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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04374149
Recruitment Status : Not yet recruiting
First Posted : May 5, 2020
Last Update Posted : May 5, 2020
Sponsor:
Information provided by (Responsible Party):
Prisma Health-Upstate

Brief Summary:
This protocol will evaluate the efficacy of Therapeutic Plasma Exchange alone or in combination with ruxolitinib in COVID positive patients with PENN grade 2, 3, 4 cytokine release syndrome. 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 SARS virus. The predominant modes of transmission are respiratory aerosolization and contaminated surface contact.1,2 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 CRS following CAR-T treatment.

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 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 IL-6, interferon-gamma, 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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)
Estimated Study Start Date : April 30, 2020
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : April 30, 2021

Resource links provided by the National Library of Medicine


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 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 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.
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




Primary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 14 days ]
    Defined as greater than or equal to 33% decrease in cytokine load in one-third or more participants



Information from the National Library of Medicine

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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 PCR or alternative accepted methodology
  2. PENN class 2,3,4 CRS10
  3. Respiratory insufficiency with supplemental oxygen to maintain O2 sat greater than 89%
  4. Clinically positive imaging by 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 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 TB
  8. History of HIV
  9. History of 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 ILD with chronic hypoxic respiratory failure requiring supplemental O2 at baseline

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04374149


Contacts
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Contact: Julie Martin, DNP 8644553667 julie.martin@prismahealth.org
Contact: Jan Kueber, RN 8644553774 jan.kueber@prismahealth.org

Sponsors and Collaborators
Prisma Health-Upstate
Investigators
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Principal Investigator: W. Larry Gluck, MD Prisma Health
Publications:

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Responsible Party: Prisma Health-Upstate
ClinicalTrials.gov Identifier: NCT04374149    
Other Study ID Numbers: PHU COVID-19-001
First Posted: May 5, 2020    Key Record Dates
Last Update Posted: May 5, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Syndrome
Disease
Pathologic Processes