Therapeutic Plasma Exchange (TPE) for Covid-19 Cytokine Release Storm (CRS)
Status:
Completed
Sponsors
UNICEF
Collaborators
Pak Emirates Military Hospital Rawalpindi
Abstract:
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).
Description:
PROTOCOL SUMMARY:
Long title: Proposed use of TPE (therapeutic plasma exchange), to Limit Coronavirus Associated Complications: An Open label, Phase 2 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 30th June 2020
Study Design: This open label phase 2 trial will assess the efficacy and safety of following treatment options
1. Standard treatment including steroids
2. Therapeutic plasma exchange in addition to standard treatment
Operational Definitions
1. 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.
2. 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).
3. 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
4. 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
1. Ferritin >1000 mcg/L and rising in last 24 hours
2. Ferritin >2000 mcg/L in patient requiring high flow oxygen or ventilation
3. Lymphopenia < 800 cells/ul or lymphocyte percentage <20% and two of the following
1. Ferritin >700 mcg/mL and rising in the last 24 hours
2. LDH>> 300 IU (reference 140-250 IU/L) and rising in the last 24 hours
3. D-Dimer >1000ng/mL (or >1mcg/ml) and rising in the last 24 hours
4. CRP >70 mg/L (or >10 hsCRP) and rising in the last 24 hours, in absence of bacterial infection
5. 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.
Last Verified:June/30/2020
First Submitted:July/20/2020
Estimated Enrollment Submitted:July/21/2020
First Posted:July/23/2020
Last Update Submitted:July/21/2020
Last Update Posted:July/23/2020
Actual Study Start Date:March/31/2020
Estimated Primary Completion Date:June/29/2020
Estimated Study Completion Date:June/29/2020
Condition or disease:COVID-19
Cytokine Release Syndrome
Intervention/treatment:
Procedure: TPE Arm
Phase:-
Study design:
Study Type:Interventional
Allocation:Non-Randomized
: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.
Primary Purpose:Treatment
Masking:None (Open Label)
Arm group:
ArmIntervention/treatment
Experimental: TPE Arm
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: TPE Arm
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
No Intervention: NON TPE arm
Only supportive treatment offered including Vit C, Zinc, Vit D, famotidine, Enoxaparin and Methylprednisolone
Eligibility Criteria:
Ages Eligible for Study:18 Years to 18 Years
Sexes Eligible for Study:All
Accepts Healthy Volunteers:Yes
Criteria:

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.

Outcome:
Primary Outcome Measures
1. Survival [28 days]
Death or recovery
Secondary Outcome Measures
1. Duration of Hospitalization [28 days]
Duration of hospitalization in days
2. Timing of PCR negativity [28 days]
Time in days to achieve viral clearance
3. Time to CRS resolution [28 days]
Time in days required to settle symptoms and laboratory parameters of CRS
4. Complications [28 days]
Complications secondary to use of TPE
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