Therapeutic Plasma Exchange in Resistant Cytokine Storm of COVID 19

• ClinicalTrials.gov Identifier: NCT04457349
• Recruitment Status: Recruiting
• First Posted: July 7, 2020
• Last Update Posted: January 5, 2021
• Sponsor: Alexandria University
• Information provided by (Responsible Party): Mohamed Mamdouh Mahmoud Mohamed Elsayed , MD, Alexandria University

Study Description

Brief Summary:

This research is planned to illustrate the efficacy of Therapeutic Plasma Exchange (TPE) treatment in COVID-19 patients with resistant cytokine storm state.

Condition or disease	Intervention/treatment	Phase
COVID 19	Procedure: Therapeutic Plasma Exchange (TPE)	Not Applicable

Detailed Description:

In early December 2019, several pneumonia cases of unknown origin were observed in Wuhan (China). A novel enveloped RNA β coronavirus was isolated and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The new virus rapidly spread across China and worldwide. On March 11th 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic. As of 19June 2020, COVID-19 has been confirmed in 8,385,440 individuals globally with deaths reaching 450,686 with a morality of 5.37%. Egypt has 50,437 confirmed cases and 1938 deaths.

The virus mainly spreads through respiratory droplets from infected patients.The clinical spectrum of COVID-19 infection ranges from asymptomatic forms to severe pneumonia requiring hospitalization and isolation in critical care units with the need of mechanical ventilation due to acute respiratory distress syndrome (ARDS). Main symptoms include fever, fatigue and dry cough. Common laboratory findings include lymphopenia and elevated lactate dehydrogenase levels. Platelet count is usually normal or mildly decreased. C reactive protein (CRP) and erythrocyte sedimentation rate are usually increased while procalcitonin levels are normal and elevation of procalcitonin usually indicates secondary bacterial infection. Ferritin, D-dimer, and creatine kinase elevation is associated with severe disease. Chest computed tomographic scans show a typical pattern of bilateral patchy shadows or ground glass opacity.

Severe COVID-19 conditions are usually due to an aggressive inflammatory response known as "cytokine storm" that is characterized by the release of a large amount of pro-inflammatory cytokines. Lung injury, multiorgan failure, and unfavorable prognosis of severe COVID-19 infection have been attributed mainly to the cytokine storm state.

Many proinflammatory cytokines elevate in COVID-19 patients including IL-1, IL-6, IL-8, IL-10, tumour necrosis factor α (TNF-α) and interferon Ȣ(IFN-Ȣ) stimulating immune cells to invade sites of infection causing endothelial dysfunction, vascular damage, alveolar damage and ARDS. Cytokine storm has been reported in several viral infections including influenza H5N1 virus, influenza H1N1 virus, and the two coronaviruses highly related to COVID-19; "SARS-CoV" and "MERS-CoV".

Therapeutic approaches to manage the COVID-19 cytokine storm might provide an avenue to decrease the COVID-19 associated morbidity and mortality. Options include immunomodulators, cytokine antagonists and cytokine removal. Tocilizumab (IL-6 antagonist), Anakinra (antagonist of IL-1 β), TNF blockers, ruxolitinib (JAK1/2 inhibitor ), corticosteroids, intravenous immunoglobulins and therapeutic plasma exchange (TPE) have been used with variable efficacy.

Therapeutic plasma exchange can remove inflammatory factors, block the "cytokine storm", to reduce the damage of inflammatory response to the body. This therapy can be used for severe and critical patients in the early and middle stages of the disease. Patel and colleagues utilized TPE during the 2009 H1N1 influenza A outbreak in three pediatric patients presenting in a similar fashion to those seen with fulminant COVID-19 today. All three had full recovery from their illness after receiving rescue TPE. Adeli at al. used TPE as a rescue therapy in patients with severe forms of COVID-19 ( septic shock, ARDS ) with very good results. Out of 8 patients, 7 patients improved and one patient died. Zhang et al. also tried TPE in three COVID-19 patients who despite receiving antiviral treatment developed respiratory distress and levels of IL-6 increased rapidly. All patients improved clinically and radiologically with negative nucleic acid testing and were discharged 10-14 days later.

In Egypt, the first line drug to treat cytokine storm of COVID-19 is tocilizumab with good results. But a considerable percentage of patients do not respond to it leaving physicians with very limited options and usually patients deteriorated rapidly with high mortality. Based on the encouraging results of TPE in severe COVID-19 infections and the familiarity of the procedure, TPE could be a good option in those patients who do not respond to tocilizumab.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Does Therapeutic Plasma Exchange Have A Role in Resistant Cytokine Storm State Of COVID-19 Infection?
• Actual Study Start Date: July 25, 2020
• Actual Primary Completion Date: December 29, 2020
• Estimated Study Completion Date: January 20, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Therapeutic Plasma Exchange (TPE); Each patient will undergo two sessions. TPE will be done through filtration technique using a plasma filter at a dose of (1-1.5) plasma volume/session. Fresh frozen plasma or albumin 5% will be used to replace plasma.	Procedure: Therapeutic Plasma Exchange (TPE); Treatment with Therapeutic Plasma Exchange (TPE); Other Name: plasmapheresis

Outcome Measures

Primary Outcome Measures :

1. mortality [ Time Frame: 28 day ]
   Number of patients deaths of the total of patients included

Secondary Outcome Measures :

1. the mean time with oxygen therapy [ Time Frame: through study completion, and average of 1 month ]
   to calculate the mean time with oxygen therapy
2. the mean time with Non-invasive mechanical ventilation [ Time Frame: through study completion, and average of 1 month ]
   to calculate the mean time with Non-invasive mechanical ventilation
3. the mean time of intubation [ Time Frame: through study completion, and average of 1 month ]
   to calculate the mean time of intubation
4. respiratory function parameters [ Time Frame: through study completion, and average of 1 month ]
   To calculate the mean of PaO2/FiO2
5. respiratory function parameters [ Time Frame: through study completion, and average of 1 month ]
   To calculate the mean of levels of oxygen saturation
6. radiological lung extension [ Time Frame: through study completion, and average of 1 month ]
   to evaluate the lung extension of pneumonia
7. mean duration of hospitalization and ICU use [ Time Frame: through study completion, and average of 1 month ]
   Days of hospitalization in survivors and/or days at ICU throughout the study
8. the requirement of additional organ support [ Time Frame: through study completion, and average of 1 month ]
   Percentage of patients with dialysis
9. the levels of IL-6 [ Time Frame: through study completion, and average of 1 month ]
   To evaluate the effect of TPE on the serum levels of inflammatory markers
10. Incidence of adverse events [ Time Frame: through study completion, and average of 1 month ]
    To calculate the number of adverse events in patients with COVID-19 treated with TPE
11. time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity [ Time Frame: through study completion, and average of 1 month ]
    To evaluate the time to RT-PCR virus negativity
12. the levels of CRP [ Time Frame: through study completion, and average of 1 month ]
    To evaluate the effect of TPE on the serum levels of inflammatory markers
13. the levels of procalcitonin (PCT) [ Time Frame: through study completion, and average of 1 month ]
    To evaluate the effect of TPE on the serum levels of inflammatory markers
14. levels of D-dimer [ Time Frame: through study completion, and average of 1 month ]
    To evaluate the effect of TPE on the serum levels of inflammatory markers
15. levels of ferritin [ Time Frame: through study completion, and average of 1 month ]
    To evaluate the effect of TPE on the serum levels of inflammatory markers

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• COVID-19 positive patients (confirmed by PCR) with cytokine storm state who will not improve after two doses of tocilizumab.

  • Criteria of failure (resistance) to tocilizumab:

    1. Persistent high IL-6 and CRP.
    2. Persistent worsening of respiratory symptoms ( dyspnea, tachypnea, increased oxygen (O2) requirements or even need for mechanical ventilation).
    3. Partial arterial pressure of oxygen to fractional inspired concentration of oxygen (PaO2/FiO2) ratio < 150.
    4. Persistent fever (˃38.5°C) despite normal procalcitonin level.

Exclusion Criteria:

• Refractory septic shock:

( It is defined according to surviving sepsis campaign as the presence of hypotension with end organ dysfunction requiring high dose vasopressor support often greater than 0.5 µg/kg/min norepinephrine or equivalent).

Contacts and Locations

Contacts

Contact: Mohamed Mamdouh Elsayed, MD; 00201068055103; dr_mohamedmamdouh87@yahoo.com

Contact: Ayman I Baess, MD; 00201006822068; Ayman.baeis@yahoo.com

Locations

Egypt

Faculty of Medicine, Alexandria university, Egypt; Recruiting

Alexandria, Egypt, 21526

Contact: Mohamed Mamdouh Elsayed, MD 00201068055103 dr_mohamedmamdouh87@yahoo.com

Sponsors and Collaborators

Alexandria University

Investigators

• Principal Investigator: Mohamed Mamdouh Elsayed, MD; Lecturer of Nephrology & Internal Medicine, Faculty of Medicine, Alexandria university, Egypt
• Study Chair: montasser M zeid, MD; Professor of Nephrology & Internal Medicine, Faculty of Medicine, Alexandria university, Egypt
• Study Chair: Akram M Fayed, MD; Professor of Critical Care Medicine, Faculty of Medicine, Alexandria university, Egypt
• Study Chair: Ehab M El Reweny, MD; Assistant Professor of Critical Care Medicine, Faculty of Medicine, Alexandria university, Egypt
• Study Chair: Nermine H Zakaria, MD; Professor of Clinical and Chemical Pathology Medicine, Faculty of Medicine, Alexandria university, Egypt
• Study Chair: Ayman I Baess, MD; Assistant Professor of Chest Diseases, Faculty of Medicine, Alexandria university, Egypt

More Information

Publications:

Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, Xing F, Liu J, Yip CC, Poon RW, Tsoi HW, Lo SK, Chan KH, Poon VK, Chan WM, Ip JD, Cai JP, Cheng VC, Chen H, Hui CK, Yuen KY. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020 Feb 15;395(10223):514-523. doi: 10.1016/S0140-6736(20)30154-9. Epub 2020 Jan 24.

Singhal T. A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr. 2020 Apr;87(4):281-286. doi: 10.1007/s12098-020-03263-6. Epub 2020 Mar 13. Review.

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.

Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-848. doi: 10.1007/s00134-020-05991-x. Epub 2020 Mar 3. Erratum in: Intensive Care Med. 2020 Apr 6;:.

Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020 May 1;130(5):2620-2629. doi: 10.1172/JCI137244.

Sun D, Li H, Lu XX, Xiao H, Ren J, Zhang FR, Liu ZS. Clinical features of severe pediatric patients with coronavirus disease 2019 in Wuhan: a single center's observational study. World J Pediatr. 2020 Jun;16(3):251-259. doi: 10.1007/s12519-020-00354-4. Epub 2020 Mar 19.

Kalaiyarasu S, Kumar M, Senthil Kumar D, Bhatia S, Dash SK, Bhat S, Khetan RK, Nagarajan S. Highly pathogenic avian influenza H5N1 virus induces cytokine dysregulation with suppressed maturation of chicken monocyte-derived dendritic cells. Microbiol Immunol. 2016 Oct;60(10):687-693. doi: 10.1111/1348-0421.12443.

Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol. 2017 Jul;39(5):529-539. doi: 10.1007/s00281-017-0629-x. Epub 2017 May 2. Review.

Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect. 2020 Jun;80(6):607-613. doi: 10.1016/j.jinf.2020.03.037. Epub 2020 Apr 10. Review.

Patel P, Nandwani V, Vanchiere J, Conrad SA, Scott LK. Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza A--an associated respiratory failure and hemodynamic shock. Pediatr Crit Care Med. 2011 Mar;12(2):e87-9. doi: 10.1097/PCC.0b013e3181e2a569.

Adeli SH, Asghari A, Tabarraii R, Shajari R, Afshari S, Kalhor N, Vafaeimanesh J. Therapeutic plasma exchange as a rescue therapy in patients with coronavirus disease 2019: a case series. Pol Arch Intern Med. 2020 May 29;130(5):455-458. doi: 10.20452/pamw.15340. Epub 2020 May 7.

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.

Bassi E, Park M, Azevedo LC. Therapeutic strategies for high-dose vasopressor-dependent shock. Crit Care Res Pract. 2013;2013:654708. doi: 10.1155/2013/654708. Epub 2013 Sep 15. Review.

• Responsible Party: Mohamed Mamdouh Mahmoud Mohamed Elsayed , MD, lecturer, Alexandria University
• ClinicalTrials.gov Identifier: NCT04457349
• Other Study ID Numbers: plasma exchange in COVID 19
• First Posted: July 7, 2020
• Last Update Posted: January 5, 2021
• Last Verified: January 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No