Therapeutic Plasma Exchange Alone or in Combination With Ruxolitinib in COVID-19 Associated CRS
Condition: Cytokine Release Syndrome; COVID19
MeSH terms: COVID-19; Syndrome; Cytokine Release Syndrome
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): Therapeutic Plasma Exchange; Ruxolitinib
Intervention type(s): Procedure; Drug
Intervention description(s): 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.
Other intervention name(s): Therapeutic Plasma Exchange
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment