Clinical trial NCT04623255: Study of Plasma Exchange in Severe COVID-19
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID19
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2020-11-10
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. Raised LDH (\> 2 x ULN)
  2. Raised D Dimers (\> 2X ULN)
  3. 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

Primary outcomes:
measure: Number of Participants With Inflammatory Marker Reduction of at Least 50% at Any Efficacy Time Point
timeFrame: The inflammatory markers recorded in this study are C reactive protein (CRP), lactate dehydrogenase(LDH) and D-Dimer, and we consider whether there is a reduction during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
measure: Change in Inflammatory Marker-CRP
timeFrame: We consider whether there is a reduction in inflammatory marker CRP during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
measure: Change in Inflammatory Marker-D Dimer
timeFrame: We consider whether there is a reduction in inflammatory marker D-dimer during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
measure: Change in Inflammatory Marker-LDH
timeFrame: We consider whether there is a reduction in inflammatory marker LDH during the designated follow-up period (i.e. follow-up days 6, 7, 14, 21 and 28).
Secondary outcomes:
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: University College London Hospital
Study officials:
affiliation: UCLH
name: Marie Scully, MD
role: PRINCIPAL_INVESTIGATOR
References: