Clinical trial NCT04634422: Plasma Exchange (PLEX) and Convalescent Plasma (CCP) in COVID-19 Patients With Multiorgan Failure
Official title: Plasma Exchange (PLEX) and Convalescent Plasma (CCP) in COVID-19 Patients With Multiorgan Failure - the COVID PLEX+CCP Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Respiratory Failure
Renal Failure, Acute
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Aalborg University Hospital
name: Aarhus University Hospital
name: Odense University Hospital
name: Zealand University Hospital
First posted: 2020-11-18
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, parallel-grouped, stratified, centrally randomised controlled trial.
Primary purpose: TREATMENT

Brief summary: This Randomized Control Trial (RCT) proposes combination of extracorporeal cytokine removal by plasma exchange (PLEX) and additional infusion of convalescent plasma (CCP) collected from COVID-19 recovered individuals at the end of the PLEX procedure. The combination of cytokine removal by PLEX and CCP infusion is in onvestigators opinion more rational compared to CCP infusion alone and as such probably more effective in reducing the duration of mechanical ventilation, length of stay in the intensive care unit, and potentially also mortality.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Confirmed SARS-CoV-2 (COVID-19) requiring intensive care AND - Use of Advanced respiratory support as Invasive mechanical ventilation OR Non-invasive ventilation or continuous use of continuous positive airway pressure (CPAP) for hypoxia OR Oxygen supplementation with an oxygen flow of at least 10 L/min independent of delivery system AND RRT (continuous or intermittent) -OR ECMO

Exclusion Criteria:

* 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 (except that for cardiac arrest; patients who are not for cardio-pulmonary-resuscitation may be enrolled).
  * Who have received RRT for more than 72 hours
  * Who have received mechanical ventilation for more than 14 days
  * We will not exclude patients enrolled in other interventional trials unless the protocols of the two trials collide (e.g. use of CCP by protocol). Co-enrolment agreements will be established with the sponsor/investigator to maintain an updated list of trials approved for co-enrolment (

Primary outcomes:
measure: Alive at Day 90th
timeFrame: 90 days
Secondary outcomes:
measure: Day 8 serious adverse events
timeFrame: 8 days
measure: Day 28 all cause mortality
timeFrame: 28 days
measure: Days alive without life support at day 90
timeFrame: 90 days
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Anders Perner, Prof
role: PRINCIPAL_INVESTIGATOR
References: