RescuE pLAsma eXchange in Severe COVID-19

Study Overview
=================
Brief Summary
-----------------
The spectrum of coronavirus disease 2019 (COVID-19) ranges from asymptomatic infection to acute respiratory distress syndrome (ARDS) and patient death. Severely affected patients may develop a cytokine storm-like clinical syndrome with high mortality. Laboratory tests in these patients show an excessive and uncontrolled immune response with consecutive multi-organ failure. In addition, there is evidence for the development of prothrombotic autoantibodies as an epiphenomenon of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Therapeutic plasma exchange (TPE) is being discussed as a therapeutic alternative in patients with severe, refractory COVID-19. The idea is that plasma exchange eliminates both endogenous and exogenous inducers of an exuberant inflammatory response as well as prothrombotic factors, thus breaking the secondary vicious circle of SARS-CoV-2 infection. In general, TPE is a safe procedure with known efficacy in other severe viral diseases as well as in cytokine storm-like diseases and ARDS of other geneses. Moreover, initial data, mostly derived from case studies, demonstrate promising therapeutic efficacy of TPE in severe COVID-19 courses with previously lacking treatment options. To further evaluate the therapeutic efficacy of TPE in severe COVID-19, a prospective randomized controlled trial of TPE in severe SARS-CoV-2 infection is being conducted at our center. Patients will be randomized to a control group (standard therapy according to center standards) and a therapy/intervention group (standard therapy + TPE).

Official Title
-----------------
RescuE pLAsma eXchange in Severe COVID-19 (RELAX Severe COVID-19)

Conditions
-----------------
Therapeutic Plasma Exchange, Covid19

Intervention / Treatment
-----------------
* Other: Therapeutic plasma exchange


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent by the study participant or their legally appointed representative. Age ≥ 18 years Evidence of acute SARS-CoV-2 infection, confirmed by PCR testing Invasive ventilation Fever ≥ 38.5°C, confirmed by a total of 3 consecutive measurements or ongoing renal replacement therapy and temperature ≥ 37.5°C D-dimers ≥ 2mg/L Dexamethasone ≥ 6mg/day or equivalent dose on at least 2 days Exclusion Criteria: Age > 85 years Pre-existing treatment limitations Pregnancy Confirmed pulmonary arterial embolism with hemodynamically relevant right heart strain ST-segment elevation myocardial infarction (STEMI) Participation in an intervention study elsewhere

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Therapeutic plasma exchange in patients with severe COVID 19
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: COVID-19 therapy according to center standard alone<br> | |
| Active Comparator: Therapeutic plasma exchange and COVID-19 therapy according to center standard<br> | Other: Therapeutic plasma exchange<br>* Treatment with therapeutic plasma exchange. Plasma from healthy donors is used.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Intention to treat analysis | 30 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Intention to treat & per protocol | 15, 30, 60, 90, 365 days after randomization | 
| Ventilator-free days |  | 15, 30, 60, 90 days after randomization | 
| Length of hospital an ICU stay |  | through study completion, an average of 1 year | 
| Improvement defined as two points on seven point ordinal WHO scale |  | through study completion, an average of 1 year | 
| Reduction of vasopressors after TPE treatments |  | through study completion, an average of 1 year | 
| Incidence of acute kidney injury, renal replacement therapy and renal recovery | AKI KDIGO criteria | 15, 30, 60, 90 days after randomization | 
| Frequency of typical complications associated to therapeutic plasma exchange |  | through study completion, an average of 1 year | 
| Reduction of inflammation mediators, (auto-)antibodies, and coagulation-associated molecules and their temporal correlation to TPE |  | through study completion, an average of 1 year | 
| D-dimer-dependent assessment of therapeutic efficacy. |  | through study completion, an average of 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Plasma exchange, Covid19