Clinical trial NCT04485169: Therapeutic Plasma Exchange for Coronavirus Disease-2019 Triggered Cytokine Release Storm;
Official title: Therapeutic Plasma Exchange for Coronavirus Disease-2019 Triggered Cytokine Release Storm; a Retrospective Propensity Matched Control Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: COVID-19
Cytokine Release Syndrome
Keywords: Therapeutic Plasma exchange
Cytokine release storm
COVID-19
ARDS
Critical disease
Lead sponsor: UNICEF
Sponsor class: OTHER
Collaborators: name: Pak Emirates Military Hospital Rawalpindi
First posted: 2020-07-24
Enrollment: 280
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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

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.

Eligibility 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.

Primary outcomes:
measure: Survival
timeFrame: 28 days
Secondary outcomes:
measure: Duration of Hospitalization
timeFrame: 28 days
measure: Timing of PCR negativity
timeFrame: 28 days
measure: Time to CRS resolution
timeFrame: 28 days
measure: Complications
timeFrame: 28 days
Other outcomes:
Locations:
city: Rawalpindi
country: Pakistan
facility: Pak Emirates Military Hospital
state: Punjab
Study officials:
affiliation: Pak Emirates Military Hospital (PEMH) Rawalpindi
name: Imran m Fazal, FCPS
role: STUDY_DIRECTOR
References:
citation: 6. Clinical Management Guidelines for COVID-19 Infections, Version 2 [Internet]. Nhsrc.gov.pk. 2020 [cited 1 July 2020]. Available from: http://www.nhsrc.gov.pk/SiteImage/Misc/files/Clinical-Management-nfection%20v2.pdf
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citation: Shi H, Zhou C, He P, Huang S, Duan Y, Wang X, Lin K, Zhou C, Zhang X, Zha Y. Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19. Int J Antimicrob Agents. 2020 Aug;56(2):105974. doi: 10.1016/j.ijantimicag.2020.105974. Epub 2020 Apr 13.
citation: Zhang L, Zhai H, Ma S, Chen J, Gao Y. Efficacy of therapeutic plasma exchange in severe COVID-19 patients. Br J Haematol. 2020 Aug;190(4):e181-e183. doi: 10.1111/bjh.16890. Epub 2020 Jun 12. No abstract available.
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