Clinical trial NCT04374149
Conditions: Cytokine Release Syndrome COVID19
Sponsor: Prisma Health-Upstate
Start date: 2020-04-30; Completion date: 2020-12-01
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

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.

Arms: arm 1: 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 arm 2: 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.
Interventions: intervention 1: Therapeutic Plasma Exchange intervention 2: Ruxolitinib
Intervention descriptions: intervention 1: 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 intervention 2: 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.

Protocol documents:
Prot_SAP_000.pdf: 
Therapeutic Plasma Exchange Alone or in Combination With Ruxolitinib in 
COVID-19 Associated CRS
NCT04374149
Study Protocol and Statistical Analysis Plan
Dated:  June 04, 2020


Page 1 of 14 
Study Title: PHU COVID-19-002 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) 
Principal Investigator: 
W. Larry Gluck, MD
Medical Director, Cancer Institute
Prisma Health
900 West Faris Rd
Greenville, SC 29605
864-455-5862
Larry.Gluck@prismahealth.org
Co-Investigators: 
Sean Callahan, MD 
Antine Stenbit, MD 
Pulmonary-Critical Care 
Pulmonary-Critical Care 
Prisma Health 
Prisma Health 
Sean.Callahan@prismahealth.org 
Antine.Stenbit@prismahealth.org 
Rob Brevetta, MD 
Julie Martin, DNP, ACON, NP 
Pulmonary-Critical Care 
Director, Cancer Research 
Prisma Health 
Prisma Health Cancer Institute 
Rob.Brevetta@prismahealth.org 
Julie.Martin@prismahealth.org 
W. Jeffery Edenfield, MD
Medical Director, Institute for Translational Oncology Research
Prisma Health Cancer Institute
Jeffery.Edenfield@prismahealth.org
Study Location: 
Prisma Health, South Carolina 

Greenville Memorial Campus

North Greenville Campus
Version No. 1 
June 4, 2020 


Page 2 of 14 
 
Background and Rationale 
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. 
P. Conti3 and colleagues have recently outlined the binding of COVID-19 to the Toll-like receptor 
(TLR) with subsequent multi step generation of mature IL-1 β to trigger fever and pneumonitis. 
Many investigators draw similarity to the evolving understanding of cytokine storm or the cytokine 
release syndrome. Mehta et al4 note the resemblance of severe COVID-19 expression to secondary 
hemaphagocytic lymphohistiocytosis (sHLH) long regarded as a fatal hypercytokinemic state with 
excessive elaboration of IL2, IL-7 TNF and macrophage inflammatory protein 1-alpha among 
others. 
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. Xiao5 and colleagues successfully incorporated TPE in the 
management of a patient with severe CRS following CAR-T treatment in conjunction with 
Tocilizumab and steroids with daily documentation of cytokine levels. 
Precedence for consideration of TPE in a variety of inflammatory dominant disease states is well 
known. Interest in adjuvant treatment for management of sepsis and multi organ dysfunction is 
reflected in Busund6 and Rimmer7 manuscripts. Patel et al8 successfully used TPE 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. Kenderion et al9 reported a murine model of CRS 
following CAR-T cellular therapy with 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. 
This protocol will evaluate the efficacy of TPE alone or in combination with ruxolitinib in COVID 
positive patients with PENN grade 2, 3, 4 CRS. It is hypothesized that dual intervention of acute 
aphaeretic 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. 


Page 3 of 14 
 
Primary Endpoints 
1. To document the efficacy of TPE alone or in conjunction with ruxolitinib in decreasing the 
cytokine load over a 14-day intervention study 
2. Analysis of all therapy related adverse events (AEs) 
Secondary Endpoints 
1. To correlate the clinical course of participants with the degree of specific cytokine reductions 
3. To calculate time to independence from mechanical ventilation 
4. To calculate time to independence from supplemental oxygen therapy 
5. To measure CRP, ferritin and cytokine levels (IL-6, IL-8, IL-10, TNFα, IFNγ, GM-CSF) to 
map the cytokine landscape over the course of the study 
6. To explore correlative biomarker studies 
7. To bank plasma and other blood derivatives in the Prisma Health ITOR Biorepository for 
future investigation 
 
Study Design 
Study type: 
Interventional Pilot Clinical Trial 
Estimated Enrollment 
20 patients 
Allocation 
Two sequential cohorts, 10 patients per cohort 
First 10 patients will receive TPE alone (Cohort 1A) 
Second 10 patients will receive TPE in combination with ruxolitinib 
Masking 
None (open label) 
Primary purpose 
Treatment efficacy 
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) 
 
 
Study Population 
COVID-19 positive patients with PENN grade 2, 3, 4 CRS and respiratory failure. 


Page 4 of 14 
 
Eligibility 
Inclusion: 
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. Adults 22 years of age or older 
Exclusion: 
1. Pregnancy 
2. Breast feeding 
3. Class 3-4 NYHA heart failure 
4. Current use of synthetic disease modifying anti-rheumatic drugs (DMARDS), with the 
exception of hydroxychloroquine, 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. AST or ALT > 5 times the upper limit of normal 
15. Clinical assessment that TPE or ruxolitinib could pose unacceptable risk by study 
participation or the treatment is deemed inappropriate by a study investigator 
16. Current enrollment on another investigational protocol for COVID-19 induced CRS 
17. 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 
 
Treatment Plan 
Device: 
Spectra Optia Apheresis System 
Intended Use of Device: Therapeutic Plasma Exchange performed per marketed labeling 
Drug: 
Ruxolitinib (generic) marketed as brand name, Jakafi ,manufactured by 
Incyte Corporation, will be used per the marketed package insert. 


Page 5 of 14 
 
Cohort 1A: 
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 per institutional protocol (Appendix A). 
Other – standard medical care 
Cohort 1B: 
TPE as in cohort 1A combined with ruxolitinib 5mg po BID beginning day 
prior to first TPE and continuing BID for total of 14 days. On days of TPE, 
ruxolitinib dosing will be immediately post procedure and a second dose 
approximately 8 hours later. 
Other – standard medical care 
Schedule of Assessments 
 
Pre Treatment 
Standard of Care Assessments 
 Complete Blood Count (CBC) 
 PT/INR 
 Comprehensive Metabolic Panel (CMP) 
 Partial Thromboplastin 
Time (PTT) 
 C-Reactive Protein (CRP) 
 Fibrinogen 
 Ferritin 
 type and screen 
 lipid panel 
 serum pregnancy test 
 Hepatitis B Surface Antigen, Hepatitis B 
Surface Antibody, Hepatitis B Core 
Antibody and Hepatitis C Antibody 
 physical examination 
Study Related Assessments 
 cytokine panel 
 peripheral blood for biorepository 
 peripheral blood for pharmacogenomics 


Page 6 of 14 
 
 
 
During Treatment (On Study) 
Standard of Care Assessments 
 daily CBC 
 daily Basic Metabolic Panel 
BMP) 
 daily CRP 
 physical examination 
 PaO2/FiO2 ratios days (with 
ABGs) per Appendix B 
 amount of supplemental O2, SPO2%, respiratory rate, imaging per MD 
discretion (for non-intubated patients) 
 measure daily SPO2% , FiO2; PEEP; and lung compliance (inspiratory pause 
– Vt/Pplat – PEEP) or plateau pressures (mechanically vented patients) 
Study Related Assessments 
 daily collection of study related adverse events and/or serious adverse events 
 Fibrinogen (on days of TPE only) 
 daily cytokine panel and GM-CSF 
 repeat cytokine panel and GM-CSF within 60 minutes post TPE (on days of 
procedure only) 
 serum ferritin per Appendix B 
 perhipheral blood and plasma waste for biorepository per Appendix B 
 day 28 office visit or virtual health visit to assess clinical status of the patient 
 
Risk Analysis 
The proposed patient population is not anticipated to be at an increased risk compared to a clinically 
similar population without COVID-19 infection. The device and drug will be used as marketed. 
Standard risks for the device and drug are outlined in the patient informed consent document. Risks 
will be minimized by conducting the trial in the inpatient setting of an acute care hospital with 
dedicated and trained therapeutic apheresis staff, licensed medical personnel and experienced 
research team members under the direction and oversight of the principal investigator. In the event 
of patient status improvement, discharge will be acceptable after completion of therapeutic plasma 
exchange.  Daily outpatient follow-up through patient completion of study required assessments 
will occur in a dedicated phase I research unit. 
 
Removal of medications with TPE is a risk.  However, consultation with a hospital pharmacist will 
occur as needed to determine if a change in timing of medication administration is needed or if 
medication reloading should occur post TPE. 
 
 


Page 7 of 14 
 
Dose Modifications 
The starting dose of ruxolitinib is 5mg po bid.  The need for dose adjustments will be assessed on a 
daily basis by the research team and pharmacist. 
 AST/ALT > 5x ULN, reduce dose of ruxolitinib to 5mg po once daily11 
 Platelet count between 25,000 and 35,000, reduce dose of ruxolitinib to 5mg po once daily.  
Platelet count < 25,000, hold ruxolitinib. May resume once platelet count >25,000 with 
dosing based on actual platelet count. 
 Absolute neutrophil count < 500, hold ruxolitinib until > 500 then resume at full dose 
 Creatinine Clearance <15ml/min, discontinue ruxolitinib 
 
Duration of Investigations 
A six month patient recruitment period is anticipated. Patient participation is 15 days in duration. 
An additional six month period of data analysis is anticipated for an overall period of investigation 
equaling 12 months 
 
Treatment Discontinuation 
Treatment discontinuation will occur under the following conditions: 
 The patient withdraws consent either from treatment or from the study 
 The patient is lost to follow-up 
 The patient experiences a side effect that per the protocol requires treatment to end 
 The physician deems treatment discontinuation is in the best interest of the patient 
 The patient is found to be eligible to participate in the study after being enrolled and 
continued treatment in this study is not in the best interest of the patient 
 The patient is found to be pregnant or intends to become pregnant 
 The patient is noncompliant with the study requirements your disease worsens 
 
Data Handling and Recordkeeping 
The principal investigator will carefully monitor study procedures to protect the safety of 
research subjects, the quality of data, and the integrity of the study. All study subject 
material will be assigned a unique identifying code or number. The key to the code will be 
kept in a locked file in the Research Division of the Prisma Health Cancer Institute. 
 
Data Collection, Analysis and Outcomes 
REDCap EDC software will be used for data management and future statistical analysis. 
Designated Cancer Institute research staff will perform extraction of patient records. 
Overall Response Rate (ORR) will be defined as > 33% decrease in the cytokine load from 
peak value through study day 14 in one-third or more participants. 
 
Ethical Considerations 
This study will be conducted in accordance will all applicable government regulations and 
Prisma Health research policies and procedures. This protocol and any amendments will be 


Page 8 of 14 
 
submitted and approved by the Prisma Health Institutional Review Board (IRB) prior to any 
study activity. 
All study participants will provide informed consent allowing for their tissue and de- 
identified clinical information to be used for research purposes. 
 
Safety Monitoring and Reporting 
A Drug Safety Monitoring Board (DSMB) will be established consisting of a hematologist, 
pulmonologist and infectious disease specialist not associated with the research team for this 
investigation.  The committee will review all serious adverse events within 48 hours and 
will review all patient outcomes for cohort 1a before proceeding to enrollment of cohort 1b. 
 
Adverse Events 
Adverse events (AEs) are defined as an unexpected medical problem that happens during 
treatment with a drug or other therapy.  The NCI Common terminology criteria for adverse 
events (CTCAE Version 5.0) will be used as the standardized severity grading system.  AEs 
will also be reported by degree of relatedness as not related, possibly related, likely related or 
related to the study drug or study therapy. 
 
SAE Reporting to Incyte 
The Principal Investigator (PI) must report all Serious Adverse Events (SAEs) to Incyte 
within 24 hours of learning of an event, regardless of the PI’s causality assessment. This 
notification will be provided on a completed Serious Adverse Event (SAE) form. SAE 
reporting for each subject begins the day the informed consent is signed by the patient and 
within 30 days after subject has completed or discontinued from the study or has taken last 
dose of the study drug, or as described in the protocol. 
SAEs, occurring using Incyte study drug, are reported in accordance with the effective 
protocol. SAEs occurring with any other commercial drug are reported to the manufacturer 
of that drug in accordance with regulations and protocol. 
Initial SAEs and/or subsequent follow-up reports will be reported via email to 
SafetyReporting@Incyte.com or fax (+) 1-866-981-2057.  SAE reports should be for a 
single subject. SAE forms should be sent with a cover sheet and any additional attachments. 
All adverse event information is reported to Incyte on MedWatch Form FDA 3500A. The 
Principal Investigator does not provide medical records (e.g., discharge summary) to Incyte, 
unless specifically requested. 
In addition, all SAEs will be reported to the Prisma Health IRB per the institutional policy for 
reporting. 
Reporting of Pregnancy to Incyte 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 within 24 hours of discovery 
of a pregnancy of a subject who has taken the Incyte product or the pregnancy of a partner 


Page 9 of 14 
 
for a subject who has taken the Incyte product. The “Follow-up Pregnancy Report Form” or 
equivalent must be completed and emailed to SafetyReporting@Incyte.com or faxed to (+) 
1-866-981-2057 within 30 days after delivery, so that Incyte is provided with information 
regarding the outcome of the pregnancy. If the pregnancy results in any events which meet 
the serious criteria (i.e., miscarriage or termination), the SAE reporting process needs to be 
followed and the timelines associated with a SAE should be followed. 
 
Statistical Analyses 
 
General Statistical Considerations 
Standard statistical methods will be employed to analyze all data.  It is anticipated that the 
following techniques may be used: descriptive statistics, t-test, Chi-square, Fisher’s exact test, 
Kaplan-Meier analysis, and graphical displays.  This protocol may not reflect all analyses 
planned for the study; additional analyses may be conducted for observational purposes only.   
 
Summary statistics will consist of numbers and percents of responses in each category for 
discrete measures, and of mean, n, standard deviation, median, minimum, maximum and 95% 
confidence intervals for continuous measures. 
 
Sample Size Determination 
The initial sample size is 20.  Each cohort will enroll 10 patients.  This number is considered 
sufficient for an exploratory pilot study to provide information for planning further 
investigations. 
 
Analysis of Safety 
The safety evaluation will compare the proportion of Subjects in each treatment group who 
exhibit treatment-related adverse effects.  These adverse events will be presented for individual 
patients as a listing of events. 
 
Dissemination of Results 
Results of this study may be used for presentations, posters, publications, or extramural 
grant applications. The publication will not contain any identifiable information that could 
be linked to a study patient. 


Page 10 of 14 
 
References 
1. Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new 
coronavirus of probable bat origin. Nature 579, 270–273 (2020). 
https://doi.org/10.1038/s41586-020-2012-7 
2. World Health Organization. Novel coronavirus situation report-2. January 22, 2020. 
https://www.who.int/docs/default-source/coronavirus/situation-reports/20200122-sitrep-2- 
2019-ncov.pdf (Accessed on April 7, 2020). 
3. P. Conti, G. Ronconi, A. Caraffa, C. Gallenga, R. Ross, I. Frydas, S. Kritas. Induction of 
pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti- 
inflammatory strategies. J Biol Regul Homeost Agents. 2020 Mar 14; 34(2). 
4. Puja Mehta,Daniel F McAuley, Michael Brown, Emilie Sanchez, Rachel S Tattersall, 
Jessica J Manson. COVID-19: consider cytokine storm syndromes and immunosuppression. 
The Lancet. 28 March–3 April 2020. 
5. Xia Xiao, Xiaoyuan He, Qing Li, Huan Zhang, Juanxia Meng, Yanyu Jiang, Qi Deng and M 
ingfeng Zhao. 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. January 1 2019 (25) (1) 29-34; doi: 10.1158/1078-0432.CCR-18- 
1379 
6. Busund R, Koukline V, Utrobin U, et al. Plasmapheresis in severe sepsis and septic shock: a 
prospective, randomized, controlled trial. Intensive Care Med. 2002; 28:1434-9 
7. Rimmer E, Houston BL, Kumar A, et al. The efficacy and safety of plasma exchange in 
patients with sepsis and septic shock; a systematic review and meta-analysis. Crit Care. 
2014: 18(6):699 
8. Patel P, Nandwani V, Vanchiere J, Conrad S, Scott K. 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 March; 12(2):e87-e89. 
doi:10.1097/PCC.0b013e3181e2a569 
9. Kenderian S, Ruella M, Shestova O. et al. Ruxolitinib prevents cytokine release syndrome 
after Car T-Cell therapy without impairing the anti-tumor effect in a xenograft model. Biol 
Blood Marrow Transplant. 23(2017) S19-S20 
10. Porter D, Frey N, Wood P, Weng Y, Grupp S. Grading of cytokine release syndrome 
associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol. 2018; 11: 35. 
doi:10.1186/s13045-018-0571-y 
11. Package Insert JAKAFI (ruxolitinib). Revised 05/2019. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202192s017lbl.pdf 


Page 11 of 14 
 
APPENDIX A: 
 
TPE-Plasma Therapy Plan 
 
Apheresis Orders 
Frequency 
 Therapeutic Plasma Apheresis with Plasma Replacement 
As Ordered 
IV Access 
 Initiate peripheral IV Protocol 
Daily 
 Access Central Venous Catheter 
Daily 
 Access A/V Fistula for Procedure 
Daily 
Pre-Procedure Labs (Baseline) 
 CBC with Differential 
Once 
 CMP 
Once 
 LDH 
Once 
 Haptoglobin 
Once 
 PT/INR 
Once 
 PTT 
Once 
 Reticulocyte Count 
Once 
 ADAM TS 13 Activity 
Once 
 Type and Screen 
Once 
 Bilirubin Total and Direct 
Once 
 Prepare Plasma 
Once 
Labs 
 CBC with Differential 
Daily 
 CMP 
Daily 
 LDH 
Daily 
 Haptoglobin 
Daily 
Anticoagulant Prime 
 Anticoagulant citrate dextrose injection 500 ml 
PRN 
Medications 
 diphenhydramine (Benadryl) 25 mg IV 
Once 
 calcium gluconate 3g in NS 250ml IV 
Once 
 calcium gluconate 3g in NS 250ml IV 
PRN 
 calcium carbonate tablet 1500 mg PO 
PRN 
 alteplase 2mg in 10ml syringe 
PRN clot clearance 
Hypersensitivity Regimen 
 at any sign of anaphylaxis, stop infusion, notify MD and 
administered prescribed medications 
PRN 
 diphenhydramine (Benadryl) 50 mg IV 
PRN 
 methyleprednisolone (Solu-Medrol) 40 mg IV 
PRN 
 famotidine (Pepcid) 20 mg IV 
PRN 
Nursing Orders 
 Transfuse Plasma 
Once 


Page 12 of 14 
 
TPE-Albumin Therapy Plan 
 
Apheresis Orders 
Frequency 
 Therapeutic Plasma Apheresis with Albumin Replacement 
As Ordered 
IV Access 
 Initiate peripheral IV Protocol 
Daily 
 Access Central Venous Catheter 
Daily 
 Access A/V Fistula for Procedure 
Daily 
Pre-Procedure Labs (Baseline) 
 CBC with Differential 
Once 
 CMP 
Once 
 Fibrinogen 
Once 
Anticoagulant Prime 
 Anticoagulant citrate dextrose injection 500 ml 
PRN 
Medications 
 calcium carbonate tablet 1000 mg PO 
PRN 
 calcium gluconate 2.5g in NS 250ml IV 
PRN 
 alteplase 2mg in 10ml syringe 
PRN clot clearance 
Hypersensitivity Regimen 
 at any sign of anaphylaxis, stop infusion, notify MD and 
administered prescribed medications 
PRN 
 diphenhydramine (Benadryl) 50 mg IV 
PRN 
 methyleprednisolone (Solu-Medrol) 40 mg IV 
PRN 
 famotidine (Pepcid) 20 mg IV 
PRN 
Nursing Orders 
 Infuse Albumin 
Once 


Page 13 of 14 
 
Appendix B: 
COHORT 1A Schedule of Assessments: Therapeutic Plasma Exchange alone 
Assessment 
Screening 
(24 hours) 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 28 
Informed Consent and Medical History 
X 
Physical Examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Blood Count (CBC) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic Panel (CMP) 
X 
Basic Metabolic Panel (BMP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-Reactive Protein (CRP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ferritin 
X 
X 
X 
X 
X 
Hepatitis Serologyb 
X 
Lipid Panelb 
X 
PT/INR 
X 
PTT 
X 
Fibrinogen 
X 
X 
X 
X 
X 
X 
Type and Screenb 
X 
Serum Pregnancy Testb 
X 
Cytokine Panel (IL-6, IL-8, IL-10, TNFα, IFNγ)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GM-CSFc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral Blood for biorepository 
X 
X 
X 
X 
 
Peripheral Blood for pharmacogenomics 
X 
PaO2/FiO2 ratios (with ABGs) - (mechanically vented patients only) 
X 
X 
X 
Supplemental O2, SPO2%, Respiratory Rate, Imaging at MD 
discretion (for NON-intubated patients) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SPO2%, FiO2, PEEP, Lung compliance (inspiratory pause - Vt/Pplat- 
PEEP) or plateua pressures (mechanically vented patients only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Therapeutic Plasma Exchange (TPE) (plus waste for biorepository) 
X 
X 
X 
X 
X 
a If patient is discharged from the hospital, daily physical examination will not be required. Perform one physical exam prior to the patient’s last study visit. Day 28 may be a virtual 
visit if needed. 
b Hepatitis serology, Lipid panel, Type and Screen, Serum Pregnancy Test acceptable within 7 days prior to enrollment. 
c Cytokine Panel and GM-CSF are to be repeated within 60 minutes post TPE on days of plasma exchange procedure only. 


Page 14 of 14 
 
Appendix B: 
COHORT 1B Schedule of Assessments: Therapeutic Plasma Exchange Plus Ruxolitinib 
Assessment 
Screening 
(24 hours) 
Study Day 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 28 
Informed Consent and Medical History 
X 
Physical Examinationa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Blood Count (CBC) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Metabolic Panel (CMP) 
X 
Basic Metabolic Panel (BMP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-Reactive Protein (CRP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ferritin 
X 
X 
X 
X 
X 
Hepatitis Serologyb 
X 
Lipid Panelb 
X 
PT/INR 
X 
PTT 
X 
Fibrinogen 
X 
X 
X 
X 
X 
X 
Type and Screenb 
X 
Serum Pregnancy Testb 
X 
Cytokine Panel (IL-6, IL-8, IL-10, TNFα, IFNγ)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GM-CSFc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral Blood for biorepository 
X 
X 
X 
X 
 
Peripheral Blood for pharmacogenomics 
X 
PaO2/FiO2 ratios (with ABGs) - (mechanically vented patients only) 
X 
X 
X 
Supplemental O2, SPO2%, Respiratory Rate, Imaging at MD 
discretion (for NON-intubated patients) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SPO2%, FiO2, PEEP, Lung compliance (inspiratory pause - Vt/Pplat- 
PEEP) or plateua pressures (mechanically vented patients only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Therapeutic Plasma Exchange (TPE) (plus waste for biorepository) 
X 
X 
X 
X 
X 
Ruxolitinib Dosing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a If patient is discharged from the hospital, daily physical examination will not be required. Perform one physical exam prior to the patient’s last study visit.  Day 28 may be a virtual 
visit if needed. 
b Hepatitis serology, Lipid panel, Type and Screen, Serum Pregnancy Test acceptable within 7 days prior to enrollment. 
c Cytokine Panel and GM-CSF are to be repeated within 60 minutes post TPE on days of plasma exchange procedure only. 

ICF_001.pdf: 
Therapeutic Plasma Exchange Alone or in Combination With Ruxolitinib in 
COVID-19 Associated CRS
NCT04374149
Informed Consent Form
IRB Approved:  June 11, 2020