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

Sponsor
Prisma Health-Upstate (Other)
Overall Status
Completed
CT.gov ID
NCT04374149
Collaborator
(none)
20
Enrollment
1
Location
2
Arms
7.1
Actual Duration (Months)
2.8
Patients Per Site Per Month

Study Details

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
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
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 :
Apr 30, 2020
Actual Primary Completion Date :
Sep 30, 2020
Actual Study Completion Date :
Dec 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 Names:
  • Therapeutic Plasma Exchange

    		•

    Outcome Measures

    Primary Outcome Measures

    1. C-reactive Protein (CRP) Levels at Baseline and Day 14 [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 [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

    Criteria

    Ages Eligible for Study:
    12 Years to 80 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Site City State Country Postal Code
    1 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)

    More Information

    Publications

    Responsible Party:
    Prisma Health-Upstate
    ClinicalTrials.gov Identifier:
    NCT04374149
    Other Study ID Numbers:
    • PHU COVID-19-001
    First Posted:
    May 5, 2020
    Last Update Posted:
    Dec 2, 2021
    Last Verified:
    Nov 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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

    Study Results

    Participant Flow

    Recruitment Details All participants were hospitalized at the time of enrollment. They were identified and referred by the critical care service physicians.
    Pre-assignment Detail Eligible patients were consecutively enrolled with the first 10 to cohort 1A and the second 10 to cohort 1B.
    Arm/Group Title 1 - TPE Alone 2 - TPE Plus Ruxolitinib
    Arm/Group Description 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 fresh frozen plasma (FFP) replacement if underlying coagulopathy 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 fresh frozen plasma (FFP) replacement if underlying coagulopathy 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 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. 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 fresh frozen plasma (FFP) replacement if underlying coagulopathy 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 twice daily (BID) beginning day prior to first TPE and continuing BID for total of 14 days.
    Period Title: Overall Study
    STARTED 10 10
    COMPLETED 10 10
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title 1 - TPE Alone 2 - TPE Plus Ruxolitinib Total
    Arm/Group Description 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 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 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. 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 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. Total of all reporting groups
    Overall Participants 10 10 20
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    51.8
    (12.6)
    57.4
    (8.8)
    54.6
    (10.7)
    Sex: Female, Male (Count of Participants)
    Female
    7
    70%
    1
    10%
    8
    40%
    Male
    3
    30%
    9
    90%
    12
    60%
    Race/Ethnicity, Customized (Count of Participants)
    Hispanic
    6
    60%
    2
    20%
    8
    40%
    White
    2
    20%
    6
    60%
    8
    40%
    Asian
    1
    10%
    0
    0%
    1
    5%
    Black
    1
    10%
    2
    20%
    3
    15%
    Region of Enrollment (participants) [Number]
    United States
    10
    100%
    10
    100%
    20
    100%
    Body Mass Index (kg/m2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m2]
    34.4
    (10.2)
    36.0
    (5.6)
    35.2
    (7.9)
    Days from COVID positive test to first therapeutic plasma exchange (TPE) (Days) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [Days]
    4.5
    9
    6.75
    ABO Blood Group (Count of Participants)
    A-
    1
    10%
    1
    10%
    2
    10%
    A+
    2
    20%
    2
    20%
    4
    20%
    B+
    2
    20%
    1
    10%
    3
    15%
    O+
    5
    50%
    6
    60%
    11
    55%
    Respiratory Status per Penn Class (Count of Participants)
    Penn Class 3
    4
    40%
    4
    40%
    8
    40%
    Penn Class 4
    6
    60%
    6
    60%
    12
    60%
    Previous or Concomitant Therapy (Count of Participants)
    Glucocorticoids
    9
    90%
    10
    100%
    19
    95%
    Convalescent Plasma
    2
    20%
    7
    70%
    9
    45%
    Remdesivir
    3
    30%
    8
    80%
    11
    55%
    Comorbidities (Count of Participants)
    Diabetes
    3
    30%
    3
    30%
    6
    30%
    Hypertension
    5
    50%
    5
    50%
    10
    50%
    Obesity
    6
    60%
    8
    80%
    14
    70%

    Outcome Measures

    1. Primary Outcome
    Title C-reactive Protein (CRP) Levels at Baseline and Day 14
    Description Defined as decreasing the CRP level from baseline to study day 14
    Time Frame Baseline and at Day 14

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 1 - TPE Alone 2 - TPE Plus Ruxolitinib
    Arm/Group Description 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 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 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. 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 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.
    Measure Participants 10 10
    CRP Baseline
    75.45
    59.8
    CRP Day 14
    41.9
    38.7
    2. Primary Outcome
    Title Cytokine Levels at Baseline and Day 14
    Description 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
    Time Frame Baseline and at Day 14

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 1 - TPE Alone 2 - TPE Plus Ruxolitinib
    Arm/Group Description 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 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 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. 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 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.
    Measure Participants 10 10
    IL-6 Baseline
    41.32
    14.22
    IL-6 Day 14
    14.8
    18.72
    IL-10 Baseline
    8.06
    5.6
    IL-10 Day 14
    2
    3.16
    TNF Baseline
    10.66
    7.06
    TNF Day 14
    9.96
    7

    Adverse Events

    Time Frame Adverse event data collected from date of consent through study day 28
    Adverse Event Reporting Description As this was a hospitalized, critically ill patient population, adverse events in this study were defined as events deemed by the investigators to be related to study treatment (TPE and / or ruxolitinib). Adverse events occurring in greater than 5% of patients were reported. All serious adverse events (SAEs) were collected and reported. Patients were assessed daily by the critical care service study investigators.
    Arm/Group Title 1 - TPE Alone 2 - TPE Plus Ruxolitinib
    Arm/Group Description 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 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 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. 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 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.
    All Cause Mortality
    1 - TPE Alone 2 - TPE Plus Ruxolitinib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/10 (10%) 2/10 (20%)
    Serious Adverse Events
    1 - TPE Alone 2 - TPE Plus Ruxolitinib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/10 (10%) 3/10 (30%)
    Cardiac disorders
    myocardial infarction 1/10 (10%) 1 0/10 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure 0/10 (0%) 0 2/10 (20%) 2
    acute respiratory failure 0/10 (0%) 0 1/10 (10%) 1
    Other (Not Including Serious) Adverse Events
    1 - TPE Alone 2 - TPE Plus Ruxolitinib
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/10 (0%) 0/10 (0%)

    Limitations/Caveats

    Pilot study with small sample size. The imbalance between cohorts with respect to previous or concomitant therapy reflects the greater adoption of convalescent plasma and antiviral medication over the time span of the study.

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Julie Martin, Director of Cancer Research
    Organization Prisma Health
    Phone (864) 455-3667
    Email julie.martin@prismahealth.org
    Responsible Party:
    Prisma Health-Upstate
    ClinicalTrials.gov Identifier:
    NCT04374149
    Other Study ID Numbers:
    • PHU COVID-19-001
    First Posted:
    May 5, 2020
    Last Update Posted:
    Dec 2, 2021
    Last Verified:
    Nov 1, 2021