Randomised Study of Plasma Exchange in Severe COVID-19 (COVIPLEX)

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)

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.

Study Overview

• Status: Unknown
• Conditions: COVID19
• Intervention / Treatment: Drug: OCTAPLAS

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.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW1 2PG
    • Recruiting
    • University College London Hospital
    • Contact: I Obu; Phone Number: 0207 679 6428; Email: uclh.ttp@nhs.net
    • Contact: Prof Marie Scully; Phone Number: 0207 679 6428; Email: uclh.ttp@nhs.net

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: STANDARD OF CARE; Standard patient care for severe COVID-19
Active Comparator: Plasma exchange; Standard patient care for severe COVID-19 with. plasma exchange daily for 5 days x 3 courses as required	Drug: OCTAPLAS; plasma exchange; Other Names: plasma exchange

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Principal Investigator: Marie Scully, MD, UCLH

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2020
• Primary Completion (Anticipated): October 15, 2021
• Study Completion (Anticipated): November 1, 2021

Study Registration Dates

• First Submitted: June 11, 2020
• First Submitted That Met QC Criteria: November 9, 2020
• First Posted (Actual): November 10, 2020

Study Record Updates

• Last Update Posted (Actual): November 10, 2020
• Last Update Submitted That Met QC Criteria: November 9, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 132796

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No