COVID19, Cytokine Release Syndrome
Conditions
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.
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.
Interventions
PROCEDURETherapeutic 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
DRUGRuxolitinib
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.
Sponsors
Prisma Health-Upstate
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to 80 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
Countries
United States
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 details
Eligible patients were consecutively enrolled with the first 10 to cohort 1A and the second 10 to cohort 1B.
Participants by arm
| Arm | Count |
|---|---|
| 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
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 | 10 |
| 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.
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. | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Total | 1 - TPE Alone | 2 - TPE Plus Ruxolitinib |
|---|---|---|---|
| ABO Blood Group A- | 2 Participants | 1 Participants | 1 Participants |
| ABO Blood Group A+ | 4 Participants | 2 Participants | 2 Participants |
| ABO Blood Group B+ | 3 Participants | 2 Participants | 1 Participants |
| ABO Blood Group O+ | 11 Participants | 5 Participants | 6 Participants |
| Age, Continuous | 54.6 years STANDARD_DEVIATION 10.7 | 51.8 years STANDARD_DEVIATION 12.6 | 57.4 years STANDARD_DEVIATION 8.8 |
| Body Mass Index | 35.2 kg/m2 STANDARD_DEVIATION 7.9 | 34.4 kg/m2 STANDARD_DEVIATION 10.2 | 36.0 kg/m2 STANDARD_DEVIATION 5.6 |
| Comorbidities Diabetes | 6 Participants | 3 Participants | 3 Participants |
| Comorbidities Hypertension | 10 Participants | 5 Participants | 5 Participants |
| Comorbidities Obesity | 14 Participants | 6 Participants | 8 Participants |
| Days from COVID positive test to first therapeutic plasma exchange (TPE) | 6.75 Days | 4.5 Days | 9 Days |
| Previous or Concomitant Therapy Convalescent Plasma | 9 Participants | 2 Participants | 7 Participants |
| Previous or Concomitant Therapy Glucocorticoids | 19 Participants | 9 Participants | 10 Participants |
| Previous or Concomitant Therapy Remdesivir | 11 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic | 8 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United States | 20 participants | 10 participants | 10 participants |
| Respiratory Status per Penn Class Penn Class 3 | 8 Participants | 4 Participants | 4 Participants |
| Respiratory Status per Penn Class Penn Class 4 | 12 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 1 Participants |
| Sex: Female, Male Male | 12 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 10 | 2 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 1 / 10 | 3 / 10 |
Outcome results
Primary
C-reactive Protein (CRP) Levels at Baseline and Day 14
Defined as decreasing the CRP level from baseline to study day 14
Time frame: Baseline and at Day 14
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 1 - TPE Alone | C-reactive Protein (CRP) Levels at Baseline and Day 14 | CRP Baseline | 75.45 mg/L |
| 1 - TPE Alone | C-reactive Protein (CRP) Levels at Baseline and Day 14 | CRP Day 14 | 41.9 mg/L |
| 2 - TPE Plus Ruxolitinib | C-reactive Protein (CRP) Levels at Baseline and Day 14 | CRP Baseline | 59.8 mg/L |
| 2 - TPE Plus Ruxolitinib | C-reactive Protein (CRP) Levels at Baseline and Day 14 | CRP Day 14 | 38.7 mg/L |
Primary
Cytokine Levels at Baseline and 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
Time frame: Baseline and at Day 14
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 1 - TPE Alone | Cytokine Levels at Baseline and Day 14 | IL-6 Baseline | 41.32 pg/ml |
| 1 - TPE Alone | Cytokine Levels at Baseline and Day 14 | IL-6 Day 14 | 14.8 pg/ml |
| 1 - TPE Alone | Cytokine Levels at Baseline and Day 14 | IL-10 Baseline | 8.06 pg/ml |
| 1 - TPE Alone | Cytokine Levels at Baseline and Day 14 | TNF Baseline | 10.66 pg/ml |
| 1 - TPE Alone | Cytokine Levels at Baseline and Day 14 | TNF Day 14 | 9.96 pg/ml |
| 1 - TPE Alone | Cytokine Levels at Baseline and Day 14 | IL-10 Day 14 | 2 pg/ml |
| 2 - TPE Plus Ruxolitinib | Cytokine Levels at Baseline and Day 14 | TNF Day 14 | 7 pg/ml |
| 2 - TPE Plus Ruxolitinib | Cytokine Levels at Baseline and Day 14 | IL-6 Baseline | 14.22 pg/ml |
| 2 - TPE Plus Ruxolitinib | Cytokine Levels at Baseline and Day 14 | TNF Baseline | 7.06 pg/ml |
| 2 - TPE Plus Ruxolitinib | Cytokine Levels at Baseline and Day 14 | IL-6 Day 14 | 18.72 pg/ml |
| 2 - TPE Plus Ruxolitinib | Cytokine Levels at Baseline and Day 14 | IL-10 Day 14 | 3.16 pg/ml |
| 2 - TPE Plus Ruxolitinib | Cytokine Levels at Baseline and Day 14 | IL-10 Baseline | 5.6 pg/ml |