Randomised Study of Plasma Exchange in Severe COVID-19

Study Overview
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Brief Summary
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The rationale in severe COVID19 infection is to undertake PEX to aid reduction of the hyperinflammation and reduce the morbidity and mortality to the lungs, but also systemically, such as the heart, kidneys and brain. A feasibility study of PEX therapy has been undertaken and confirmed a reduction in the inflammatory markers, no VTE/arterial events and normalisation of the renal function and cardiac function throughout the period of therapy. As plasma exchange is an intensive treatment modality, blocks of 5 daily PEX will be undertaken. Further blocks of PEX treatment can be initiated as dictated by the clinical and laboratory parameters. Unlike many therapeutic schedules, there is no immunosuppression associated with PEX; indeed, the resulting decrease in inflammatory markers were shown to be associated with an increase and sustained lymphocytes count.

Detailed Description
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COVID19 is a viral pandemic associated with primarily respiratory pathology, in the form of microvascular and macrovascular thrombosis. In patients requiring hospital admission, there is severe disease, requiring respiratory support, from high dose oxygen therapy or ventilatory assistance, which may be invasive or non invasive. The pathology of COVID19 is poorly understood, but it is accepted there is an inflammatory-thrombotic basis. Despite current therapeutic platforms, there is no consensus on a specific therapy within a trial setting that has proven benefit in severe COVID 19. Thrombotic microangiopathies, such as TTP, are a different disease, but have a comparable prothrombotic phenotype, and similar or higher inflammatory parameters, including D Dimers, ferritin, LDH and IL-6 at acute presentation and resolve with plasma exchange (PEX). The rationale in severe COVID19 infection is to undertake PEX to aid reduction of the hyperinflammation and reduce the morbidity and mortality to the lungs, but also systemically, such as the heart, kidneys and brain. A feasibility study of PEX therapy has been undertaken and confirmed a reduction in the inflammatory markers, no VTE/arterial events and normalisation of the renal function and cardiac function throughout the period of therapy. As plasma exchange is an intensive treatment modality, blocks of 5 daily PEX will be undertaken. Further blocks of PEX treatment can be initiated as dictated by the clinical and laboratory parameters. Unlike many therapeutic schedules, there is no immunosuppression associated with PEX; indeed, the resulting decrease in inflammatory markers were shown to be associated with an increase and sustained lymphocytes count. Therefore, as patients with COVID-19 have elevated procoagulant factors including VWF and factor VIII secondary to direct endothelial activation. This is associated with an exaggerated pro-inflammatory immune response and microvascular thrombosis; resulting in multi-organ dysfunction and eventually death. PEX will improve coagulopathy, as measured by VWF:ADAMTS 13 ratio and D Dimers, with an associated reduction in inflammation, organ-related microthrombosis, and ventilatory support.

Official Title
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A Randomised Controlled Trial of Plasma Exchange With Standard of Care Compared to Standard of Care Alone in the Treatment of Severe COVID-19 Infection (COVIPLEX)

Conditions
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COVID19

Intervention / Treatment
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* Drug: OCTAPLAS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-70 Proven COVID-19/high clinical suspicion of COVID-19 Hypoxia/respiratory compromise defined as requiring respiratory support of >2L/min of oxygen by nasal cannulae to maintain SpO2<96%. Raised inflammatory parameters: at least 2 of the following: Raised LDH (> 2 x ULN) Raised D Dimers (> 2X ULN) Raised CRP (>2X ULN) Females of childbearing potential have a negative pregnancy test within 7 days prior to being randomised. Participants are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal Exclusion Criteria: Significant co-morbid illness with treatment escalation limited to CPAP Active bleeding PF ratio < 100 on mechanical ventilation OR noradrenaline requirement > 0.5mcg/kg/min to maintain MAP > 65mmHg (suggests futility) Known allergies to Octaplas or excipients Females who are pregnant

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| No Intervention: STANDARD OF CARE<br>Standard patient care for severe COVID-19 | |
| Active Comparator: Plasma exchange<br>Standard patient care for severe COVID-19 with. plasma exchange daily for 5 days x 3 courses as required | Drug: OCTAPLAS<br>* plasma exchange<br>* Other names: plasma exchange;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Inflammatory Marker-CRP | To compare the change in inflammatory markers with Plasma Exchange and control groups in patients with severe COVID-19 | 5 days | 
| Change in Inflammatory Marker-D Dimer | To compare the change in inflammatory markers with Plasma Exchange and control groups in patients with severe COVID-19 | 5 DAYS | 
| Change in Inflammatory Marker-LDH | To compare the change in inflammatory markers with Plasma Exchange and control groups in patients with severe COVID-19 | 5 DAYS | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of mechanical ventilation | To compare rates of mechanical ventilation between Plasma Exchange (PEX) and control groups in patients with severe COVID requiring CPAP/ NIV at treatment onset | 28 days | 
| Rates of clinical thrombotic events | To compare rates of clinical thrombotic events either venous (deep vein thrombosis DVT or pulmonary embolism PE) or arterial thrombus (cardiac, neurological and peripheral vascular) between Plasma Exchange (PEX) and control groups in patients with severe Covid-19 | 28 days | 
| Change in inflammatory-thrombotic response | To compare the change in the inflammatory-thrombotic response by monitoring von Willebrand factor VWFA antigen/ADAMTS 13 activity ratio between Plasma Exchange (PEX) and control groups in patients with severe COVID-19 | 28 days | 
| To compare the incidence of acute kidney injury | To compare the incidence of acute kidney injury as defined by KDIGO criteria between Plasma Exchange (PEX) and control groups in patients with severe COVID-19 | 28 days | 
| Mortality at day 28 | To compare mortality at day 28 between the PEX and control groups | 28 days |