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Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04441996
Recruitment Status : Active, not recruiting
First Posted : June 22, 2020
Last Update Posted : January 14, 2021
Sponsor:
Information provided by (Responsible Party):
Cheryl Maier, 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).


Condition or disease Intervention/treatment Phase
COVID-19 Biological: Therapeutic plasma exchange (TPE) Other: Standard of care Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity
Actual Study Start Date : July 17, 2020
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021

Arm Intervention/treatment
Experimental: Therapeutic plasma exchange (TPE)
Participants with COVID-19-associated hyperviscosity randomized to receive therapeutic plasma exchange (TPE).
Biological: Therapeutic plasma exchange (TPE)
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.

Active Comparator: Standard of care
Participants with COVID-19-associated hyperviscosity randomized to receive standard of care treatment.
Other: Standard of care
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.




Primary Outcome Measures :
  1. Change in Plasma Viscosity [ Time Frame: Baseline (Study Day 1 prior to TPE), up to Day 4 (within 24 hours of last TPE) ]
    Plasma viscosity will be measured in centipoise (cP). The normal range is 1.4 - 1.8 cP and measurements above this range indicate increased viscosity.


Secondary Outcome Measures :
  1. All Cause Mortality [ Time Frame: Up to Day 31 ]
    The number of participants dying from any cause will be compared between study arms.

  2. Bleeding and Thromboembolic Complications [ Time Frame: Up to Day 31 ]
    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.

  3. Time to Treatment Failure [ Time Frame: Up to Day 31 ]
    Time to treatment failure will be assessed in hours and is defined as plasma viscosity > 3.5 cP and/or the participant is a candidate for TPE as salvage therapy, as assessed by clinical team.

  4. Duration of ICU Stay [ Time Frame: Up to Day 31 ]
    The number of days spent in the ICU will be compared between study arms.

  5. Duration of Hospital Stay [ Time Frame: Up to Day 31 ]
    The number of days spent in the hospital will be compared between study arms.

  6. Discharge Disposition [ Time Frame: Up to Day 31 ]
    The number of participants in each study arm discharged to home or to a long-term acute care hospital, versus palliative care or death.

  7. Change in Clinical Status [ Time Frame: Days 6, 10, 17, and 31 ]
    The clinical status of participants will be assessed with a single-item, 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.

  8. Change in Body Temperature [ Time Frame: Days 6, 10, 17, and 31 ]
    Body temperature will be assessed in degrees Celsius.

  9. Change in Systolic Blood Pressure [ Time Frame: Days 6, 10, 17, and 31 ]
    Systolic blood pressure will be assessed in millimeters of mercury (mm Hg).

  10. Change in Diastolic Blood Pressure [ Time Frame: Days 6, 10, 17, and 31 ]
    Diastolic blood pressure will be assessed in millimeters of mercury (mm Hg).

  11. Change in Heart Rate [ Time Frame: Days 6, 10, 17, and 31 ]
    Heart rate will be assessed as beats per minute.

  12. Change in Respiratory Rate [ Time Frame: Days 6, 10, 17, and 31 ]
    Respiratory rate will be assessed as breaths per minute.

  13. Change in Ventilator Days [ Time Frame: Days 6, 10, 17, and 31 ]
    The number of days participants are on a ventilator will be compared between study arms.

  14. Change in Ventilator Oxygen Percent (FiO2) [ Time Frame: Days 6, 10, 17, and 31 ]
    The oxygen percent delivered with a ventilator that is needed to maintain blood oxygen levels will be compared between study arms.

  15. Change in Positive End-Expiratory Pressure (PEEP) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  16. Change in Vasopressor Requirements [ Time Frame: Days 6, 10, 17, and 31 ]
    Whether or not breathing assistance from vasopressors is needed will be compared between study arms.

  17. Change in Need for Treatment from a Registered Respiratory Therapist (RRT) [ Time Frame: Days 6, 10, 17, and 31 ]
    Whether or not breathing assistance from an RRT is needed will be compared between study arms.

  18. Change in Sequential Organ Failure Assessment (SOFA) Score [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  19. Change in Partial Pressure of Arterial Oxygen (PaO2)/Percentage of Inspired Oxygen (FiO2) Ratio [ Time Frame: Days 6, 10, 17, and 31 ]
    The PaO2/FiO2 ratio is decreased with hypoxia. A value of less than 200 indicates acute respiratory distress syndrome (ARDS).

  20. Change in Ventilatory Ratio [ Time Frame: Days 6, 10, 17, and 31 ]
    Ventilatory ratio will be documented. The formula for the ventilatory is [minute ventilation (ml/min) × PaCO2 (mm Hg)]/(predicted body weight × 100 × 37.5).

  21. Change in White Blood Count (WBC) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  22. Change in Hemoglobin (Hb) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  23. Change in Hematocrit (Hct) [ Time Frame: Days 6, 10, 17, and 31 ]
    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%

  24. Change in Platelet Count [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  25. Change in Mean Platelet Volume (MVP) [ Time Frame: Days 6, 10, 17, and 31 ]
    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).

  26. Change in Blood Urea Nitrogen (BUN) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  27. Change in Creatinine [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  28. Change in Bilirubin [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  29. Change in Total Protein [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  30. Change in Albumin [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  31. Change in C-reactive Protein (CRP) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  32. Change in Interleukin 6 (IL-6) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  33. Change in Prothrombin Time (PT) [ Time Frame: Days 6, 10, 17, and 31 ]
    Prothrombin time is a measurement of the time it takes (in seconds) for blood to clot. A normal value is 10 to 14 seconds.

  34. Change in International Normalized Ratio (INR) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  35. Change in Activated Partial Thromboplastin Time (aPTT) [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  36. Change in Anti-factor Xa (anti-Xa) [ Time Frame: Days 6, 10, 17, and 31 ]
    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).

  37. Change in Fibrinogen [ Time Frame: Days 6, 10, 17, and 31 ]
    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.

  38. Change in D-dimer [ Time Frame: Days 6, 10, 17, and 31 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    • A diagnostic test (e.g., nasopharyngeal swab, tracheal aspirate, other) OR
    • Positive serological test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies OR
    • 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 hrs
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04441996


Locations
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United States, Georgia
Emory Saint Joseph's Hospital
Atlanta, Georgia, United States, 30308
Emory University Hospital Midtown
Atlanta, Georgia, United States, 30308
Emory University Hospital
Atlanta, Georgia, United States, 30322
Sponsors and Collaborators
Emory University
Investigators
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Principal Investigator: Cheryl Maier, MD, PhD Emory University
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Responsible Party: Cheryl Maier, Assistant Professor, Emory University
ClinicalTrials.gov Identifier: NCT04441996    
Other Study ID Numbers: STUDY00000949
First Posted: June 22, 2020    Key Record Dates
Last Update Posted: January 14, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Cheryl Maier, Emory University:
Hyperviscosity