Therapeutic Plasma Exchange for Coronavirus Disease-2019 Triggered Cytokine Release Storm;

Study Overview
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Brief Summary
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Background: investigators have seen recently from experience in Western countries with best health care systems that pandemics cannot be managed in hospitals. Investigators have seen ICUs crowded to capacity, healthcare workers being exposed and going to quarantine or dying after exposure to large doses of viral inoculums. Investigators recommend that institutions should register for Clinical trials and consider emergency use of TPE. In Pandemics, time is of essence to avoid mortality by intervening early with available evidence, preferably as part of clinical trial. Scientific rationale: Beyond supportive care, there are currently no proven treatment options for coronavirus disease (COVID-19) and related pneumonia, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). However, literature review has shown that most common cause of death in severe SARS-COV-2 is Cytokine release syndrome and Hemophygocytic Lymphohistocytosis (HLH). In this context, Investigators seek to treat patients who are sick enough to warrant hospitalization prior to the onset of overwhelming disease including a systemic inflammatory response, sepsis, and/or Acute Respiratory Distress Syndrome (ARDS).

Detailed Description
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PROTOCOL SUMMARY: Therapeutic plasma exchange for coronavirus disease-2019 triggered cytokine release storm; a retrospective propensity matched control study Clinical Phase: Two arms, Phase 2 Open Label Conducted by: Department of Pulmonology and Critical Care; Pak Emirates Military Hospital. Sample Size: 280 Study Population: Hospitalized COVID-19 patients aged ≥18 years to 80 years of with Moderate- severe-critical disease and evidence of Cytokine release storm (CRS) Study Duration: 1st April, 2020 to 31st July 2020 Study Design: A retrospective propensity matched control trial will assess the efficacy and safety of following treatment options Standard treatment including steroids Therapeutic plasma exchange in addition to standard treatment Operational Definitions Moderate disease: COVID-19 positive case with lung infiltrates < 50% of total lung fields on Chest X-ray / peripheral ground glass opacities (GGOs) on High Resolution Computerized Tomography (HRCT)chest but no evidence of hypoxemia. Severe disease: COVID-19 pneumonia with evidence of hypoxemia (RR > 30/minute or PaO2 on ABGs < 80mmHg or PaO2/FiO2 (PF ratio) < 300 or lung infiltrates > 50% of the lung field). Critical illness: COVID-19 pneumonia with evidence of either respiratory failure (PaO2 < 60mmHg) or multiorgan dysfunction syndrome (MODS) measured by Sequential Organ Failure assessment (SOFA score) > 10 or septic shock (Systolic BP less than 90 or less than 40mm Hg of baseline in hypertensive or Urine output < 0.5 ml/kg/hour).Age, sex, comorbidities, date of symptoms, source of infection, type of admission SOFA score, Clinical status, vital signs including temperature, respiratory rate, oxygen saturation, oxygen requirement, Complete Blood counts (CBC) with neutrophil counts, lymphocytes count, C-reactive Proteins (CRP), chest imaging (CT or X-ray), location and status in hospital Cytokine release storm (CRS): Diagnostic criteria of Cytokine release syndrome (CRS) CRS is defined as fever of equal to or more than 100 F persisting > 48 hours in absence of documented bacterial infection and ANY of the following in the presence of moderate, severe or critical disease Ferritin >1000 mcg/L and rising in last 24 hours Ferritin >2000 mcg/L in patient requiring high flow oxygen or ventilation Lymphopenia < 800 cells/ul or lymphocyte percentage <20% and two of the following Ferritin >700 mcg/mL and rising in the last 24 hours LDH > 300 IU (reference 140-250 IU/L) and rising in the last 24 hours D-Dimer >1000ng/mL (or >1mcg/ml) and rising in the last 24 hours CRP >70 mg/L (or >10 hsCRP) and rising in the last 24 hours, in absence of bacterial infection If any 3 of above presents on admission no need to document rise 5. Standard treatment: As per Institutional COVID-19 Management Guidelines all patients of moderate, severe and critical COVID-19 received standard protocol of aspirin, anticoagulation, ulcer prophylaxis, awake Proning (if PaO2 < 80mmHg) and corticosteroids. All patients of CRS received Methylprednisolone 1 mg/kg irrespective of disease severity. 6. Therapeutic Plasma exchange (TPE) Therapeutic plasma exchange: 1-1.5 plasma exchange daily (1-5 sessions) with replacement fluid Fresh frozen Plasma (FFP) (whole volume) to 70 willing patients of moderate, severe and critical disease with evidence of CRS after explaining the investigational role of this therapy. TPE will be given in addition to standard treatment to 70 patients randomly. TPE related complications to be documented 7. Recovery Recovery to be defined by de-escalation of patients condition from severe to moderate, or from moderate to mild, plus at least 2 of the following; serum Ferritin < 1000 ug/ml (and decreasing trend on two consecutive days), serum LDH normalization, C-reactive protein > 50% fold reduction (and decreasing trend in on two consecutive days),), ALC > 1000 and PT/APTT normalization.

Official Title
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Therapeutic Plasma Exchange for Coronavirus Disease-2019 Triggered Cytokine Release Storm; a Retrospective Propensity Matched Control Study

Conditions
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COVID-19, Cytokine Release Syndrome

Intervention / Treatment
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* Procedure: Therapeutic Plasma Exchange


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: COVID-19 diagnosed by Polymerase Chain Reaction (PCR) positivity for SARS-CoV2 CRS at presentation or developing during hospitalization 10-80 years age and both genders hospital admission At least 1 completed session of plasma-exchange in patients included in TPE arm No other novel therapy administered. Exclusion criteria were: Death within 48 hours of admission severe septic shock at time of admission Congestive cardiac failure (EF<20%) (4) Those receiving immunotherapy, Anti-thymocyte globulin or hematopoietic stem cell transplant in recent past Patients of hematological or solid organ malignancies patients receiving other investigational drugs including Tocilizumab, Convalescent plasma, Remdesivir, or Mesenchymal stem cells.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: It was an interventional retrospective Propensity score matched (PSM) single centre based cohort study in Pak Emirates Military Hospital Rawalpindi (PEMH), Pakistan from 1st April to 30th June 2020. This study was carried out at the Department of Pulmonology and Critical care. PEMH is the largest Covid-19 designated hospital in the country. Data of all hospitalized patients is maintained by PEMH Covid-19 Research and evaluation cell. The study was approved by Institutional Review Board.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TPE Arm<br>In addition to standard care TPE was performed once daily using COBE Spectra Apheresis machine version 7 (Manufacturer TERUMO BCT, Lakewood, CO, USA INC) having continuous flow centrifugation. Venous access was achieved using an ultrasound guided double lumen catheter (Arrow - 12 FR) via femoral vein. Patient's total blood volume was calculated as per Nadler's formula. Anticoagulant acid dextrose ratio was 1:10 and flow rate 30-40 ml/minutes (Adjusted as per hemodynamic status). Patients' blood pressure, pulse, oxygen saturation was monitored throughout procedure. Duration of procedure varied from 2-4 hours and 1-1.5 times total plasma volume was removed during each procedure. Replacement fluid was fresh frozen plasma (FFP) and normal saline in 2:1 respectively. All procedures were performed in intensive care or high dependency unit by Apheresis Department of PEMH. TPE was continued till recovery | Procedure: Therapeutic Plasma Exchange<br>* a. 1-1.5 plasma volume exchange, 2/3rd plasma should be replacing with FFP to avoid coagulopathy, adequate dieresis to prevent volume overload, 1-5 sessions in total, 1 session daily<br>|
| No Intervention: NON TPE arm<br>Only supportive treatment offered including Vit C, Zinc, Vit D, famotidine, Enoxaparin and Methylprednisolone | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Death or recovery | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Hospitalization | Duration of hospitalization in days | 28 days | 
| Timing of PCR negativity | Time in days to achieve viral clearance | 28 days | 
| Time to CRS resolution | Time in days required to settle symptoms and laboratory parameters of CRS | 28 days | 
| Complications | Complications secondary to use of TPE | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Therapeutic Plasma exchange, Cytokine release storm, COVID-19, ARDS, Critical disease