Clinical trial NCT04441996: Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity
Official title: Therapeutic Plasma Exchange for COVID-19-associated Hyperviscosity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: COVID-19
Keywords: Hyperviscosity
Lead sponsor: Emory University
Sponsor class: OTHER
First posted: 2020-06-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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

Primary outcomes:
measure: Plasma Viscosity
timeFrame: Day 1 (within 24 hours prior to TPE), Day 4 (within 24 hours of last TPE)
measure: Cumulative Incidence of Adverse Events
timeFrame: Up to Day 28
Secondary outcomes:
measure: Cumulative All Cause Mortality
timeFrame: Up to Day 28
measure: Cumulative Count of Bleeding and Thromboembolic Complications
timeFrame: Up to Day 28
measure: Time to Treatment Failure
timeFrame: Up to Day 28
measure: Duration of ICU Stay
timeFrame: Up to Day 48
measure: Duration of Hospital Stay
timeFrame: Up to Day 48
measure: Discharge Disposition
timeFrame: Up to Day 48
measure: Clinical Status Score
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
measure: Body Temperature
timeFrame: Days 7, 14, 21, and 28
measure: Systolic Blood Pressure
timeFrame: Days 7, 14, 21, and 28
measure: Diastolic Blood Pressure
timeFrame: Days 7, 14, 21, and 28
measure: Heart Rate
timeFrame: Days 7, 14, 21, and 28
measure: Respiratory Rate
timeFrame: Days 7, 14, 21, and 28
measure: Ventilator Days
timeFrame: Up to Day 28
measure: Ventilator Oxygen Percent (FiO2)
timeFrame: Days 7, 14, 21, and 28
measure: Positive End-Expiratory Pressure (PEEP)
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
measure: Vasopressor Requirements
timeFrame: Days 7, 14, 21, and 28
measure: Need for Treatment From a Registered Respiratory Therapist (RRT)
timeFrame: Days 7, 14, 21, and 28
measure: Sequential Organ Failure Assessment (SOFA) Score
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
measure: Partial Pressure of Arterial Oxygen (PaO2)/Percentage of Inspired Oxygen (FiO2) Ratio
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
measure: Ventilatory Ratio
timeFrame: Days 7, 14, 21, and 28
measure: White Blood Count (WBC)
timeFrame: Days 7, 14, 21, and 28
measure: Hemoglobin (Hb)
timeFrame: Days 7, 14, 21, and 28
measure: Hematocrit (Hct)
timeFrame: Days 7, 14, 21, and 28
measure: Platelet Count
timeFrame: Days 7, 14, 21, and 28
measure: Mean Platelet Volume (MVP)
timeFrame: Days 7, 14, 21, and 28
measure: Blood Urea Nitrogen (BUN)
timeFrame: Days 7, 14, 21, and 28
measure: Creatinine
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
measure: Bilirubin
timeFrame: Days 7, 14, 21, and 28
measure: Total Protein
timeFrame: Days 7, 14, 21, and 28
measure: Albumin
timeFrame: Days 7, 14, 21, and 28
measure: C-reactive Protein (CRP)
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
measure: Interleukin 6 (IL-6)
timeFrame: Days 7, 14, 21, and 28
measure: Prothrombin Time (PT)
timeFrame: Days 7, 14, 21, and 28
measure: International Normalized Ratio (INR)
timeFrame: Days 7, 14, 21, and 28
measure: Activated Partial Thromboplastin Time (aPTT)
timeFrame: Days 7, 14, 21, and 28
measure: Anti-factor Xa (Anti-Xa)
timeFrame: Days 7, 14, 21, and 28
measure: Fibrinogen
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
measure: D-dimer
timeFrame: Day 1 (day of study enrollment), Day 4 (one day after second TPE treatment), Days 7, 14, 21, and 28
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Saint Joseph's Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
Study officials:
affiliation: Emory University
name: Cheryl Maier, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: