Plasma Exchange Therapy for Post- COVID-19 Condition: A Pilot, Randomized Double-Blind Study

Study Overview
=================
Brief Summary
-----------------
PAX is a prospective, randomized (1:1), double-blind, placebo-controlled study, that have as a objective to evaluate the safety and tolerability of plasma exchange (PE) in patients with Post Acute Covid-19 Syndrome (PCC) comparing to sham plasma exchange. The participants will be randomized in two arms: (1) 6 sessions of PE (Plasma Exchange) with human serum albumin 5% or (2) 6 sessions with placebo (infusion of of sterile saline solution 0.9%) on days 1, 3, 8, 10, 15 and 17.

Detailed Description
-----------------
Randomized participants will receive plasma exchange (PE) or sham PE (placebo) (6 sessions: V2, V3, V4, V5, V6 and V7) and will continue their follow-up visits(V8d22, V9d45, V10d90). Plasma volumes will be replaced, which will vary depending on sex, height, weight and hematocrit.

Official Title
-----------------
Plasma Exchange Therapy for Post- COVID-19 Condition: A Pilot, Randomized Double-Blind Study

Conditions
-----------------
Post-COVID19 Condition

Intervention / Treatment
-----------------
* Combination Product: Plasma Exchange Procedure
* Other: Sham Plasma Exchange Procedure


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female individuals 18 years-old or older. Evidence of previous SARS-CoV-2 infection at least 90 days prior to study recruitment, defined by either (a) Nasopharyngeal SARS-CoV-2 nucleic acid test (Polymerase chain reaction [PCR] or Transcription-Mediated Amplification [TMA] (b) validated Nasopharyngeal Lateral Flow Assay rapid antigen test [RAT], or (c) SARSCoV-2 serology before SARS-CoV-2 vaccination. Symptoms of PCC after 90 days of infection and that last for at least 2 months and cannot explained by an alternative diagnosis. Not able to perform all usual duties/ activities due to symptoms, pain, depression or anxiety, defined as grades 3 or 4 in the post-COVID-19 Functional Status (PCFS) scale. Availability of an adequate peripheral venous cannulation. If women of childbearing potential, use of a highly effective method of contraception (abstinence, hormonal contraception, intra-uterine device [IUD], or anatomical sterility in self). Willing to comply with the requirements of the protocol and available for followup for the planned duration of the study. Has understood the information provided and capable of giving informed consent. Exclusion criteria Exclusion Criteria: SARS-CoV-2 infection diagnosed during the previous 90 days. Last SARS-CoV-2 vaccine dose during the previous 30 days. No significant limitations in the subject's ability to perform all usual duties/activities (i.e., grades 0, 1 or 2 in PCFS scale). Medical conditions for which 250 mL of intravenous fluid is considered dangerous (i.e., decompensated heart failure or renal failure with fluid overload, among others). Pregnant or breastfeeding women. Contraindications for therapeutic PE: Non-availability of an adequate peripheral venous catheter, hemodynamic instability, septicemia, known allergy to fresh frozen plasma or replacement colloid/albumin, known allergy to heparin. Current or planned hospital admission for any cause during the study follow-up. Inability to consent and/or comply with study requirements, in the opinion of the investigator. Currently participating or planning to participate in any other clinical trial until day 90 of follow-up.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized (1:1), double-blind, placebo-controlled study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasma Exchange<br>6 sessions of PE with human serum 5% albumin. Plasma exchange sessions will occur on days 1, 3, 8, 10, 15 and 17 | Combination Product: Plasma Exchange Procedure<br>* Plasma exchanges will be performed with 5% albumin as the replacement fluid. The typical schedule prescribed will be an exchange of 1 volemia. Blood will be separated into cells and plasma; the cells will be combined with reconstituted 5% human serum albumin and reinfused into the patient with normal saline<br>* Other names: Plasmapheresis;|
| Sham Comparator: Sham Plasma Exchange<br>6 sessions of sham plasma exchange (one infusion of sterile saline solution 0.9%) on days 1, 3, 8, 10, 15 and 17. | Other: Sham Plasma Exchange Procedure<br>* For sham plasma exchange procedures, a sound behind the curtain will be performed imitating the sound of the cell processing platform. In these cases, only one infusion of 200 to 250ml of sterile saline solution 0.9% will be performed during the time stablished for all procedures. Albumin will not be necessary for those patients in the Sham plasma exchange arm<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of PE in patients with Post-Acute Covid-19 Syndrome (PCC) comparing to sham plasma exchange (placebo) | Proportion of adverse events (AEs) through day 90, considering: All AEs Grade 3 and 4 AEs AEs leading to study discontinuation | Within 90 days from the treatment start | 
| Proportion of subjects with Grade 0, 1 o 2 functional disability assessed by the functional status scale (PCFS) | Grade 0, 1 o 2 functional disability assessed by the functional status scale (PCFS), being 0 the better outcome and 4 the worse outcome | From baseline to day 90 | 
| Proportion of subjects with Grade 0, 1 o 2 functional disability assessed by the fatigue severity scale (FSS) | Grade 0, 1 o 2 functional disability assessed by the fatigue severity scale (FSS), being 1 the better outcome and 70 the worse outcome | From baseline to day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the ability of PE to improve PCC symptoms | Can Ruti PCC symptoms scale questionnare by days 0, 8, 15, 22, 45 and 90 | At days 0, 8, 15, 22, 45 and 90 | 
| Assess the impact of PE on quality of life in subjects with PCC | Quality of life questionnaires: EuroQol-5D questionnaire being 5 the better outcome and 15 the worse outcome. | At day 0, 8, 15, 22, 45 and 90. | 
| Assess the impact of PE on quality of life in subjects with PCC using MOS-HIV questionnaire | Quality of life questionnaires: MOS-HIV questionnaire being 4 the better outcome and 1 the worse outcome. | At day 0, 8, 15, 22, 45 and 90. | 
| Assess the impact of PE on neurocognitive symptoms in subjects with PCC using NeuScreen fluency Test | The neurocognitive evaluation assessed by the NeuScreen fluency test (Seconds) | At days 0, 22 and 90 | 
| Assess the impact of PE on neurocognitive symptoms in subjects with PCC using MEF-30 questionnaire | The neurocognitive evaluation assessed by the MEF-30 questionnaire, with being 0 the better outcome and 120 being the worse outcome. | At days 0, 22 and 90 | 
| Assess the impact of PE on neurocognitive symptoms in subjects with PCC using HADs questionnaire | The neurocognitive evaluation assessed by the HADs questionnaire, with being 0 as the better outcome and 21 being the worse outcome. | At days 0, 22 and 90 | 
| Changes in cellular anti-SARS-CoV-2 immunity associated with PE in subjects with PCC by the determination of SARS-CoV-2 specific igG | Changes in cellular anti-SARS-CoV-2 immunity associated with PE in subjects with PCC by the determination of SARS-CoV-2 specific igG in plasma (Arbitrary Units, AU) | At day 0, 8, 15, 22, 45 and 90. | 
| Changes in cellular anti-SARS-CoV-2 immunity associated with PE in subjects with PCC by the neutralization activity evaluation | Changes in cellular anti-SARS-CoV-2 immunity associated with PE in subjects with PCC by the analysis of reciprocal titers of neutralizing antibodies against SARS-CoV-2 | At day 0, 8, 15, 22, 45 and 90. | 
| Changes in cellular anti-SARS-CoV-2 immunity associated with PE in subjects with PCC by the T-Cell response | Changes in cellular anti-SARS-CoV-2 immunity associated with PE in subjects with PCC by the reduction of T-Cell response (%) from plasma samples | At day 0, 8, 15, 22, 45 and 90. | 
| Determination of residual SARS-CoV-2 particles (RNA) in plasma from subjects with PCC | Virological assessment to determine the residual SARS-CoV-2 RNA (copies/mL) | At days 0, 8, 15, 22, 45, and 90 | 
| Changes in microbiota associated with PE in subjects with PCC | Stool assessment to determine the residual SARS-CoV-2 RNA (copies/mL) | At day 1, 8, 15, 22, 45 and 90 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-CoV-2, COVID-19, Long COVID19, Plasma exchange (PE), Plasmapheresis