Plasma Exchange (PLEX) and Convalescent Plasma (CCP) in COVID-19 Patients With Multiorgan Failure

Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a pandemic
of coronavirus disease (COVID-19) with many patients developing severe hypoxia and some
multiple organ failure. Many patients have died, and healthcare systems in several countries
have been or will be overwhelmed because of a surge of patients needing hospitalisation and
intensive care. There is no available proven treatment for COVID-19; the care is supportive,
including respiratory, circulatory and renal support. For other patient groups with similar
critical illness (acute respiratory disease syndrome and septic shock) multiple inflammatory
mediators (cytokines) are linked to and probably responsible for such conditions. Thus,
extracorporeal cytokine removal by plasma exchange (PLEX) has been tried in these conditions.
Convalescent plasma on the other hand, may offer specific actions against SARS-CoV-2 and
COVID-19. With this trial, the investigators will test the use of combined PLEX and infusion
of convalescent plasma collected from COVID-19 recovered individuals at the end of the PLEX
procedure in the most severely ill patients with COVID-19.

Objectives The investigators will aim to assess the effects of combination of PLEX and
convalescent plasma on the number of days alive and out of hospital in adult patients with
COVID-19 and multiple organ failure.

Inclusion and exclusion criteria All adult patients who have documented COVID-19 and multiple
organ failure will be screened (use of respiratory and renal support). The patients who have
received convalescent plasma for COVID-19, who have known hypersensitivity to plasma, who are
pregnant, who the clinical team has decided not to escalate therapy, and those in whom
informed consent cannot be obtained will be excluded.

Experimental intervention In addition to standard care, 2 plasma exchange procedures within
24 hours by membrane or centrifuge method. Exchange volume of 60 ml of plasma per kg of body
weight with Albumin 5% in Ringer/saline as a substitution Fluid 50% at the beginning /Fresh
Frozen Plasma 50% towards the end of the session and in addition 2 bags of CCP (equalling 600
ml CCP) with an administration rate of 100 to 250 ml/hr at the end of the 2nd procedure.

Control group with no intervention Standard care without the use of PLEX or convalescent
plasma. Outcomes The primary outcome is days alive and out of hospital at day 90. Secondary
outcomes are serious adverse events (anaphylactic reaction to CCP, new episode of septic
shock or invasive fungal infection); days alive without life support at day 90; and all-cause
mortality at day 28 and day 90.

Statistics Primary outcome will be compared using non-parametric statistics adjusting for the
stratification variable (site). Differences will be quantified as differences in medians
along with 95% confidence intervals. The mortality outcomes will be analysed using Fisher's
exact test and binomial regression models with log links adjusted for the stratification
variable (site) with results quantified as risk supplemented with risk differences and
ratios, both with 95% confidence intervals.

Trial size Sample size calculation is based on preliminary data on days alive and out of
hospital at day 90 in COVID-19 patients with multiple organ failure receiving standard of
care (mean: 18 days (SD±18.36)). A sample size of n=100 per group would enable verification
of a delta of 7.31 days, corresponding to a relative risk reduction of 40% with a power of
1-β = 0.80 for a two-sided t-test with α=0.05. To compensate for drop-out and sample
variation a total of 110 patients are planned for inclusion in each treatment arm; i.e. 220
in total.