States

Emory Saint Joseph's Hospital; 🇺🇸 Atlanta, Georgia, United States

Emory University Hospital; 🇺🇸 Atlanta, Georgia, United States