Therapeutic Plasma Exchange Alone or in Combination With Ruxolitinib in COVID-19 Associated CRS

• ClinicalTrials.gov Identifier: NCT04374149
• Recruitment Status: Completed
• First Posted: May 5, 2020
• Results First Posted: December 2, 2021
• Last Update Posted: December 2, 2021
• Sponsor: Prisma Health-Upstate
• Information provided by (Responsible Party): Prisma Health-Upstate

Study Description

Brief Summary:

This protocol will evaluate the efficacy of Therapeutic Plasma Exchange (TPE) alone or in combination with ruxolitinib in COVID positive patients with PENN grade 2, 3, 4 cytokine release syndrome (CRS). It is hypothesized that dual intervention of acute apheretic depletion of cytokines and concomitant suppression of production will produce superior amelioration of the cytokine load and to help to prevent cytokine load rebound. This protocol is envisioned as a pilot study (n=20) for hypothesis generation for future investigation.

Condition or disease	Intervention/treatment	Phase
Cytokine Release Syndrome; COVID19	Procedure: Therapeutic Plasma Exchange; Drug: Ruxolitinib	Phase 2

Detailed Description:

A virally mediated pandemic of 2020 is linked to a novel Beta Coronavirus (COVID-19) sharing subgenus classification with the severe acute respiratory syndrome (SARS) virus. The predominant modes of transmission are respiratory aerosolization and contaminated surface contact. COVID-19 infection is characterized by a wide range of severity and disease manifestations from asymptomatic to respiratory and multi organ failure. Definitive treatment is lacking, but there is an increasing awareness of its associated systemic cascade of inflammatory molecules that offers avenues to explore therapeutically.

Therapeutic plasma exchange (TPE) offers an immediate and scientifically grounded intervention for the removal of a host of pathogenic antibodies and toxic molecules by centrifugal separation of plasma or plasma membrane filtration. TPE in conjunction with Tocilizumab and steroids has been used successfully in the management of severe cytokine release syndrome (CRS) following chimeric antigen receptor T-cell therapy (CAR-T).

Precedence for consideration of TPE in a variety of inflammatory dominant disease states is also well known. Interest in adjuvant treatment for management of sepsis and multi organ dysfunction has been studied. TPE has also been used in three pediatric patients with pH1N1 influenza A acute respiratory failure and hemodynamic shock despite failure of best supportive care. All three survived with "good functional recovery."

Ruxolitinib is a Janus kinase (JAK) and signal transducer and activator of transcription (STAT) (JAK/STAT) pathway inhibitor which is FDA approved for polycythemia rubra vera, myelofibrosis and graft versus host disease. A murine model of CRS following CAR-T cellular therapy has been developed showing marked elevation of interleukin-6 (IL-6), interferon-gamma, tumor necrosis factor (TNF) alpha mimicking human CAR-T therapy induced CRS. Ruxolitinib treated mice demonstrated clinical amelioration and decrement in inflammatory cytokines. Incyte Corporation has announced plans to launch a Phase III trial of single agent ruxolitinib for COVID-19 associated cytokine storm.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Interventional Study to Evaluate the Efficacy of Therapeutic Plasma Exchange (TPE) Alone or in Combination With Ruxolitinib in COVID-19 Positive Patients With PENN Grade 2, 3, 4 Cytokine Released Syndrome (CRS)
• Actual Study Start Date: April 30, 2020
• Actual Primary Completion Date: September 30, 2020
• Actual Study Completion Date: December 1, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1 - TPE Alone; TPE, five single plasma volume exchanges over 7 days (every day x 2 then every other day x 3) with albumin or fresh frozen plasma (FFP) replacement if underlying coagulopathy	Procedure: Therapeutic Plasma Exchange; TPE, five single plasma volume exchanges over 7 days (every day x 2 then every other day x 3) with albumin or FFP replacement if underlying coagulopathy
Experimental: 2 - TPE Plus Ruxolitinib; TPE, five single plasma volume exchanges over 7 days (every day x 2 then every other day x 3) with albumin or fresh frozen plasma (FFP) replacement if underlying coagulopathy combined with ruxolitinib 5mg po twice daily (BID) beginning day prior to first TPE and continuing BID for total of 14 days.	Procedure: Therapeutic Plasma Exchange; TPE, five single plasma volume exchanges over 7 days (every day x 2 then every other day x 3) with albumin or FFP replacement if underlying coagulopathy; Drug: Ruxolitinib; TPE, five single plasma volume exchanges over 7 days (every day x 2 then every other day x 3) with albumin or FFP replacement if underlying coagulopathy combined with ruxolitinib 5mg po BID beginning day prior to first TPE and continuing BID for total of 14 days.; Other Name: Therapeutic Plasma Exchange

Outcome Measures

Primary Outcome Measures :

1. C-reactive Protein (CRP) Levels at Baseline and Day 14 [ Time Frame: Baseline and at Day 14 ]
   Defined as decreasing the CRP level from baseline to study day 14
2. Cytokine Levels at Baseline and Day 14 [ Time Frame: Baseline and at Day 14 ]
   Defined as decreasing the interleukin (IL) IL-6 and IL-10 load and the tumor necrosis factor (TNF) load from baseline to study day 14

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 80 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients positive for COVID-19 by polymerase chain reaction (PCR) assay or alternative accepted methodology
2. PENN class 2,3,4 CRS
3. Respiratory insufficiency with supplemental oxygen to maintain O2 sat greater than 89%
4. Clinically positive imaging by chest x-ray (CXR) or CT scan with evidence of bilateral pulmonary infiltrates, ground glass opacification or other pattern of consolidation felt likely to be linked to COVID infection or complication thereof
5. Age 12-80 years of age

Exclusion Criteria:

1. Pregnancy
2. Breast feeding
3. Class 3-4 New York Heart Association (NYHA) heart failure
4. Current use of synthetic disease modifying anti-rheumatic drugs (DMARDS) or IL-6 inhibitors or other immunosuppressive therapies outside of number five below
5. Current use of chronic corticosteroids if in excess of prednisone 10mg per day or equivalent
6. Suspected or confirmed clinically significant bacterial infection
7. History of tuberculosis (TB)
8. History of HIV
9. History of irritable bowel disease (IBD)
10. JAK inhibitor use within last 30 days
11. Creatinine clearance less than 15 ml / min
12. Absolute neutrophil count < 1000
13. Platelet count < 50,000
14. Clinical assessment that the trial could pose unacceptable risk by study participation
15. Current enrollment on another investigational protocol for COVID-19 induced CRS
16. Stage 4 obstructive lung disease with chronic hypoxic respiratory failure requiring supplemental O2 at baseline, or interstitial lung disease (ILD) with chronic hypoxic respiratory failure requiring supplemental O2 at baseline

Contacts and Locations

Locations

United States, South Carolina

Prisma Health

Greenville, South Carolina, United States, 29605

Sponsors and Collaborators

Prisma Health-Upstate

Investigators

• Principal Investigator: W. Larry Gluck, MD; Prisma Health

  Study Documents (Full-Text)

Documents provided by Prisma Health-Upstate:

Study Protocol and Statistical Analysis Plan  [PDF] June 4, 2020

Informed Consent Form  [PDF] June 11, 2020

More Information

Publications:

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270-273. doi: 10.1038/s41586-020-2012-7. Epub 2020 Feb 3. Erratum In: Nature. 2020 Dec;588(7836):E6.

Jernigan DB; CDC COVID-19 Response Team. Update: Public Health Response to the Coronavirus Disease 2019 Outbreak - United States, February 24, 2020. MMWR Morb Mortal Wkly Rep. 2020 Feb 28;69(8):216-219. doi: 10.15585/mmwr.mm6908e1.

Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, Kritas SK. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020 March-April,;34(2):327-331. doi: 10.23812/CONTI-E.

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.

Xiao X, He X, Li Q, Zhang H, Meng J, Jiang Y, Deng Q, Zhao M. Plasma Exchange Can Be an Alternative Therapeutic Modality for Severe Cytokine Release Syndrome after Chimeric Antigen Receptor-T Cell Infusion: A Case Report. Clin Cancer Res. 2019 Jan 1;25(1):29-34. doi: 10.1158/1078-0432.CCR-18-1379. Epub 2018 Oct 15.

Busund R, Koukline V, Utrobin U, Nedashkovsky E. Plasmapheresis in severe sepsis and septic shock: a prospective, randomised, controlled trial. Intensive Care Med. 2002 Oct;28(10):1434-9. doi: 10.1007/s00134-002-1410-7. Epub 2002 Jul 23.

Rimmer E, Houston BL, Kumar A, Abou-Setta AM, Friesen C, Marshall JC, Rock G, Turgeon AF, Cook DJ, Houston DS, Zarychanski R. The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis. Crit Care. 2014 Dec 20;18(6):699. doi: 10.1186/s13054-014-0699-2.

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.

Porter D, Frey N, Wood PA, Weng Y, Grupp SA. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol. 2018 Mar 2;11(1):35. doi: 10.1186/s13045-018-0571-y. Erratum In: J Hematol Oncol. 2018 Jun 13;11(1):81.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gluck WL, Callahan SP, Brevetta RA, Stenbit AE, Smith WM, Martin JC, Blenda AV, Arce S, Edenfield WJ. Efficacy of therapeutic plasma exchange in the treatment of penn class 3 and 4 cytokine release syndrome complicating COVID-19. Respir Med. 2020 Dec;175:106188. doi: 10.1016/j.rmed.2020.106188. Epub 2020 Nov 7.

• Responsible Party: Prisma Health-Upstate
• ClinicalTrials.gov Identifier: NCT04374149
• Other Study ID Numbers: PHU COVID-19-001
• First Posted: May 5, 2020
• Results First Posted: December 2, 2021
• Last Update Posted: December 2, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All individual participant date (IPD) that underlie results in a publication.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: Available April 2021 through December 2021
• Access Criteria: Data can be requested from the Principal Investigator via email and should include a description of the request and the associated project or use of the data.

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

Additional relevant MeSH terms:

COVID-19; Syndrome; Cytokine Release Syndrome; Disease; Pathologic Processes; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Shock