Safe & Timely Antithrombotic Removal-Direct Oral Anticoagulants (STAR-D): Prospective, Multicenter, Double-blind, Randomized Study of Apixaban & Rivaroxaban Removal to Reduce Risk of Serious Bleeding in Urgent Cardiac Surgery Patients
Phase: NA
Conditions: Hemorrhage, Surgical, Hemorrhage Postoperative, Blood Loss, Surgical, Blood Loss, Postoperative
Sponsor: CytoSorbents, Inc

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TITLE PAGE 
Clinical Investigation Plan 
Safe and Timely Antithrombotic Removal – Direct Oral Anticoagulants 
Apixaban & Rivaroxaban (STAR-D): A Prospective, Multi-center, Double-
blind, Randomized, Study to Evaluate DrugSorb-ATR Removal of 
Apixaban and Rivaroxaban to Reduce Likelihood of Serious Bleeding in 
Patients Undergoing Urgent Cardiothoracic Surgery. 
Clinical Investigation Plan Status: Final 
Clinical Investigation Plan Version 2.1 Date: 09-March-2022 
Investigational Medical Device: DrugSorb-ATR 
Global Trade Item Number: 01230000006002 
  
CytoSorbents Clinical Investigation Plan Reference Number: 2021-02 
 
 
 
 
Sponsor: 
CytoSorbents, Inc. 
7 Deer Park Drive, Suite K 
Monmouth Junction, New Jersey 08852 
 
 
 
Sponsor Signatory: 
Victoria T. Lee, MD 
 
 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the Sponsor. 
 
 
 
 
 
 

Versi o n 2. 1 
S T A R - D 
Pa ge 2 of 7 7 
SI G N A T U R E P A G E  – S P O N S O R A P P R O V A L  
T his Cli nical I n vesti gati o n Pla n is i n acc or da nce wit h t he cli nical researc h g ui deli nes esta blis he d b y 
t he U S C o de of Fe deral Re g ulati o ns ( Title 2 1, Parts 5 0, 5 4, 5 6, a n d 8 1 2), t he re g ulati o ns a n d 
g ui deli nes of I nter nati o nal C o u ncil f or Har m o nisati o n  f or G o o d Cli nical Practice, a n d I nter nati o nal 
Or ga nizati o n f or Sta n dar dizati o n 1 4 1 5 5 ( Cli nical I n vesti gati o n of Me dical De vices f or H u ma n 
S u bjects - G o o d Cli nical Practice). St u d y d oc u me nts will be mai ntai ne d i n acc or da nce wit h a p plica ble 
re g ulati o ns. 
 
S P O N S O R A P P R O V A L  
I ha ve rea d t he Cli nical I n vesti gati o n Pla n a n d a p pr o ve it: 
 
    
  
  
 
0 9 -Marc h -2 0 2 2  
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Vict oria T. Lee, M D   
  
  
  
 
Date  
Se ni or Direct or of Cli nical Affairs  
 
B RI E F P R O T O C O L R E VI SI O N HI S T O R Y  
Versi o n  
D ate  
Brief Descri pti o n of C h a n ges  
1. 0  
0 9 -Se pte m ber -2 0 2 1  
Ori gi nal  S u b missi o n  
1. 1  
2 2 -Se pte m ber -2 0 2 1  
T he f oll o wi n g secti o ns a n d s u bsecti o ns were u p date d t o a d dress 
re vie w s u g gesti o ns b y t he A ge nc y:  
• 
S y n o psis  
• 
Secti o n 4. 4. 1 I ncl usi o n Criteria  
• 
Secti o n 4. 4. 2 E xcl usi o n Criteria  
• 
Secti o n 1 0 C o nc o mita nt Me dicati o ns  
• 
A p pe n di x 4. Ta ble 6. Sc he d ule of Assess me nts  
T he f oll o wi n g secti o n s were u p date d t o rectif y err ors fr o m t he 
i nitial d oc u me nt 
• 
Secti o n 4. 4. 2 E xcl usi o n Criteria  
• 
Secti o n 1 1. 1 Statistical P o wer a n d Sa m ple Size 
Deter mi nati o n  
• 
A p pe n di x 5  
1. 2  
2 8 -Se pte m ber -2 0 2 1  
T he f oll o wi n g secti o ns a n d s u bsecti o ns were u p date d t o a d dress 
re vie w s u g gesti o ns b y t he A ge nc y : 
• 
S y n o psis  
• 
Secti o n 4. 4. 2 E xcl usi o n Criteria  
• 
Secti o n 1 1. 3 Effecti ve ness A nal ysis  
F o ot n ote “ b” i n A p pe n di x 2 a n d f o ot n ote “f” i n Ta ble 6 u p date d t o 
matc h e xact la n g ua ge of e xcl usi o n criteri o n # 1 0  
1. 3  
1 3 -Oct o ber -2 0 2 1  
T y p o gra p hic err ors c orrecte d i n t he f oll o wi n g l ocati o ns:  
• 
D oc u me nt hea der, pa ges 7 1 -7 3  
• 
D urati o n of scree ni n g peri o d i n T a ble 6 . Sc he d ule of 
Assess me nts (t w o l ocati o ns: 1) ti me p oi nt b o x a n d 2) 

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footnote “e”)  
 
Section 9.2.1 Adverse Events updated to include additional safety 
reports requested by the Agency at intervals independent of annual 
IDE safety reporting 
2.0 
25-February-2022 
• 
Increased number of study sites from 25 to 30 
• 
Language around inclusion criteria #3 has been updated 
to allow enrollment of patients with up to 36hrs of time 
between last apixaban or rivaroxaban dose and start of 
surgery. The change to the inclusion criteria itself is 
reflected in the protocol Synopsis and Section 4.4.1 
Inclusion Criteria. References to this time-point have 
been updated through-out the remainder of the text as 
relevant (including in Table 5 and Table 6 of the protocol 
appendices) 
• 
Language around exclusion criteria #1 has been revised to 
exclude those patients who have had >48hrs between last 
apixaban/rivaroxaban dose and start of surgery. This 
update has been made within the protocol Synopsis and 
Section 4.4.2 Exclusion Criteria 
• 
Language has been added to exclusion criterion #3 to 
clarify intent of excluding subjects whose index operation 
is for “implant or revision of LVAD or RVAD.”. This 
update has been made in the Synopsis and Protocol 
Section 4.4.2 (Exclusion Criteria) 
• 
Language has been added within exclusion criterion #12 
to clarify that the 30-day life expectancy does not include 
“the critical condition that is requiring the cardiac 
operation under study.” This update has been made in the 
Synopsis and Protocol Section 4.4.2 (Exclusion Criteria) 
• 
“Primary endpoint (Win Ratio) results stratified by 
DOAC (apixaban vs. rivaroxaban) type” has been 
removed as an “Additional Secondary Effectiveness 
Endpoint.” This change was made to the protocol 
Synopsis and Section 4.3.3 (Additional Secondary 
Effectiveness Endpoints) and Section 11.3 (Effectiveness 
Analysis)  
• 
Section 9.2.5 (Physical Exam) and footnote “r” in Table 
6 has been updated to allow physical exams performed as 
part of standard of care on the day of screening to be 
documented as a screening assessment  
• 
The following sections/subsections were updated to 
address Statistical Considerations proposed by the 
Agency in their response to the STAR-D IDE: Section 11 
(Statistical Considerations), Section 11.1 (Statistical 
Power and Sample Size Determination), and Section 11.3  
• 
The definition of the modified intent-to-treat (mITT) 
population has been updated in the Synopsis and Section 
11.2 (Analysis Populations) 
• 
The definition of the Safety Analysis population has been 
updated in the Synopsis and Section 11.2 (Analysis 
Populations)  
• 
The primary analyses of the trial will be performed on the 
modified intent-to-treat (mITT) population rather than the 
intent-to-treat (ITT) population. This language has been 
updated in the protocol Synopsis and Section 11.2 
Analysis Populations accordingly 
• 
New section added: Section 11.4 Subgroup Analysis 

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• 
The stopping boundaries for the pre-specified interim 
analysis have been updated in Section 11.6 (Interim 
Analysis) at the guidance of the DSMB. Rather than the 
Lan-DeMets Pocock approximation, a Lan-DeMets 
O’Brien-Fleming spending function is instead being used 
for determination of stopping boundaries (which are now 
more conservative than prior) 
o 
Power calculations within Table 3 (Win Ratio 
Effect Size Assumptions and Power and Sample 
Size Estimates Under Varying Conditions) have 
been updated to reflect changes related to the 
new stopping boundaries 
• 
Appendix 2 has been updated to reflect the Schedule of 
Assessments (Table 6) more accurately by clearly 
distinguishing the timing of Point of Care Tests (ACT) as 
compared to the timing of local laboratory coagulation 
tests (Coagulation Panel). The updated language does not 
alter the timing of assessments as described in the 
protocol but reduces confusion from similar terminology 
2.1 
09-March-2022 
• 
Additional language update to exclusion criterion #12, per 
FDA Interactive Review: “Subjects with life expectancy 
of <30 days (not inclusive of the critical condition that is 
requiring the cardiac operation under study for which 
there is a reasonable expectation that cardiac surgery 
with the device may prolong life for more than 30 days” 
• 
Section 11.6 (Interim Analysis) has been further modified 
to include the following points: a) the Sponsor will defer 
to the DSMB for decision on early study termination at 
the time of the interim analysis, and b) the FDA will be 
immediately notified of the decision of whether the study 
has been halted or terminated 

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SIGNATURE PAGE – INVESTIGATOR AGREEMENT 
This Clinical Investigation Plan is in accordance with the clinical research guidelines established by 
the US Code of Federal Regulations (Title 21, Parts 50, 54, 56, and 812), the regulations and 
guidelines of International Council for Harmonisation for Good Clinical Practice, and International 
Organization for Standardization 14155 (Clinical Investigation of Medical Devices for Human 
Subjects - Good Clinical Practice). Study documents will be maintained in accordance with applicable 
regulations. 
 
INVESTIGATOR AGREEMENT 
I have read the Clinical Investigation Plan and agree to conduct the investigation as described herein. 
 
 
 
Principal Investigator (Printed) 
 
 
 
 
 
 
Principal Investigator (Signature) 
 
Date 
 
 
 
 
Clinical Site 
 
 
 
 
 
 
 
 
 
 
 

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SYNOPSIS 
Title of investigation: Safe and Timely Antithrombotic Removal – Direct Oral Anticoagulants Apixaban & 
Rivaroxaban (STAR-D): A Prospective, Multicenter, Double-blind, Randomized, Study to Evaluate 
DrugSorb-ATR Removal of Apixaban and Rivaroxaban to Reduce Likelihood of Serious Bleeding in 
Patients Undergoing Urgent Cardiothoracic Surgery. 
 
Objectives: 
• 
To demonstrate reductions in surgical and early post-surgical bleeding with the intraoperative use 
of DrugSorb-ATR in patients undergoing cardiothoracic surgery ≤36hrs since last apixaban or 
rivaroxaban dose. 
• 
To demonstrate reductions in apixaban or rivaroxaban blood levels (∆[DOAC]) with the 
intraoperative use of DrugSorb-ATR. 
• 
To establish the safety of the intraoperative use of DrugSorb-ATR in the intended population. 
 
Background and rationale: 
Apixaban and rivaroxaban are both factor Xa inhibitors that fall into a category of drugs generally referred to 
as direct oral anticoagulants (DOACs).  They share significant similarities, as both of these DOACs are 
indicated for stroke prevention in patients with non-valvular atrial fibrillation (A. fib), and for secondary 
prevention of venous thromboembolic events (VTE).[1] [2] Together, apixaban and rivaroxaban account for 
the vast majority of DOAC use in both the U.S and globally, with >75% of the U.S Medicare market share 
since 2015. [3] Data from the Medical Expenditure Panel Survey (MEPS), show that apixaban is prescribed 
more frequently than rivaroxaban resulting in an approximate 3:2 ratio in the year 2018 
(https://meps.ahrq.gov/mepstrends/hc_pmed/), however market data suggests that apixaban has had further 
gains since that time.[4, 5] As with all antithrombotic medications, the predominant safety concern 
associated with DOAC use is bleeding, whether spontaneous or secondary to injury or invasive/surgical 
procedures. As such, DOAC therapy is routinely stopped for several days prior to invasive/surgical 
procedures in current clinical practice. The 2017 ACC Expert Consensus Decision Pathway and the 2018 
European Heart Rhythm Association Practical Guide on use of non-vitamin K antagonist DOACs in patients 
with atrial fibrillation specifically recommend that both apixaban and rivaroxaban should be discontinued at 
least 48hrs prior to elective cardiothoracic surgeries (which are known to carry a high risk of major 
bleeding). [6] [7] It is widely accepted that longer periods of DOAC interruption may be necessary for 
patients with impaired renal function, or those on concomitant medications that may decrease the efficiency 
of drug metabolism (such as several antiarrhythmic agents).[8]  
 
However, published reports suggest that ~10% of patients on chronic DOAC therapy will require urgent or 
emergent procedures annually. [9] In such situations, scheduled pre-operative drug discontinuation is 
generally not possible, thus exposing these patients to high bleeding risk. This is especially relevant in cases 
of urgent cardiothoracic surgery where the presence of antithrombotic agents greatly increases the risk of 
life-threatening bleeding. [10] 
 
The DrugSorb-Anti Thrombotic Removal (ATR) device has high affinity for binding hydrophobic small 
molecules and drugs (~5-kDa to 60-kDa). Data on the antithrombotic drug removal capabilities of 
DrugSorb-ATR have previously been published in Europe under the name CytoSorb®, which has been CE 
marked for both ticagrelor and rivaroxaban removal. DrugSorb-ATR is the name of the device in the U.S, 
specifically intended to align with intended use in antithrombotic drug removal (ATR). Within this clinical 
investigation plan, the name CytoSorb® will be used when citing previously published data, to remain 
consistent with the literature.   
 
DrugSorb-ATR can efficiently remove apixaban and rivaroxaban from whole blood.  
Benchtop experiments published by Koertge et. al. utilized a small in vitro recirculation model with human 
whole blood, in which 91.6% of circulating rivaroxaban was removed within 1hr of recirculation. [11] 
Sponsor preclinical studies have supported these results, demonstrating approximately 95.1% removal of 
rivaroxaban from bovine whole blood after one hour of DrugSorb-ATR hemoadsorption (data on file, 
CytoSorbents). 
 
Preclinical studies with the same experimental setup have also been performed with apixaban and 

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demonstrated 96.3% removal from bovine whole blood following one hour of DrugSorb-ATR 
hemoadsorption (data on file, CytoSorbents). Indeed, the drug removal curves were nearly identical for both 
apixaban and rivaroxaban, with >60% of the circulating drug removed within the first 15 minutes of 
DrugSorb-ATR exposure.  
 
A retrospective case-series from Asklepios Klinik St. Georg (Hamburg, Germany) evaluated the use of the 
CytoSorb® device in patients on rivaroxaban undergoing emergent cardiothoracic surgery with 
cardiopulmonary bypass (CPB). Patients on rivaroxaban operated on CPB alone (control) were compared to 
patients operated on CPB with CytoSorb® (treatment). Results showed significant reductions in multiple 
measures of postoperative bleeding for patients managed with CytoSorb® compared to the control cohort. 
[12] No device-related adverse events (AEs) or device malfunctions/deficiencies were reported. No similar 
series has yet been published for patients on apixaban, however a case report by Mendes et. al. was 
published in 2020, in which they used the CytoSorb® device to treat a high-risk elderly female undergoing 
emergent redo mitral valve replacement on apixaban.[13] The subject did well post-operation, and suffered 
no bleeding complications. Given the similar drug removal mechanics in benchtop models, and the 
consistent clinical experience to date, it is expected that DrugSorb-ATR will provide the same clinical 
benefits in patients who are on either apixaban or rivaroxaban.  
 
Thus, the Sponsor proposes to conduct a prospective, multi-center, double-blind, randomized, clinical trial to 
demonstrate that use of DrugSorb-ATR during CPB significantly reduces surgical and early post-surgical 
bleeding and efficiently removes apixaban and rivaroxaban in patients undergoing cardiothoracic surgery 
within 36 hours of their last dose.  
 
Hypothesis:  
In patients undergoing cardiothoracic surgery on CPB within 36 hours of last apixaban or rivaroxaban dose, 
intraoperative use of DrugSorb-ATR will significantly reduce surgical and post-surgical bleeding 
complications. 
 
Endpoints: 
Primary Effectiveness Endpoint: 
• 
Surgical and early post-surgical bleeding, assessed by the ranked composite of:  
1) Fatal bleeding occurring within 48hrs post-index operation,  
2) Moderate, severe, or massive bleeding events based on the Universal Definition of 
Perioperative Bleeding in Cardiac Surgery (UDPB) ≥2 classification, and 
3) 24-hour chest tube drainage. 
 
Key Secondary Effectiveness Endpoints:  
• 
Change in blood apixaban levels (∆[apixaban]) pre- vs. post-CPB measured by liquid 
chromatography/tandem mass spectrometry, 
• 
Change in blood rivaroxaban levels (∆[rivaroxaban]) pre- vs. post-CPB measured by liquid 
chromatography/tandem mass spectrometry. 
 
Additional Secondary Effectiveness Endpoints: 
• 
24-hour chest tube drainage (volume); 
• 
Total platelet transfusions during hospitalization (volume and units); 
• 
Total PRBC transfusions during hospitalization (volume and units); 
• 
Total UDPB events (by class); 
• 
All surgical re-exploration for excessive bleeding 
• 
Total fatal perioperative bleeding events 
 
Exploratory Endpoints:  
• 
Area under the concentration time curve (AUC), for intraoperative apixaban or rivaroxaban 
pharmacokinetic (PK) concentration  
• 
Duration of index operation (minutes); 
• 
Length of ICU stay; 
• 
Length of hospital stay; 
• 
30-day hospital readmissions. 

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Primary Safety Endpoint: 
• 
GCP-level assessment of all AEs during the study period 
 
Additional Safety Endpoints: 
• 
30-day cardiac mortality 
• 
30-day all-cause mortality; 
• 
Postoperative stroke during index hospitalization 
• 
Postoperative myocardial infarction (MI) during index hospitalization 
• 
Urgent postoperative coronary revascularization during the index hospitalization 
• 
Postoperative venous thromboembolic events (VTE) during index hospitalization 
• 
Serious device-related adverse events 
 
Investigational design: 
This study is a prospective, multi-center, double-blind, randomized pivotal trial to evaluate the safety and 
effectiveness of DrugSorb-ATR to reduce surgical and early post-surgical bleeding in patients undergoing 
cardiothoracic surgery requiring CPB ≤36hrs after last dose of apixaban or rivaroxaban. Bleeding will be 
measured by a ranked composite endpoint of: fatal bleeding occurring within 48hrs of the index operation, 
moderate, severe, or massive perioperative bleeding events (UDPB ≥2), and 24-hour chest tube drainage. 
Subjects will be randomized in a 1:1 ratio to either standard of care (SOC) alone (control arm) or standard of 
care plus intraoperative apixaban/rivaroxaban removal with DrugSorb-ATR integration in the CPB circuit 
(investigational arm). In the control arm a sham device that is not actively connected to the CPB circuit will 
be placed in the identical location as the DrugSorb-ATR cartridge in the investigational arm, with the entire 
set-up covered by a drape to maintain the blind. Subjects will be followed out to 30 days after the surgical 
procedure for assessments of adverse events (AE) and survival. 
 
Prior to randomization, subjects will be stratified based on a) DOAC type (either apixaban or rivaroxaban), 
b) site, and c) type of planned cardiothoracic surgery [either CABG alone, or all other surgeries (including 
but not limited to combination cardiac procedures, and aortic interventions)]. Stratification is intended to 
control for potential confounding effects arising from differing drug therapies, institutional practices, and 
from procedure-specific CPB duration (i.e., device exposure – treatment duration) and bleeding risk. 
 
As apixaban and rivaroxaban have a similar mechanism of action, approved use indications, bleeding risk, 
and response to the investigational therapy, the trial will evaluate both drugs as a combined population for 
effectiveness and safety. The intent is to have a balanced contribution of apixaban and rivaroxaban patients 
in the trial with each drug contributing a target minimum of 40% of the total study population at the time of 
final analysis. 
  
Number of subjects: 
Approximately 120 subjects will be randomized into the study (60 into each arm). Assuming a 5% dropout 
rate, at total of 114 subjects (57 per arm) are expected to be evaluable for effectiveness and safety.  
 
Number of sites: 
Approximately 30 investigational sites in the US will participate in the study. 
 
Subjects must meet all inclusion criteria to be eligible to participate in the study. Subjects meeting any of the 
exclusion criteria are not eligible to participate in the study.   
 
Inclusion criteria: 
1. Males and females aged ≥18 
2. Written full informed consent 
3. Cardiothoracic surgery requiring CPB ≤36 hours from the last dose of either apixaban or 
rivaroxaban: 
• CABG alone 
• Valve repair or replacement 
• Combination surgery (i.e., CABG + valve operation) 

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• Aortic surgery 
Only patients taking apixaban or rivaroxaban for one of the following indications are eligible for enrollment: 
a) reduction of stroke/systemic embolism in nonvalvular atrial fibrillation, or b) initial or extended treatment 
of a venous thromboembolic event (VTE) which includes deep vein thrombosis (DVT) and/or pulmonary 
embolism (PE). 
 
Exclusion criteria: 
1. Cardiothoracic surgery >48 hours after last known dose of apixaban or rivaroxaban  
2. Patients on low dose apixaban or rivaroxaban for prophylactic indications (see Section 4.4.2 for 
details)  
3. Heart-lung transplant procedures 
4. Procedures for ventricular assist device (i.e., implant or revision of LVAD or RVAD) 
5. Any of the below conditions that pose a known risk for increased bleeding: 
• Heparin induced thrombocytopenia 
• Preoperative platelet count < 50,000 µ/L 
• Hemophilia 
• INR  ≥ 1.8 
6. Prohibited concomitant antithrombotic medications (reference Appendix 5 of study protocol); 
7. Acute sickle cell crisis 
8. Known allergy to any of the device components 
9. Subjects with active (untreated) systemic infection  
10. Subjects with a history of major organ transplantation and those currently receiving 
immunosuppressive medication (corticosteroids excluded) or who are profoundly immune 
suppressed 
11. Women of childbearing potential with a positive pregnancy test performed during the current 
admission or who are breast-feeding 
12. Subjects with life expectancy of <30 days (not inclusive of the critical condition that is requiring 
the cardiac operation under study for which there is a reasonable expectation that cardiac surgery 
with the device may prolong life for more than 30 days) 
13. Inability to comply with the requirements of the study protocol 
14. Treatment with an investigational drug or device within 30 days prior to surgery 
15. Subjects with previous enrollment in this trial  
 
Duration of subject participation in the investigation: 
Duration of treatment with the DrugSorb-ATR device is limited to the CPB duration. Subjects will undergo 
scheduled study procedures until hospital discharge. Hospital discharge means the date of initial discharge 
from the hospital after the index procedure, irrespective of whether the subject is discharged to home care, 
secondary care or other rehabilitation unit.  
 
Study follow-up will continue out to 30-days after the index operation to monitor occurrence of adverse 
events and vital status of study participants.  
 
Test device and subject treatment: 
DrugSorb-ATR is a sorbent-filled hemoperfusion cartridge that can efficiently adsorb apixaban and 
rivaroxaban, and thereby reduce circulating drug levels in blood. The device is placed into a parallel bypass 
circuit (between the oxygenator and the venous reservoir) to the main blood flow in a standard CPB circuit. 
Standard CPB anticoagulation protocols will be followed since Heparin is not adsorbed by DrugSorb-ATR. 
 
Statistical methods: 

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Effectiveness Analysis 
The primary effectiveness endpoint will be evaluated using the Win Ratio method of analysis for a 
hierarchical composite endpoint based on the Finkelstein-Schoenfeld test (Finkelstein and Schoenfeld, 1999; 
Pocock, et al., 2012) with three components: a) fatal bleeding events occurring within 48hrs of the index 
procedure, b) moderate, severe, or massive bleeding based on the Universal Definition of Perioperative 
Bleeding in Cardiac Surgery (UDPB) ≥2 classification, and c) 24-hour chest tube drainage (volume, mL). 
The Win Ratio assigns “wins”, “losses”, or “ties” between randomized groups in a serial fashion across all 
components of the composite endpoint adhering to the declared hierarchical order from higher to lower 
clinical importance.[14] [15] A ratio of “wins” greater than 1.0 favors the treatment arm; when the lower 
bound of a 95% confidence interval (CI) around the ratio exceeds 1.0, the treatment is shown to be 
statistically superior to control at alpha = 0.05. The primary effectiveness analysis will be performed in the 
overall study population comprised of both apixaban and rivaroxaban patients to evaluate the difference 
between the SOC (control) arm and the DrugSorb-ATR (investigational) arm. 
 
The key secondary effectiveness endpoints are the pre-CBP vs. post-CPB change in drug levels (apixaban 
and/or rivaroxaban) measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) [drug 
removal endpoint]. Change in each subject’s blood concentration of apixaban or rivaroxaban from 
immediately before to immediately after CPB will be collected and analyzed by a central core laboratory. 
Drug removal will be analyzed for apixaban and rivaroxaban independently.  
 
Change from baseline in blood concentration of apixaban or rivaroxaban is defined as:  
 
               pre-CPB [apixaban]blood - post-CPB [apixaban]blood  *100% 
pre-CPB [apixaban]blood 
 
or 
 
pre-CPB [rivaroxaban]blood - post-CPB [rivaroxaban]blood  *100% 
pre-CPB [rivaroxaban]blood 
 
Based on existing benchtop evidence, a conservative estimate of 40% reduction in blood concentration of 
DOAC between pre- and post- DrugSorb-ATR removal is expected, with a standard deviation of 40%, in the 
treatment arm. Minimal change is expected in the control arm. A two-sample t-test will be used to evaluate 
the difference between treatment arms.  
 
Additional powered secondary endpoints include 24-hour CTD (volume [mL]), total platelet transfusions 
(volume [mL] and units), and total PRBC transfusions (volume [mL] and units) during the index 
hospitalization. Twenty-four-hour CTD (mL) will be assessed via two-sample t-test for mean difference. The 
transfusion endpoints will all be analyzed using two-sample t-tests for mean differences, and Fisher-
Freeman-Halton exact tests for units. In the event the assumptions for a two-sample t-test are not met in any 
of the above, a nonparametric test such as a Mann-Whitney test will be employed, with median and range 
values provided in the output. An additional analysis of 24-hour CTD will compare the frequency of subjects 
falling into volume categories (i.e., <500 mL, 500 to <750 mL, 750 to <1000 mL, 1000 to <1250 mL, 1250 
to <1500 mL, and  ≥1500 mL), and will use a Fisher-Freeman-Halton exact test to compare treatment 
groups. Other secondary endpoints include the remaining Win Ratio component parts: proportions of fatal 
perioperative bleeding events will be assessed via Fisher’s exact test; and proportions of UDPB events (by 
category) will be assessed via a Fisher-Freeman-Halton exact test. The secondary endpoint of surgical re-
exploration for bleeding will take into account time to re-exploration.  
 
Sample Size 
Approximately 120 subjects will be randomized in a 1:1 ratio to the treatment and control arms. Assuming a 
5% dropout rate, at total of 114 subjects (57 per arm) are expected to be evaluable for effectiveness and 
safety. Sample size is based on assumed response rates for the primary effectiveness endpoint, and power 
can be calculated via an iterative simulation process with programming code available in an appendix to 
Redfors et al. (2019).[16] With a Finkelstein-Schoenfeld test, total of 57 subjects per arm ensures power of 
>99.2%, using a two-sided alpha (α) of 0.05, and assuming an interim analysis for efficacy at 70% 
completion. Power for each of the key secondary endpoints is estimated at 96.3%, and for 24-hour chest tube 
drainage (mL), >99.9%, based on a two-sample t-test assuming equal variance and a two-sided alpha of 0.05. 

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Similarly, although assuming unequal variances, power for comparisons of platelet transfusions (volume 
[mL]) and PRBC transfusions (volume [mL]), is estimated at 98.0% and 96.7%, respectively. 
 
Interim Analysis 
A planned interim analysis will be performed after 70% of study subjects have completed the study, to allow 
for early stopping for overwhelming efficacy according to a pre-specified boundary. 
 
Subgroup Analyses 
Subgroup analyses will be conducted to investigate efficacy of treatment. These include analyses by DOAC 
drug type, site, and type of planned cardiothoracic surgery. 
 
Analysis Populations 
Enrolled subjects include all subjects who provide informed assent/consent. Enrolled subjects who do not 
meet criteria for study eligibility are screening failures and will exit the study. 
 
The Intent-to-Treat (ITT) Population will include all enrolled (assented/consented) subjects who are 
randomized. The modified Intent-to-Treat (mITT) Population will include all randomized subjects who 
undergo the index surgical procedure and receive a study device (whether DrugSorb-ATR or sham). The 
primary analyses of the trial will be performed on the mITT Population. Baseline demographic and clinical 
variables will be summarized for each of the treatment groups for the ITT and mITT populations. So long as 
the ITT and mITT populations are not identical, the ITT patients who do not fall within the mITT population 
will be presented in a listing, including the reasons for why they did not receive a study device The Per 
Protocol (PP) Population will include all mITT subjects who have no major protocol violations. Analysis of 
the primary efficacy endpoint will be performed in the PP population as a sensitivity analysis. 
 
The Safety Analysis Population will include all enrolled subjects who are treated or attempted treatment with 
a study device. “Attempted treatment” refers to any subject(s) who initiate treatment with a study device 
(whether DrugSorb-ATR or sham) during the index procedure but experience early discontinuation. 
 
Safety Analysis 
All AEs occurring after the start of the CPB procedure will be listed and summarized using descriptive 
methodology. The incidence of AEs will be presented by severity and by relationship to the investigational 
device (DrugSorb-ATR or sham) as determined by the Investigator (or designee). Each AE will be coded 
using the Medical Dictionary for Regulatory Activities®. Observed values for clinical laboratory test data 
and vital signs, along with change from baseline results, will be summarized by collection time point. A 
summary of clinically notable values will be provided. 
 
Safety oversight committees: 
DSMB: 
Three physicians with relevant clinical/medical and investigational expertise together with an independent 
statistician will form the Data Safety Monitoring Board (DSMB) that will be independently managed by an 
academic research organization. The primary role of the DSMB is to oversee the safety of subjects enrolled 
in the study and also oversee the interim analysis. All DSMB members will be independent from the 
investigative sites and the study sponsor. The schedule and process associated with DSMB activities will be 
outlined in the DSMB charter. 
 
CEC: 
An independent group of physicians with relevant clinical expertise relating to the study outcomes who are 
not otherwise involved in the study will act as the Clinical Events Committee (CEC). The CEC will be 
independently managed by an academic research organization. The CEC will be responsible for the review 
and adjudication of effectiveness endpoints and safety events that occur during study duration (i.e., within 30 
days post-operation) according to standardized definitions as outlined in the CEC charter. 
 
 

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STUDY ORGANIZATION 
Sponsor:  
CytoSorbents, Inc. 
 
Executive Committee: 
Principal Investigators: 
• 
Michael Mack, MD (Baylor Scott & White Health) 
• 
C. Michael Gibson, MD (Beth Israel Deaconess Medical Center) 
Members: 
• 
David J. Schneider, MD (University of Vermont Medical Center) 
• 
E. Magnus Ohman, MD (Duke Health) 
• 
Frank W. Sellke, MD (Brown University; Rhode Island Hospital and The Miriam Hospital) 
• 
Vinod H. Thourani, MD (Piedmont Heart Institute) 
• 
James D. Douketis, MD (St. Joseph’s Healthcare Hamilton) 
• 
Efthymios N. Deliargyris, MD (CMO, CytoSorbents Inc. Sponsor Representative) 
 
Clinical Events Committee (CEC):  
Baim Institute for Clinical Research (previously known as the Harvard Clinical Research Institute) 
 
Data Safety and Monitoring Board (DSMB):  
Center for Interventional Cardiovascular Research and Clinical Trials, Icahn School of Medicine at 
Mount Sinai 
 
Independent Statistician for the DSMB:  
Stuart J. Pocock, PhD (London School of Hygiene & Tropical Medicine)  
 
Contracted Research Organization (CRO):  
Medpace 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SIGNATURE PAGE – SPONSOR APPROVAL .....................................................................2 
SIGNATURE PAGE – INVESTIGATOR AGREEMENT ......................................................5 
SYNOPSIS .................................................................................................................................6 
STUDY ORGANIZATION .....................................................................................................12 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF TABLES AND FIGURES........................................................................................15 
LIST OF ABBREVIATIONS ..................................................................................................17 
1. 
INTRODUCTION ...........................................................................................................19 
1.1. 
Background and Clinical Need ..............................................................................19 
1.2. 
Preclinical Data Informing Study Design ..............................................................20 
1.3. 
Clinical Data Informing Study Design ..................................................................22 
1.4. 
Device Background and Nomenclature .................................................................22 
1.5. 
Study Design ..........................................................................................................23 
2. 
DRUGSORB -ATR DESCRIPTION AND INTENDED USE ....................................23 
2.1. 
Description of the DrugSorb-ATR Device and Principle of Operation ..............23 
2.2. 
Treatment Materials ...............................................................................................25 
2.3. 
Device Accountability ...........................................................................................25 
2.4. 
Use of the Investigational Device ..........................................................................26 
2.5. 
Investigational Device/Procedures Training ..........................................................26 
3. 
STUDY JUSTIFICATION ..............................................................................................26 
4. 
INVESTIGATIONAL PLAN ..........................................................................................29 
4.1. 
Study Objective(s) .................................................................................................29 
4.2. 
Study Design ..........................................................................................................29 
4.3. 
Study Outcomes .....................................................................................................29 
4.3.1. 
Primary Effectiveness Endpoint: .................................................................29 
4.3.2. 
Key Secondary Effectiveness Endpoints: .....................................................30 
4.3.3. 
Additional Secondary Effectiveness Endpoints: ..........................................30 
4.3.4. 
Exploratory Endpoint(s): .............................................................................30 
4.3.5. 
Primary Safety Endpoint: ............................................................................30 
4.3.6. 
Additional Safety Endpoints: .......................................................................30 
4.4. 
Subjects and Selection of Study Population ..........................................................30 
4.4.1. 
Inclusion Criteria: ........................................................................................31 
4.4.2. 
Exclusion Criteria: .......................................................................................31 
4.4.3. 
Informed Consent & Enrollment Procedures:..............................................31 
4.4.4. 
Subject Withdrawal/Discontinuation: ..........................................................32 
5. 
POTENTIAL RISK/BENEFIT ........................................................................................33 
5.1. 
Potential Investigational Device Risks ..................................................................33 

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5.2. 
Potential Benefits ...................................................................................................33 
5.3. 
Risk Mitigation ......................................................................................................33 
6. 
STUDY TREATMENT ...................................................................................................36 
6.1. 
Pre-randomization Stratification ............................................................................36 
6.2. 
Subject Randomization ..........................................................................................36 
6.3. 
Blinding..................................................................................................................37 
6.3.1. 
Maintaining the Study Blind ........................................................................37 
6.4. 
Field Clinical Specialists........................................................................................39 
6.5. 
Device Quality Complaints: Deficiencies, Malfunctions, and Observations ........39 
7. 
STUDY OVERSIGHT.....................................................................................................40 
7.1. 
Data and Safety Monitoring Board (DSMB) .........................................................40 
7.2. 
Clinical Events Committee (CEC) .........................................................................40 
7.3. 
Executive Committee .............................................................................................40 
7.4. 
Central Laboratory .................................................................................................40 
8. 
STUDY MONITORING .................................................................................................40 
8.1. 
Monitor Training ....................................................................................................41 
8.2. 
Site/Investigator Training ......................................................................................41 
8.3. 
Site Monitoring ......................................................................................................41 
8.4. 
Regulatory Agency Inspection ...............................................................................41 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................41 
9.1. 
Procedures and Assessments by Study Phase ........................................................42 
9.1.1. 
Screening Phase and the Pre-CPB Phase .....................................................43 
9.1.2. 
Operation Phase ...........................................................................................44 
9.1.3. 
Postoperative phase through 30-day evaluation ..........................................44 
9.2. 
Safety and Tolerability Assessments .....................................................................45 
9.2.1. 
Adverse Events ............................................................................................45 
9.2.2. 
Medical History ...........................................................................................46 
9.2.3. 
Clinical Laboratory Evaluations ..................................................................46 
9.2.4. 
Vital Signs ....................................................................................................47 
9.2.5. 
Physical Examination...................................................................................47 
9.2.6. 
Other Assessments: Blood Products and Blood Loss ..................................47 
9.3. 
Blood Sampling for Drug Removal .......................................................................47 
10. CONCOMITANT MEDICATIONS ...............................................................................48 
11. STATISTICAL CONSIDERATIONS.............................................................................48 
11.1. Statistical Power and Sample Size Determination .................................................48 
11.2. Analysis Populations ..............................................................................................52 
11.3. Effectiveness Analysis ...........................................................................................52 
11.4. Subgroup Analysis .................................................................................................54 
11.5. Exploratory endpoints ............................................................................................54 
11.6. Interim Analysis .....................................................................................................55 

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11.7. Treatment of Missing Data ....................................................................................55 
11.8. Safety Analysis ......................................................................................................55 
11.9. Device Malfunctions/Deficiencies .........................................................................56 
11.10. Disposition and Baseline Characteristics ...............................................................56 
12. DATA HANDLING AND RECORD KEEPING ...........................................................56 
12.1. Data Management Procedures ...............................................................................56 
12.2. Subject Data Protection..........................................................................................57 
12.3. Data retention .........................................................................................................57 
12.4. Investigator Records ..............................................................................................57 
12.5. Investigator Reports ...............................................................................................58 
13. QUALITY CONTROL AND ASSURANCE .................................................................59 
13.1. Site and Investigator Selection ...............................................................................59 
13.2. Protocol Deviations ................................................................................................59 
13.3. Protocol Deviation Process ....................................................................................59 
13.4. Corrective/Preventative Action ..............................................................................59 
13.5. Data Quality Assurance .........................................................................................60 
14. TERMINATION OF STUDY OR STUDY SITE PARTICIPATION ............................60 
15. ETHICS/PROTECTION OF HUMAN SUBJECTS .......................................................61 
15.1. Statements of Compliance .....................................................................................61 
15.2. Institutional Review Board (IRB) ..........................................................................61 
15.3. Informed Consent Process .....................................................................................61 
15.4. Subject Confidentiality ..........................................................................................61 
16. PROTOCOL AMENDMENTS .......................................................................................62 
17. PUBLICATION POLICY ...............................................................................................62 
18. REFERENCES ................................................................................................................63 
19. APPENDICES .................................................................................................................65 
Appendix 1: Adverse Event Reporting ..............................................................................66 
Appendix 2: Clinical Laboratory Evaluations ...................................................................70 
Appendix 3: Regulatory and Ethical Considerations .........................................................71 
Appendix 4: Study Schedules ............................................................................................73 
Appendix 5: Antithrombotic Medications Allowed/Disallowed in the Preoperative 
Period .....................................................................................................................77 
 
LIST OF TABLES AND FIGURES 
Table 1. Bleeding Class According to the Universal Definition of Perioperative 
Bleeding in Adult Cardiac Surgery ..............................................................................28 
Table 2. Risks and Mitigation Strategies ...........................................................................34 
Table 3. Win Ratio Effect Size Assumptions with Power and Sample Size Estimates 
Under Varying Conditions ...........................................................................................51 

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Table 4. Responsibilities for Preparing and Submitting Reports .......................................58 
Table 5. Schedule of Antithrombotic and Anticoagulation Management .........................73 
Table 6: Schedule of Assessments .....................................................................................74 
 
Figure 1. Removal of Rivaroxaban From Whole Bovine Blood Ex Vivo ..........................21 
Figure 2. Removal of Apixaban From Whole Bovine Blood Ex Vivo ...............................22 
Figure 3. DrugSorb-ATR ...............................................................................................24 
Figure 4. DrugSorb-ATR Integration in the Cardiopulmonary Bypass Circuit .............25 
Figure 5. Investigation Schematic ......................................................................................43 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACS 
Acute coronary syndrome 
ADE 
Adverse device effect 
ADP 
Adenosine diphosphate 
AE 
Adverse event 
A. FIB  
Atrial fibrillation 
ATR 
Anti-Thrombotic Removal 
AUC 
Area under the concentration time curve 
CABG 
Coronary artery bypass grafting 
CAD 
Coronary Artery Disease 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPB 
Cardiopulmonary bypass 
CIP 
Clinical investigation plan 
CRO 
Contract Research Organization 
Cryoppt 
Cryoprecipitate 
DOAC 
Direct Oral Anticoagulant 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
eCRF 
Electronic case report form 
EC 
Ethics committee 
ECG 
Electrocardiogram 
FDA 
US Food and Drug Administration 
FCS 
Field Clinical Specialist 
FFP 
Fresh frozen plasma 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICU 
Intensive care unit 
IFU 
Instructions for use 
ISO 
International Organization for Standardization 
ITT 
Intent-to-Treat 
IxRS 
Interactive Voice/Web response 
mITT 
Modified Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSTEMI 
Non-ST segment elevation myocardial infarction 
PAD 
Peripheral Arterial Disease 
PCC 
Prothrombin complex concentrates 
PE 
Pulmonary Embolism 
PK 
Pharmacokinetic 

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PLT 
Platelet concentrates 
PP 
Per Protocol 
PRBC 
Packed red blood cells 
RCT 
Randomized controlled trial  
rFVIIa 
Recombinant activated factor VII 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
Standard of care 
UADE 
Unanticipated adverse device effect 
UDPB 
Universal definition of perioperative bleeding in cardiac surgery 
VTE 
Venous thromboembolic event 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 

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1. INTRODUCTION 
1.1. 
Background and Clinical Need 
The risk of bleeding during cardiothoracic surgery is significantly increased by the presence of 
antithrombotic drugs, including direct oral anticoagulants (DOACs). [10] [17] Apixaban and 
rivaroxaban are factor Xa inhibitors that are both indicated for reduction in risk of stroke and systemic 
embolization in patients with non-valvular atrial fibrillation (A. fib), treatment of venous 
thromboembolism (VTE), and as prophylaxis of deep venous thrombosis.[1] [2] They are the two 
dominant representatives of the DOAC class in the US and worldwide.[18] Within the US Medicare 
population, apixaban and rivaroxaban in combination have accounted for >75% of the U.S DOAC 
market share since 2015. [3] By the first quarter of 2017, only 21.1% of commercial or Medicare 
Advantage patients on chronic oral anticoagulation for atrial fibrillation were being prescribed 
warfarin. In contrast, 50.1% were being prescribed apixaban, 25.0% rivaroxaban, and 3.8% 
dabigatran. [19] Consistent with Medicare data, the Medical Expenditure Panel Survey (MEPS) also 
demonstrated a market dominance of apixaban over rivaroxaban, with a prescription ratio of 
approximately 3:2 between the two drugs in the year 2018, and minimal usage of all the other DOACs 
(https://meps.ahrq.gov/mepstrends/hc_pmed/).  
As with any anticoagulant, the predominant safety concern with DOAC use is the possibility of major 
bleeding events, especially in relation to surgery and thus drug discontinuation is recommended prior 
to surgery to reduce the risk of bleeding. [20] The 2017 ACC Expert Consensus Decision Pathway 
and the 2018 European Heart Rhythm Association Practical Guide on use of non-vitamin K antagonist 
oral anticoagulants recommend discontinuing apixaban and rivaroxaban at least 48hrs prior to 
surgeries carrying a high risk of major bleeding, including cardiothoracic surgery. [6] [7] It is widely 
accepted that longer periods of DOAC interruption may be necessary for patients with impaired renal 
function, or those on concomitant medications that may decrease the efficiency of drug metabolism 
(such as several antiarrhythmic agents). [8]  
 
However, emergent, and urgent interventions are commonly required in cardiovascular patients, 
where there is no option for delay to allow full drug washout. According to a publication utilizing data 
from the Society of Thoracic Surgery (STS) Database from a major US medical center, >30% of 
CABG procedures in their experience were performed urgently, while an additional 3.6% of 
procedures were true emergencies. [21] As mentioned above, patients on DOACs undergoing 
cardiothoracic surgery without adequate time for natural washout experience very high rates of 
bleeding complications. [17] [10] Postoperative bleeding worsens overall prognosis, and in a study 
evaluating outcomes from urgent aortic surgeries, preoperative DOAC use was the leading risk factor 
associated with postoperative mortality. [17]  The hazard ratio was 9.6, which was nearly 40% greater 
than the next-highest risk factor: extracardiac arteriopathy, and nearly 4x greater than the hazard ratio 
associated with recent MI (HR 2.5). [17]  Incidence of re-operation for bleeding was 60% in the same 
population. This is a massive, 10-fold increase compared with a re-thoracotomy rate of only 6% in a 
population of patients with 4 days of DOAC washout prior to CT surgery. [22]  In a study published 
by Hassan et al., it was demonstrated that timing of preoperative DOAC discontinuation strongly 
influenced post-operative 24hr chest tube drainage volume. [10] This metric has been demonstrated in 
the literature to strongly correlate with other critical outcomes including in-hospital mortality, 
increased need for postoperative supportive ventilation, and/or renal replacement therapy, transfusion 
volume, length of ICU stay, and length of hospital stay. [23] [24]  
 
Thus, a real and significant unmet clinical need exists for an intervention to address the very high risk 
of bleeding, morbidity, and mortality among patients on DOACs who require urgent cardiothoracic 
surgery. Currently there are no U.S. approved alternatives to meet this significant unmet medical 
need. Apixaban and rivaroxaban together account for the vast majority of DOAC use, and currently 
management of urgent surgical patients on these two DOACs center on reversal of coagulopathy in 

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the setting of active bleeding. [3] [19] Historically, this included off-label use of non-specific pro-
hemostatic agents such as prothrombin complex concentrate/activated prothrombin complex 
concentrate (PCC/aPCC) and KCentra (4F-PCC), however supporting clinical evidence remains 
limited or controversial. [25] [26] More recently, Andexanet Alfa, a variant of human recombinant 
factor Xa received FDA approval (in 2018) for specific reversal of the oral factor Xa inhibitors in the 
setting of life-threatening or uncontrolled bleeding. [27] However, its safety and effectiveness has 
not yet been adequately tested in the surgical population. [28] It is for this reason, DrugSorb-ATR 
has been designated a Breakthrough Device by the FDA for the removal of apixaban and rivaroxaban 
to reduce likelihood of serious bleeding in patients undergoing urgent cardiothoracic surgery. 
1.2. 
Preclinical Data Informing Study Design 
Preclinical studies have shown that both apixaban and rivaroxaban are rapidly and efficiently removed 
from whole blood by DrugSorb-ATR hemoadsorption. Of note, DrugSorb-ATR utilizes the same 
technology as the CytoSorb® device, which has previously received CE Mark approval for 
rivaroxaban removal in emergency CT surgery. To maintain consistent nomenclature with any 
referenced corresponding literature, DrugSorb-ATR will be referred to by its historic name 
CytoSorb®, whenever published clinical and pre-clinical data on apixaban or rivaroxaban removal is 
cited.  
Human Whole Blood Experiments 
Experimental removal of rivaroxaban from human whole blood ex vivo by CytoSorb® 
hemoadsorption was performed utilizing a model device and 1,000 mL of citrate-anticoagulated blood 
with baseline rivaroxaban concentrations of 571 ± 20µg/L. [11] The model included a 60mL column 
containing the adsorbent beads typically found within the CytoSorb®-300mL device, and the blood 
was recirculated at a flow rate of 40mL/min for a total of 120min treatment time using a standard 
infusion pump. This relatively high drug concentration was selected to be well above the median 
therapeutic peak plasma concentrations seen in clinical use (which range from 46-270µg/L, depending 
on the indication for rivaroxaban therapy). Blood pH was monitored and adjusted to range from 7.35 
to 7.45 by administration of Tris buffer, and blood temperature was maintained at 37οC. Blood was 
tested following 5min, 15min, 30min, 60min, and 120min of recirculation. Rivaroxaban 
concentrations were determined using chromogenic anti-factor Xa assays and drug-specific calibration 
(BIOPHEN Heparin LRT; HYPHEN BioMed, France). Within one hour of recirculation, 91.6% of 
circulating rivaroxaban was removed from the human whole blood. Between 60-120min of CytoSorb® 
hemoperfusion, the incremental decrease in rivaroxaban concentration was minimal. A similar 
recirculation system was studied without the CytoSorb® column, and after 5hrs showed no significant 
depletion of drug (data on file, CytoSorbents Corporation). 
 
No human whole blood experiments have been performed for apixaban.  
Bovine Whole Blood Experiments 
Studies were conducted to evaluate the removal of rivaroxaban from bovine whole blood ex vivo by 
DrugSorb-ATR and were similar in design to the human whole blood experiments described above. 
[unpublished data] Approximately 4L of bovine whole blood spiked with 600ng/mL of rivaroxaban 
was recirculated within the model. Starting concentration of rivaroxaban was measured to be 450 ± 
46ng/mL, a concentration exceeding standard therapeutic plasma drug levels (which range from 
159.6-359.8ng/mL, depending on indication for treatment, and dosing schedule). [29]  The control 
circuit was an identical system that incorporated an inactive device. The pump circulated blood 
through the DrugSorb-ATR cartridge at a rate of 300mL/min, which is similar to the rate used in 
humans. Blood samples to assay for rivaroxaban concentration were drawn from the reservoir bag at 
specific intervals after start of flow through the DrugSorb-ATR cartridge. Concentrations of 

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rivaroxaban were determined using tandem liquid chromatography mass spectrometry (LC-MS/MS). 
The results (Figure 1) showed that >95% of the rivaroxaban was removed from bovine whole blood 
ex vivo within 60 minutes of DrugSorb-ATR hemoadsorption (data on file, CytoSorbents 
Corporation). 
 
Results from corresponding benchtop models for apixaban removal using DrugSorb-ATR are shown 
in Figure 2 and demonstrate a nearly identical pattern of adsorption. As discussed above, the model 
incorporated a single DrugSorb-ATR cartridge into an extracorporeal circuit, using 4L of bovine 
whole blood. The blood was spiked with 300ng/ML of apixaban, resulting in a starting circulating 
concentration of 206.8 ± 8.1ng/mL. Again, this is in excess of standard therapeutic plasma drug 
levels. [30] Results demonstrated that >95% of the apixaban was removed from the bovine whole 
blood ex vivo within 60 minutes of DrugSorb-ATR hemoadsorption (data on file, CytoSorbents 
Corporation). 
 
Figure 1. Removal of Rivaroxaban From Whole Bovine Blood Ex Vivo 
 

Cli nical I n vesti gati o n Pla n ( CI P)  
C O N FI D E N TI A L  
 
 CI P  Refere nce  N u m ber: 2 0 2 1- 0 2 
Versi o n 2. 1 
S T A R -D  
Pa ge 2 2 of 7 7 
 
Fi g ure 2. Re m o v al of A pi x a b a n Fr o m W h ole B o vi ne Bl o o d E x Viv o  
1. 3.  
Cli nic al D at a  I nf or mi n g St u d y Desi g n 
T o date, o ver 1 2 0, 0 0 0 C yt o S or b ®  treat me nts ha ve bee n perf or me d gl o bal l y. It is esti mate d t hat 
a p pr o xi matel y 1 0 % of t he treat me nts ha ve bee n i ntra- o perati ve o n car di o p ul m o nar y b y pass ( C P B) 
i ncl u di n g a si g nifica nt n u m ber f or a ntit hr o m b otic re m o val  (tica grel or a n d ri var o xa ba n, f or w hic h t he 
de vice has C E mar k a p pr o v al). O verall, t he de vice has a fa v ora ble safet y pr ofile  wit h o ut a n y 
u na ntici pate d de vice relate d a d verse e ve nts re p orte d t o date . 
A retr os pecti ve case-c o ntr ol series fr o m As kle pi os Kli ni k St. Ge or g ( Ha m b ur g, Ger ma n y) e val uate d 
t he use of t he C yt o S or b ®  de vice i n patie nts o n ri v ar o x a b a n  u n der g oi n g e mer ge nt car di ot h oracic 
s ur ger y wit h C P B. A h ist orical c o h ort of patie nts w h o u n der we nt sta n dar d s ur ger y o n C P B b ut 
wit h o ut t he use of C yt o S or b ®  was c o m pare d t o  t he c o h ort of patie nts w h o recei ve d C yt o S or b®  
he m oa ds or pti o n d uri n g C P B. Res ults s h o we d si g nifica nt re d ucti o ns i n m ulti ple meas ures of 
p ost o perati ve blee di n g wit h t he  i ntra-o perati ve u se of C yt o S or b ®  t hat i ncl u de d bl o o d pr o d ucts 
tra nsf use d, 2 4- hr c hest t u be drai na ge v ol u me, rate of s ur gical re-e x pl orati o n, le n gt h of I C U a n d t otal 
h os pital sta y.  [1 2 ] I m p orta ntl y, no de vice- relate d a d verse e ve nts ( A Es), u na ntici pate d a d verse de vice 
e ve nts ( U A D Es) or de vice malf u ncti o ns were re p orte d . 
A case re p ort p u blis he d i n 2 0 2 0 descri b e d t he use of t he C yt oS or b  de vice i n a n 8 3- year - ol d fe male 
o n a pi x a b a n  u n der g oi n g e mer ge nt re d o mitral val ve re place me nt at La ussa nee U ni versit y H os pital i n 
S witzerla n d . [1 3 ] T he patie nt’s last d ose of a pi xa ba n was 7 h o urs pri or t o s ur ger y, a n d t otal C P B 
d urati o n was 1 0 0 mi n utes . A pi xa ba n-s pecific a nti-fact or Xa le vels were m o nit ore d pre-a n d p ost -
treat me nt. At t he ti me of C P B i nitiati o n, t he a nti-fact or Xa le vel was 1 1 4 n g/ m L a n d dr o p pe d t o 3 2 
n g/ m L after wea ni n g off C P B. T he patie nt s uffere d n o p ost o perati ve blee di n g c o m plicati o ns or 
de vice- relate d a d verse e ve nts.  
1. 4.  
De vice B ac k gr o u n d a n d N o me ncl at ure 
Dr u g S or b -A T R  utilizes t he sa me tec h n ol o g y as  t he C yt o S or b®  de vice  disc usse d i n t he a b o ve 
precli nical a n d cli nical data.  T he na me Dr u g S or b -A T R  was rece ntl y  i m ple me nte d t o better  ali g n 
wit h i nte n de d use . As s uc h, f or t he p ur p oses of t his st u d y, t he de vice will hereafter be referre d t o as 

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DrugSorb-ATR whenever reference is being made to its use in the indication of antithrombotic drug 
removal. 
1.5. 
Study Design 
The STAR-D study is designed to demonstrate reductions in surgical and early post-surgical bleeding 
with the intraoperative use of DrugSorb-ATR in patients undergoing cardiothoracic surgery ≤36hrs 
after last apixaban or rivaroxaban dose. These patients have been demonstrated in the literature to be 
at risk for significant bleeding complications (as previously discussed in Section 1.1). The study also 
aims to establish the safety of intraoperative DrugSorb-ATR use in the target population.  
 
The mechanism of action, approved indications for use, and expert guideline recommendations for 
perioperative management of apixaban and rivaroxaban (with a recommended washout of at least 48 
hours) are effectively the same. [1, 2, 6] Accordingly, it is assumed within our study that subjects 
using either one of these DOACs will have the same bleeding risk and experience the same treatment 
effect from DrugSorb-ATR. Indeed, a real-world registry of perioperative DOAC management found 
no differences in the bleeding risk associated with either apixaban or rivaroxaban [31] and a 
pharmacokinetic study by Kruetz et. al. demonstrated similar plasma drug concentrations of both 
drugs beginning at ~24hrs after last dose. [32] Given the anticipated equivalency in our study for both 
drug removal and clinical outcomes between the apixaban and rivaroxaban subjects, they will be 
evaluated as a combined population when assessing  treatment effect for the DrugSorb-ATR 
(investigational) arm as compared to SOC (control) arm. Drug removal, as assessed by serial 
intraoperative serum level measurements, will be evaluated individually for apixaban and 
rivaroxaban. DOAC drugs other than apixaban or rivaroxaban will not be specifically addressed or 
studied here, due to the infrequency of their use in the U.S population. 
 
The mechanism of action for the investigational device is removal of apixaban and/or rivaroxaban 
from active circulation through hemoadsorption while the patient is on cardiopulmonary bypass. 
Thus, change in total blood concentration of apixaban and rivaroxaban following CPB will be 
measured as key secondary endpoints. To do so, patient blood samples will be obtained during the 
pre-operative, operative, and immediate post-CPB time periods for drug concentration testing. 
Sampling every 30 ± 15min for quantification of serial changes in blood DOAC levels will be 
performed through the first 2 hours of therapy on CPB. The subsequent drug removal curve will be 
analyzed as an exploratory endpoint for each drug. Additional outcome measures to be evaluated 
include those that are documented as part of routine care and are detailed in Section 4.3.  
 
A planned interim analysis will allow for early stopping for overwhelming efficacy according to pre-
specified boundaries. Details are provided in Section 11.4. 
2. DRUGSORB -ATR DESCRIPTION AND INTENDED USE 
2.1. 
Description of the DrugSorb-ATR Device and Principle of Operation 
(Note:  This information is identical to the information provided in approved IDE G210081, and 
Breakthrough Device Designations Q200526 and Q211323.) 
DrugSorb-ATR is a sorbent-filled hemoperfusion cartridge (Figure 3). The cartridge consists of a 
cylinder and end-cap assembly filled with biocompatible porous polymer beads. At either end of the 
cylinder, a fine mesh screen is placed to retain the polymer beads within the device. Each endcap has 
a standard blood tubing connector, which is compatible with standard CPB blood tubing lines. 
The polymer beads are composed of a divinylbenzene/polyvinyl pyrrolidone co-polymer, where each 
bead has hundreds of thousands of tightly controlled pores and channels that are generated via 

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suspension polymerization. These pores and channels, in turn, enable the porous polymer beads to 
remove middle molecular weight substances between ~5-kDa - 60-kDa, based on pore capture (size) 
and surface adsorption. 
Figure 3. DrugSorb-ATR  
 
The polymer in the DrugSorb-ATR hemoadsorption cartridge is effective at binding small molecules 
with the molecular moieties contained in apixaban and rivaroxaban. These molecules easily pass into 
the pores of the polymer where it adsorbs onto the internal polymer surface. This surface adsorption is 
governed by the hydrophobic nature of the polymer, through a combination of non-polar interactions, 
hydrogen bonding, and Van der Waals forces. These drug-polymer interactions favor removal of 
hydrophobic molecules over hydrophilic ones.  
DrugSorb-ATR is designed for use in extracorporeal circuits. For this investigation, the DrugSorb-
ATR hemoadsorption cartridge will be incorporated as a shunt in the standard CPB circuit (Figure 4), 
in accordance with the device Instructions For Use (IFU). In standard subjects, flow rates through the 
DrugSorb-ATR cartridge should be maintained at 500 ± 100mL/min. In subjects on hypothermic 
circulatory arrest (HCA) where CPB flow rates are diminished, flow through the device should be 
maintained ≥100mL/min.  In accordance with the IFU, maximum blood flow through the DrugSorb-
ATR device should not exceed 700mL/min at any point during the procedure. Blood flow is 
controlled via an adjustable roller clamp distal to the cartridge and is monitored through ultrasonic 
flow detection (provided by Sponsor) to maintain a target blood flow consistent with protocol 
recommendations. 
For this investigation the duration of device exposure will be limited to the duration of CPB since the 
use of DrugSorb-ATR will be initiated at the start of CPB and terminated at the end of CPB.  
Treatment is continuous and is expected to be of a shorter duration than the maximum treatment time 
provided in the IFU.  Exceptions to continuous treatment could occur in the event of a device quality 
complaint (i.e., device deficiency/observation) in which case the treatment (and therefore the flow 
through the device) may be terminated before the end of CPB.     
The intraoperative use of anticoagulants (e.g., heparin) in this investigation will be per the standard 
procedures of each clinical institution and in accordance with the IFU. 

Cli nical I n vesti gati o n Pla n ( CI P)  
C O N FI D E N TI A L  
 
 CI P  Refere nce  N u m ber: 2 0 2 1- 0 2 
Versi o n 2. 1 
S T A R -D  
Pa ge 2 5 of 7 7 
  
 
Fi g ure 4. Dr u g S or b -A T R I nte gr ati o n i n t he C ar di o p ul m o n ar y B y p ass Circ uit 
2. 2.  
Tre at me nt M ateri als  
I n a d diti o n t o t he Dr u g S or b- A T R  he m oa ds or pti o n cartri d ge, t he f oll o wi n g c o m p o ne nts will be 
pr o vi de d b y t he S p o ns or: 
•  
Dis p osa ble c o n nect or a n d t u bi n g sets t o c o n nect t he i n vesti gati o nal de vice t o t he C P B circ uit  
•  
Sta n dar d r oller cla m p  
•  
Dis p osa ble he m ostats 
•  
I F U of t he de vice 
•  
Trai ni n g fr o m a Fiel d Cli nical S pecialist  ( F C S) t o pr o vi de g ui da nce o n i nc or p orati n g a n d 
usi n g t he de vice wit hi n a C P B circ uit  
•  
A Tra ns o nic  ( or e q ui vale nt) fl o w detect or 
2. 3.  
De vice Acc o u nt a bilit y  
T he pr oce d ures f or t he acc o u nta bilit y of i n vesti gati o nal de vices s h o ul d f oll o w t he s pecificati o ns 
bel o w: 
•  
Access t o i n vesti gati o nal de vices s hall be c o ntr olle d a n d t he i n vesti gati o nal de vices s hall be 
use d o nl y i n t he cli nical i n vesti gati o n a n d acc or di n g t o t he Cli nical I n vesti gati o n Pla n ( CI P). 
•  
T he S p o ns or or its desi g nees s hall kee p rec or ds t o d oc u me nt t he p h ysical l ocati o n of all 
i n vesti gati o nal de vices fr o m s hi p me nt of i n vesti gati o nal de vices t o t he i n vesti gati o n sites, use 
of t he i n vesti gati o nal de vices, a n d eit her ret ur n or dis p osal.  
•  
T he Pri nci pal I n vesti gat or or a n a ut h orize d desi g nee s hall kee p rec or ds d oc u me nti n g t he 
recei pt, use, ret ur n, a n d dis p osal of t he i n vesti gati o nal de vices, w hic h s hall i ncl u de: 
o  t he date of recei pt 
o  i de ntificati o n of eac h i n vesti gati o nal de vice (l ot n u m ber a n d serial n u m ber) 
o  t he e x pir y date, if a p plica ble 
o  t he date or dates of use 

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o patient identification 
o the date of return of unused, expired, or malfunctioning investigational devices, if 
applicable 
2.4. 
Use of the Investigational Device 
The proposed investigative use of DrugSorb-ATR is for the removal of the DOACs apixaban and 
rivaroxaban, as an adjunct to the standard of care in subjects undergoing cardiothoracic surgery 
requiring CPB within 36 hours of receiving these medications. DrugSorb-ATR will only be used for 
this purpose as specified by this clinical protocol.  
2.5. 
Investigational Device/Procedures Training 
DrugSorb-ATR is easily integrated in a standard CPB circuit. In this study, one DrugSorb-ATR 
cartridge will be placed in a bypass circuit connected between the oxygenator and cardiotomy 
reservoir as shown in Figure 4, and separate from the main blood flow to the subject. Blood flow 
through this circuit is controlled via an adjustable roller clamp distal to the cartridges and monitored 
via ultrasonic flow detection to maintain flow. 
The target flow rate through the device is to be 500 ± 100 mL/minute (approximately 15% to 20% of 
a typical flow rate in CPB). In patients on hypothermic circulatory arrest (HCA) where the clinical 
needs during CPB do not always allow the flow rate through the device to be maintained at 500 ± 100 
mL/min, the flow rate through the device may range from 100 to 700 mL/min in accordance with the 
minimum/maximum parameters stated in the device IFU.  
The circuit containing the DrugSorb-ATR cartridge will be connected prior to the start of the 
procedure. Blood flow through the DrugSorb-ATR cartridge will commence when the subject goes on 
CPB. Use of DrugSorb-ATR will stop at the end of CPB. At this time the entire circuit containing the 
device is flushed with saline or drained by gravity, which is consistent practice with all CPB circuits. 
The blood in the circuit is delivered back to the subject, per the hospital protocol.  
DrugSorb-ATR training for the device users involved in this study will occur prior to any DrugSorb-
ATR use and will be documented in a training log. 
3. STUDY JUSTIFICATION 
As discussed previously, apixaban and rivaroxaban have the same mechanism of action, the same 
indications for use, and are the most widely utilized DOACs in the U.S market. [1] [2] [19] As with 
any anticoagulant, patients undergoing surgical intervention in the setting of DOAC use carries a risk 
of bleeding. [33] Currently, there are no approved agents to either prevent or treat bleeding related to 
DOAC-induced coagulopathy in the surgical setting. Existing strategies for management of surgical 
patients on apixaban and rivaroxaban have prioritized preoperative drug washout wherever possible 
and use of non-specific pro-hemostatic agents with supportive strategies (blood product transfusions) 
when bleeding cannot be avoided. [25] 
 
While recommendations for perioperative anticoagulant management in patients on Warfarin is 
supported by significant clinical experience, and determinants of perioperative outcomes in these 
patients are well-described in the literature, similarly robust data is lacking for the DOACs. [20] In the 
published literature, recommendations for perioperative management of patients on DOACs are based 
on drug half-life, renal function, and presumed bleeding risk of the planned procedure. [22] As 
discussed above, standard recommendations for DOAC washout prior to elective, high bleeding risk 
surgeries is ≥48hrs, but prolonged washout is recommended for patients with significantly impaired 
renal function. [6] [34] However, patients with emergent or urgent cardiovascular conditions 

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(including but not limited to acute ascending aortic dissection, left main or multi-vessel coronary 
disease not amenable to PCI, or complications of PCI) cannot always wait for this washout period, 
and may require surgery to avoid risking permanent injury, disability, or death. 
 
Integration of a DrugSorb-ATR cartridge into the CPB circuit provides an option for clinicians to 
accelerate wash-out via active drug removal. In the previously discussed case report by Mendes et. al., 
when the authors extrapolated expected apixaban concentration based on half-life, they found that 
post- CytoSorb+CPB levels of anti-factor Xa were 39-44% lower than would be anticipated from 
normal washout over the same period (range reflects expectations for normal vs. reduced renal 
function). [13]  It is hypothesized that this accelerated removal of circulating DOAC will translate to 
significant reductions in surgical and post-surgical bleeding. This effect is most meaningful in those 
patients undergoing cardiac surgery ≤36 hours after their last DOAC dose, as these patients are at 
greatest risk of major bleeding complications due to high residual drug levels. Pre-clinical data 
demonstrate nearly identical drug removal rates for apixaban and rivaroxaban with DrugSorb-ATR. 
Based on the same mechanism of action, similar bleeding risks, and benchtop data suggesting 
consistent removal efficiency for both drugs, clinical treatment effect is also anticipated to be nearly 
identical. Accordingly, the trial will evaluate both drugs as a combined population for the primary 
effectiveness endpoint. The evaluable study population is planned to be similarly distributed with 
respect to apixaban and rivaroxaban, and monitoring will be employed throughout the study to ensure 
that each drug will contribute at least 40% of the study population at the time of final analysis. 
 
Primary Effectiveness Endpoint: The composite primary endpoint of the trial was specifically 
constructed to assess the ability of DrugSorb-ATR to impact the full spectrum of surgical and early 
post-surgical bleeding. The primary effectiveness endpoint will be evaluated using the Win Ratio 
method of analysis for a hierarchical composite endpoint based on the Finkelstein-Schoenfeld test 
(Finkelstein and Schoenfeld, 1999; Pocock, et al., 2012) with three components ranked according to 
clinical importance. [14] [15] The three components are: a) fatal bleeding occurring within 48hrs 
post-index operation, b) moderate, severe, or massive bleeding events based on the Universal 
Definition of Perioperative Bleeding in Cardiac Surgery (UDPB) ≥2 classification, and c) 24-hour 
chest tube drainage (mL).  
 
The fatal bleeding events within the primary effectiveness endpoint are limited to the 48-hour 
postoperative window to include only those events likely to be modifiable by the intervention. Timing 
of re-initiation for therapeutic anticoagulation will be at the discretion of the treating physician, based 
on his/her assessment of continued bleeding risk vs. thrombotic risk (Section 9.1.3). Given that there 
is reasonable likelihood for resumption of anticoagulation as early as postoperative day two, there is 
high probability that fatal bleeding occurring >48 hours post-op would be independent of DrugSorb-
ATR effectiveness.  
 
The UDPB scale is a standardized bleeding definition that was specifically designed by experts to 
capture early bleeding after cardiac surgery and is based on the following 9 criteria occurring either in 
surgery or during the first postoperative day: (1) delayed sternal closure, (2) postoperative chest tube 
output, (3) packed red blood cell transfusion, (4) fresh frozen plasma transfusion, (5) platelet 
transfusion, (6) cryoprecipitate transfusion, (7) use of factor concentrates, (8) use of recombinant 
activated factor VII (rFVIIa), and (9) surgical re-exploration. [35] The UDPB scale defines 5 
perioperative bleeding classes (0-4) as shown in Table 1 (below). Importantly, it has been 
demonstrated that higher classification within the UDPB is associated with significantly worse 
immediate and late outcomes, including both in-hospital and 30-day mortality rates. [35] [36]

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Table 1. Bleeding Class According to the Universal Definition of Perioperative Bleeding in Adult 
Cardiac Surgery 
Class 
Sternal 
closure 
delayed 
Postoperative 
chest tube 
blood loss 
within 12 h 
(mL) 
PRBC 
(units) 
FFP 
(units) 
PLT 
(units) 
Cryoppt 
PCCs 
rFVIIa 
Reexploration/ 
tamponade 
0 
(Insignificant) 
No 
< 600 
0* 
0 
0 
No 
No 
No 
No 
1 
(Mild) 
No 
601-800 
1 
0 
0 
No 
No 
No 
No 
2 
(Moderate) 
No 
801-1000 
2-4 
2-4 
Yes 
Yes 
Yes 
No 
No 
3 
(Severe) 
Yes 
1001-2000 
5-10 
5-10 
N/A 
N/A 
N/A 
No 
Yes 
4 
(Massive) 
N/A 
>2000 
>10 
>10 
N/A 
N/A 
N/A 
Yes 
N/A 
PRBC = packed red blood cells; FFP = fresh frozen plasma; PLT = platelet concentrates; Cryoppt = Cryoprecipitate; PCCs = prothrombin 
complex concentrates; rFVIIa = recombinant activated factor VIIa; N/A, not applicable 
For purposes of UDPB, PRBC, PLT, FFP, and Cryoppt transfusions are counted beginning at chest closure. PCC and rFVIIa transfusions are 
counted beginning at the start of the procedure. 
* Correction of preoperative anemia or hemodilution only; the number of PRBCs used should only be considered in the UDPB when 
accompanied by other signs of perioperative bleeding. Prophylactic/preoperative transfusion of blood products and factor concentrates do not 
contribute to UDPB. 
 
Exact measurement of postoperative blood loss is difficult, given that laboratory values such as 
hemoglobin and hematocrit are heavily influenced by intra- and postoperative fluid shifts, and 
transfusion protocols may vary by institution. However, chest tube drainage (CTD) in the early 
postoperative period (≤24 hours) is a metric that is easily quantifiable and routinely used in clinical 
practice. Enhanced Recovery After Surgery (ERAS) guidelines in cardiac surgery recommend chest 
tube placement and drainage to prevent accumulation of blood in the chest and mediastinum during 
the postoperative period, and their placement is standard of care following open cardiac surgery. [37]  
 
The inclusion of CTD in the composite primary effectiveness endpoint is underscored by its clinical 
relevance evidenced by the use of CTD in everyday clinical practice protocols for postoperative 
decision-making (e.g., criteria for surgical re-exploration) that rely on rate and volume of chest tube 
drainage. [38] While postoperative CTD volume during the first 12 hours is already included within 
the UDPB classification, volume of 24-hr CTD has been identified as an important independent 
metric. The 24-hr CTD volume has been demonstrated to correlate with other important clinical 
outcomes, including transfusion requirements and duration of hospital stay in linear regression 
models. [39, 40] Excessive 24-hr CTD as defined by >1000mL has been shown to be an independent 
predictor of postoperative acute kidney injury (odds ratio 1.40, p < 0.001). [41] Most importantly, 24-
hr CTD is an independent predictor of in-hospital mortality with a linear, dose-dependent relationship 
that is independent of blood transfusion requirement. [23]  
 
Key Secondary Endpoints: Evaluation of the change in preoperative to postoperative apixaban and 
rivaroxaban drug concentrations will be the key secondary endpoints. These drug removal endpoints 
will quantify the extent of DrugSorb-ATR’s apixaban and rivaroxaban removal capabilities, while 
also providing a mechanistic relationship to the improved surgical and post-surgical bleeding 
outcomes (i.e., less drug = less bleeding).  
 
Pre-randomization stratification based on a) type of DOAC (either apixaban or rivaroxaban), b) study 
site, and c) planned operation will address potential confounding effects that may not be fully 
controlled in the randomization process. Stratification by DOAC type is intended to control for any 

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unanticipated differences between apixaban and rivaroxaban. Stratification by site is intended to 
control for institutional differences in standard practices, such as transfusion and re-operation 
protocols. Stratification by the type of planned operation will separate subjects undergoing CABG-
alone from those undergoing all other cardiothoracic surgeries. The category of “all other” cardiac 
surgeries include combination cases (e.g., CABG + valve, double valve, etc.) and ascending aortic 
interventions. Compared to CABG-alone, these operations have a significantly different profile 
regarding bleeding risk and procedure/CPB duration. This distinction is important since device 
exposure is directly related to the amount of time spent on CPB. Details of the statistical 
considerations around the endpoints discussed above will be provided in Section 11.  
 
In summary, the objective of this randomized, double-blind investigation is to examine the ability of 
DrugSorb-ATR (a non-pyrogenic, sterile, single-use device designed to remove the small hydrophobic 
drugs, apixaban and rivaroxaban) to reduce surgical and post-surgical bleeding compared to current 
standard of care. Measurements of drug removal will be performed to correlate the clinical outcomes 
(i.e., reductions in bleeding) to reductions in circulating apixaban and rivaroxaban levels. The safety 
of the device in this setting will be assessed by systematic capture of all AEs at CGP level. 
4. INVESTIGATIONAL PLAN 
4.1. 
Study Objective(s)  
Patients undergoing cardiothoracic surgery ≤36hrs after last apixaban or rivaroxaban dose are at 
increased risk of bleeding due to the anticoagulant effect of these medications. The DrugSorb-ATR 
hemoadsorption cartridge removes circulating apixaban and rivaroxaban at rates much higher than 
normal washout, thus reversing anticoagulation, improving hemostasis, and reducing surgical and 
early post-surgical blood loss.  
The objectives of this study are as follows: 
• 
To demonstrate reductions in surgical and early post-surgical bleeding with the intraoperative 
use of DrugSorb-ATR in patients undergoing cardiothoracic surgery with CPB ≤36hrs after 
last apixaban or rivaroxaban dose; 
• 
To demonstrate reductions in circulating apixaban or rivaroxaban blood levels (∆[DOAC]) 
with the intraoperative use of DrugSorb-ATR; 
• 
To establish the safety of the intraoperative use of DrugSorb-ATR in the intended population. 
The hypothesis is that, for patients undergoing cardiothoracic surgery with CPB ≤36hrs after last 
apixaban or rivaroxaban dose, the intraoperative use of DrugSorb-ATR will significantly reduce 
surgical and early post-surgical bleeding as measured by a ranked composite endpoint of clinically 
meaningful bleeding metrics: 1) fatal bleeding occurring within 48hrs post operation, 2) moderate, 
severe, or massive bleeding events based on the Universal Definition of Perioperative Bleeding in 
Cardiac Surgery (UDPB) ≥2 classification, and 3) 24-hour chest tube drainage (CTD).  
4.2. 
Study Design  
This will be a prospective, multi-center, randomized, double-blind clinical study. Subjects will be 
randomized in a 1:1 ratio to either standard of care (SOC) or standard of care plus intraoperative 
treatment with DrugSorb-ATR. 
4.3. 
Study Outcomes 
4.3.1. 
Primary Effectiveness Endpoint:  

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• 
Ranked composite of surgical and early post-surgical bleeding events:  
1) Fatal bleeding events occurring within 48hrs post-index procedure,  
2) UDPB ≥2 perioperative bleeding, and 
3) 24-hour chest tube drainage volume (mL).  
Refer to Table 1 for details of the UDPB classification of bleeding events. 
4.3.2. 
Key Secondary Effectiveness Endpoints: 
• 
Percent change in pre-CPB vs. post-CPB blood apixaban levels as measured by liquid 
chromatography/tandem mass spectrometry (i.e., ∆[Apixaban]).  
• 
Percent change in pre-CPB vs. post-CPB blood rivaroxaban levels as measured by liquid 
chromatography/tandem mass spectrometry (i.e., ∆[Rivaroxaban]) 
4.3.3. 
Additional Secondary Effectiveness Endpoints:  
• 
24-hour chest tube drainage volume 
• 
Total platelet transfusions during the index hospitalization (volume and units) 
• 
Total PRBC transfusions during the index hospitalization (volume and units) 
• 
Total UDPB events (by class) 
• 
All surgical re-exploration for excessive bleeding 
• 
Total fatal perioperative bleeding events 
4.3.4. 
Exploratory Endpoint(s):  
• 
Area under the concentration time curve (AUC), for intraoperative apixaban or 
rivaroxaban pharmacokinetic (PK) concentration  
• 
Operative time (measured from start of skin incision to completion of chest closure) 
• 
Duration of ICU stay 
• 
Duration of hospital stay 
• 
30-day hospital readmissions 
4.3.5. 
Primary Safety Endpoint: 
• 
The primary safety endpoint of this trial is to evaluate the product safety profile through the 
GCP-level assessment of AEs during the study period. 
4.3.6. 
Additional Safety Endpoints: 
• 
30-day cardiac mortality 
• 
30-day all-cause mortality 
• 
Postoperative stroke during the index hospitalization 
• 
Postoperative myocardial infarction (MI) during the index hospitalization 
• 
Urgent postoperative coronary revascularization during the index hospitalization 
• 
Postoperative venous thromboembolic events (VTE) during the index hospitalization 
• 
Serious device-related adverse events 
4.4. 
Subjects and Selection of Study Population 
Subjects must meet all inclusion criteria to be eligible to participate in the study.  Subjects meeting 
any of the exclusion criteria are not eligible to participate in the study. 

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4.4.1. 
Inclusion Criteria: 
1. Males and females aged ≥18 
2. Written full informed consent 
3. Undergoing cardiothoracic surgery with CPB ≤36 hours following last dose of apixaban or 
rivaroxaban.  
Only patients taking apixaban or rivaroxaban for one of the following indications are eligible for 
enrollment: a) reduction of stroke/systemic embolism in nonvalvular atrial fibrillation, or b) initial 
or extended treatment of venous thromboembolism (VTE), which includes deep vein thrombosis 
(DVT) and/or pulmonary embolism (PE).  
4.4.2. 
Exclusion Criteria: 
1. Cardiothoracic surgery >48 hours after last known dose of apixaban or rivaroxaban 
2. Patients on low dose apixaban or rivaroxaban for prophylactic indications (e.g., DVT 
prophylaxis after hip/knee replacement surgery, or risk reduction of major CV events in 
patients with CAD/PAD) 
3. Heart-lung transplant procedures 
4. Procedures for ventricular assist device (i.e., implant or revision of LVAD or RVAD) 
5. Any of the below conditions that pose a known risk for increased bleeding: 
a. Heparin induced thrombocytopenia 
b. Preoperative platelet count < 50,000 / µL 
c. Hemophilia 
d. INR  ≥ 1.8  
6. Prohibited concomitant antithrombotic medications (reference Appendix 5) 
7. Acute sickle cell crisis 
8. Known allergy to any of the device components 
9. Subjects with active (untreated) systemic infection 
10. Subjects with a history of major organ transplantation and those currently receiving 
immunosuppressive medication (corticosteroids excluded) or who are profoundly immune 
suppressed 
11. Women of childbearing potential with a positive pregnancy test performed during the current 
admission or who are breast-feeding 
12. Subjects with life expectancy of <30 days (not inclusive of the critical condition that is 
requiring the cardiac operation under study for which there is a reasonable expectation that 
cardiac surgery with the device may prolong life for more than 30 days) 
13. Inability to comply with the requirements of the study protocol 
14. Treatment with an investigational drug or device within 30 days prior to surgery 
15. Subjects with previous enrollment in this trial 
4.4.3. 
Informed Consent & Enrollment Procedures:  
Informed consent shall be obtained in writing from the subject, or their legally authorized 
representative and the process shall be documented before any procedure specific to the clinical 

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investigation is applied to the subject; additional details are provided in Appendix 3. If during the 
course of the study assessments, a subject is found not to be eligible for inclusion in the study, the 
subject or their representative should be notified and the reason for ineligibility documented on the 
screening log/form. 
The general process for obtaining informed consent shall: 
• 
Ensure that the principal investigator or his/her authorized designee conducts the 
informed consent process 
• 
Include all aspects of the clinical investigation that are relevant to the subject’s decision 
to participate throughout the clinical investigation 
• 
Avoid any coercion or undue improper influence on, or inducement of, the subject to 
participate 
• 
Not waive or appear to waive the subject’s legal rights 
• 
Use native non-technical language that is understandable to the subject 
• 
Provide ample time for the subject to read and understand the Informed Consent Form 
(ICF) and to consider participation in the clinical investigation 
• 
Include personally dated signatures of the subject and the principal investigator or an 
authorized designee responsible for conducting the informed consent process; 
• 
Provide the subject with a copy of the signed and dated ICF and any other written 
information 
• 
Ensure important new information is provided to new and existing subjects throughout 
the clinical investigation 
4.4.4. 
Subject Withdrawal/Discontinuation: 
Investigation subjects may withdraw voluntarily from the research investigation for any reason and at 
any time during the course of the investigation. Subjects may also be discontinued from the 
investigation for the following medical or administrative reasons: 
• 
At the request of the Investigator, if he/she feels that the subject can no longer fully comply 
with the requirements of the study or if any of the study procedures would not be in the best 
interest of the subject. 
• 
Termination of the study by the Sponsor. 
• 
Non-compliance with CIP procedures. 
• 
The subject is lost to follow-up. A subject will be considered “lost to follow-up” when all the 
following criteria are met: 
o Failure to complete the 30-day follow-up visit or follow-up telephone call without 
due cause; and  
o Documentation of three unsuccessful attempts to contact the subject via telephone 
and/or by certified mail.  
If a subject is withdrawn from treatment, the Sponsor will be notified and the date and reason(s) for 
the withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). For subjects 
who withdraw assent/consent and those withdrawn at the request of the Investigator, details of the 
reason for withdrawal will be captured to the extent possible. If a subject is withdrawn, efforts will be 
made to perform all follow-up assessments, if possible. Other procedures may be performed at the 
Investigator’s (or designee’s) and/or Sponsor’s discretion. The Investigator (or designee) may also 
request that the subject return for an additional Follow-up Visit. All withdrawn subjects will be 
followed until resolution of all their AEs or until the unresolved AEs are judged by the Investigator 
(or designee) to have stabilized. 

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Subjects who are withdrawn for reasons not related to investigation treatment may be replaced 
following discussion between the Investigator and the Sponsor. For subjects who withdraw or 
discontinue at any point prior to completion of the required follow-up period, all available data will be 
used in the analysis, following the intent-to-treat principle. In cases where analysis criteria are not 
met, for example for the Per Protocol population, such subjects may not be included in the analysis. 
Subjects withdrawing or discontinuing early will be summarized as described in Section 11.8, and 
will be flagged in a listing of disposition information that includes reason for early 
withdrawal/discontinuation. 
 
5. POTENTIAL RISK/BENEFIT 
5.1. 
Potential Investigational Device Risks  
DrugSorb-ATR is a hemoadsorption cartridge that is incorporated into an extracorporeal CPB circuit. 
For the study described in this protocol, use of DrugSorb-ATR will be limited to the duration of CPB. 
The risk profile associated with DrugSorb-ATR is expected to be consistent with other extracorporeal 
treatments currently in clinical use. Potential risks associated with the use of the device are described 
below. 
Risks Specific to DrugSorb-ATR: 
• 
Removal of therapeutic drugs <60kDa in size, that contain hydrophobic or aromatic moieties. 
• 
Removal of endogenous, non-pathogenic, physiologic substances from the blood: A risk of 
removal of substances ≥900Da – 60kDa in size; this risk is greater the longer DrugSorb-ATR 
hemoperfusion is performed on a subject. 
• 
Hemolysis (if maximum recommended flow rate per the IFU is exceeded). 
• 
Allergic response to device materials. 
• 
Device leakage. 
• 
Death. 
 
Risks commonly associated with extracorporeal therapies themselves will not be detailed here, 
however such risks would also apply to the DrugSorb-ATR device, given its incorporation into these 
circuits. 
5.2. 
Potential Benefits 
The observed and potential benefits of using DrugSorb-ATR intra-operatively during cardiothoracic 
surgery to remove apixaban and rivaroxaban include: 
• 
Decrease in surgical and post-surgical bleeding complications, including: 
• 
Decrease in intra-operative blood loss 
• 
Decrease in post-operative blood loss, including that measured in chest/mediastinal 
drains 
• 
Decrease in blood product transfusions 
• 
Reduced risk of re-operation for bleeding 
• 
Reduced risk of fatal bleeding 
• 
Improvement in hemodynamic stability and reduction in vasopressor requirements, as a result 
of decreased bleeding 
5.3. 
Risk Mitigation 
Mechanical and performance concerns have been reduced by extensive human, animal, and bench 

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testing. The device materials have been shown to be biocompatible and acceptable for human use 
through ISO10993 testing and prior human clinical studies of the device for removal of beta-2 
microglobulin in subjects with end stage renal disease and removal of cytokines in the treatment of 
sepsis. The DrugSorb-ATR cartridge has CE Mark approval under the name of CytoSorb® for 
removal of ticagrelor and/or rivaroxaban in subjects undergoing emergent cardiothoracic surgery with 
CPB and is believed to pose minimal additional risks compared to standard CPB circuits without 
DrugSorb-ATR. Those risks and their mitigation strategies are presented in Table 2 below. 
 
DrugSorb-ATR does not remove heparin or citrate, and therefore does not impact heparin- or citrate-
mediated anticoagulation during CPB. Adherence to protocol will be stressed by CytoSorbents’ 
personnel during in-service training. All subjects will be monitored per routine standard of care. 
Additionally, the Data and Safety Monitoring Board (DSMB) will be reviewing safety information on 
an ongoing basis, thus providing an additional level of risk mitigation. 
 
Table 2. Risks and Mitigation Strategies 
Potential Device/Intervention Risk 
Action for Risk Mitigation  
Risk of coagulation within the device or the 
CPB circuit, and associated thromboembolic 
events (e.g., stroke, peripheral embolus, etc.) 
Visual inspection for signs of coagulation within the device 
or the circuit during CPB on a regular basis.  
 
Constant supervision during the CPB procedure. 
Removal of drugs (such as antibiotics) and 
hormones 
If a drug(s) is known to have high likelihood of removal by 
DrugSorb-ATR, and a selective test is available for that 
drug(s), the treating physician is recommended to check the 
concentration of applied drugs following CPB and adapt the 
dosages accordingly. 
 
This theoretical risk is greater, the longer DrugSorb-ATR 
hemoperfusion is performed on a subject. Therefore, it 
would be anticipated that this risk would be acceptable 
when device exposure is limited to the brief intraoperative 
period with CPB. 
Allergic/ anaphylactic response to device 
materials 
Subjects with known allergies against device materials 
(including but not limited to polystyrene/divinylbenzene, 
polycarbonate, polypropylene, silicone, and polyester) will 
be excluded from the study. 
 
If applicable, in subjects manifesting unexpected signs of 
allergic reaction during therapy with DrugSorb-ATR, the 
exposure will be discontinued immediately. In addition, 
aggressive first-line therapy shall be applied to control the 
allergic or anaphylactic reaction. 
Risks related to blood composition: 
• 
Reduction in platelet count 
• 
Reduction in white blood cell count 
• 
Reduction in proteins (albumin or 
total protein) 
• 
Hemolysis 
Close monitoring of blood parameters prior, during, and 
after extracorporeal therapy according to the prescribed 
routine (reference the Schedule of Assessments in Table 6) 
 
Flow through the device will be monitored closely through-
out the procedure. The DrugSorb-ATR device maximum 
flow rate has been validated for hemolysis, and there are no 
independent risks associated with the maximum 
recommended flow rate of the DrugSorb-ATR device. 

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Impairment of device function (DrugSorb-
ATR and CPB) in combination with parenteral 
nutrition (most notably: lipid emulsions) 
In case of needed artificial nutrition, gastric application or 
other-than-parenteral application shall be preferred.  
 
In case of need for parenteral application of lipid-containing 
nutrition, it is recommended to postpone the application 
only after the procedure or to stop the application at least 
two hours prior to the CPB-procedure. 
Bleeding events due to necessary 
anticoagulation with CPB and DrugSorb-ATR 
use 
Constant supervision of coagulation parameters during the 
procedure, in accordance with standards of care. 
Infection 
DrugSorb-ATR is sterile and is delivered in sterile 
packaging. The packaging will be checked for possible 
damage before use. Products with visible defects will not be 
used and will be reported to the Sponsor. 
Blood loss  
Return of the blood sucked from the surgical field to the 
CPB circuit (i.e., Cell Saver) for reduction of blood loss. 
 
Constant supervision of the extracorporeal circuit for blood 
loss through-out the procedure. 
General complications within in context of 
extracorporeal therapies (including but not 
limited to): 
• 
Dyspnea 
• 
Hypoxia 
• 
Changes in body temperature  
• 
Muscle cramps 
• 
Headache 
• 
Nausea 
• 
Vomiting 
• 
Pruritus 
Constant supervision of the subject during and after the 
CPB-procedure. 
 
Designation of personnel duly trained in the use of 
extracorporeal therapies. 
Device or circuit leakage 
Visual inspection for signs of leakage within the device, or 
the circuit during the CPB-procedure on a regular basis. 
Unwanted penetration of air into the 
extracorporeal circuit, and risk of associated 
events such as pulmonary embolism and death 
due to pulmonary embolism 
Checking of connections, lines, and circuit components for 
integrity of the system, and use of appropriate precautions 
to avoid introduction of air into the system when 
incorporating the device into the circuit. The device will be 
setup in a standardized configuration under positive 
pressure; the volume will be returned to the reservoir pre-
pump and pre-oxygenator membrane, thus essentially 
eliminating risk for air introduction to the patient. 
 
Constant supervision of the subject during the CPB-
procedure. 

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6. STUDY TREATMENT 
All treatments will be provided by trained professionals. Use of DrugSorb-ATR will follow the 
Instructions For Use (IFU) under the guidance and/or training of a Field Clinical Specialist. 
6.1. 
Pre-randomization Stratification 
Pre-randomization stratification will be performed on three levels, based on the rationale described 
below:  
1. By preoperative DOAC type (either apixaban or rivaroxaban), to control for unanticipated 
differences between component drugs 
2. By study site, to control for differences in institutional protocols for bleeding and 
transfusion management. Institutions may also differ in metrics utilized for clinical 
decision-making (e.g., decision to delay sternal closure, or surgical reoperation). 
3. By the intended surgical procedure, to control for differing procedure-specific bleeding 
risks, and duration of CPB (i.e., device exposure) as detailed below: 
• 
CABG alone (irrespective of number of grafts); or 
 
• 
All other cardiothoracic procedures including but not limited to combination 
procedures (i.e., CABG + aortic/mitral valve procedures, double heart valve 
procedures, etc.), aortic interventions, and combination aortic + cardiac 
interventions. These surgeries generally require longer CPB time than CABG 
alone. 
 
Of note, during the pre-procedure and intraoperative periods, the intended procedure may change due 
to factors that could not be adequately anticipated in advance of the procedures. These day-of-surgery 
changes to the planned operations may result in the completion of a procedure that a) does not align 
with eligibility criteria, or b) alters stratification. Any change to the intended procedure occurring on 
the day of surgery that is not updated in the final IxRS assignment will be considered a protocol 
deviation. These protocol deviations will be noted in a deviation log for data analysis considerations 
at the conclusion of the trial. All subjects who have any of the above changes to their intended 
procedures should progress through the study as per the protocol. 
6.2. 
Subject Randomization 
All subjects will be prospectively randomized via an Interactive Voice/Web response (IxRS) system. 
Randomization must occur prior to the start of the cardiothoracic surgery procedure requiring CPB, 
but only after subject eligibility criteria is confirmed and written informed consent is provided by the 
subject or the subject’s legally authorized representative/designated proxy. Subjects will be randomly 
assigned in a one to one (1:1) ratio to either the control arm (SOC) or the investigation arm (SOC + 
DrugSorb-ATR).   
To ensure even distribution of subjects among the factors most likely to impact the primary and 
secondary outcomes, they will undergo pre-randomization stratification based on DOAC type, study 
site, and type of CT surgery. Neither the investigator nor the subjects will be told their assignment 
prior to surgery. See below (Section 6.3.1) for details of the randomization assignment. A copy of the 
randomization assignment will be maintained in a confidential file maintained by the Randomization 
and Unblinding Administrator. If the subject withdraws consent following randomization but prior to 
surgery, the reason for failure to treat according to randomization will be recorded in the subject’s 

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study records.  
To maintain the balance between sites in terms of numbers of subjects randomized, study sites will be 
capped at randomizing a maximum of 15% of the overall study sample (i.e., 18 subjects). Sites may 
be allowed to randomize beyond the cap on a case-by-case basis in consultation with the sponsor, 
considering overall study goals, randomization balances between sites, and prior quality of data 
collected by the site. For sites with a total enrollment consisting of only one type of the two eligible 
DOAC drugs, the randomization cap will be replaced by a maximum of 10% of the overall study 
sample (i.e., 12 subjects). In order to maintain the study-wise ratio of apixaban vs. rivaroxaban 
subjects within planned limits (a range of anywhere between 40% - 60% for each), the IxRS system 
will be used to limit enrollment accordingly. 
6.3. 
Blinding  
Blinding of the study subjects and site personnel (e.g., Surgeon, Anesthesiologist, operating room 
staff, study coordinator) to treatment assignment is implemented starting at the point of randomization 
and extending through the duration of the entire study. Accordingly, the blinding procedure will 
minimize any potential bias in both surgical and postoperative care decisions that may be introduced 
by knowledge of treatment assignment.  
 
Each site will assign an unblinded perfusionist to execute the necessary intraoperative study 
procedures. Extreme caution should be exercised by the perfusionist to prevent inadvertently 
revealing treatment assignment to individuals making clinical decisions on subject care.  
 
The unblinded perfusionist at the site will ensure the placement of a barrier that covers the 
device/sham set-up from view of the surgical staff. A Field Clinical Specialist, as designated by the 
Sponsor, may be present to assist with set up of the blind and provide guidance during the procedure. 
Details on the roles and responsibilities of the Sponsor FCS are provided in Section 6.4.   
 
6.3.1. Maintaining the Study Blind  
The following describes the measures being taken to maintain the study blind:  
a)  Subjects: Subjects will not be told their randomization assignment by any site study 
personnel involved in the trial and will receive the same care throughout the trial.  
b)  Randomization Assignment: Each site will randomize subjects using an Interactive 
Voice/Web response (IxRS) system. After the appropriate information is entered, an 
assignment is made (Standard of Care vs. Standard of Care + DrugSorb-ATR). This 
randomization process is performed by the unblinded team prior to the procedure.  
 
c)  Site Study Personnel: There are two designated teams at each site:  
1.   Blinded: These individuals remain blinded from the point of randomization 
through the duration of the study, inclusive of all subjects enrolled at the site. 
Responsibilities of blinded site personnel are detailed below. 
- 
Surgical team (including the surgeon, surgical assistant, circulating nurse, 
scrub tech, and other operating room staff); 
- 
Anesthesiologist and anesthesia team; 
- 
ICU staff; 
- 
Study coordinator. 

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2. Unblinded: These individuals will be aware of treatment assignment and will 
refrain from revealing it to any other study personnel for the duration of the 
study, inclusive of all subjects enrolled at the site. Additional responsibilities 
are detailed below. 
- 
Perfusionist(s); 
- 
Sponsor FCS. 
The Blinded Team is responsible for administering all pre-, intra- and post-procedure 
subject testing and care as designated by the protocol. The blinded site study 
coordinator(s) will be responsible for data entry into the EDC, including input of 
follow-up visit data into the relevant eCRF. The blinded study coordinator will also 
be responsible for ensuring required follow-up care/visits for all study subjects are 
scheduled; The Sponsor will work with each individual site to determine the 
documentation needed in the subjects’ medical records (e.g., procedure notes) to 
protect the study blind. 
The Unblinded Team is responsible for activities related to the procedure, including 
set-up of the device according to randomization assignment (sham or DrugSorb-
ATR), oversight of the device during the procedure, and recording the device study 
data (e.g., device lot number, start/stop time of flow through the device, device flow 
rates, and any device quality complaints) in the eCRFs and device accountability log. 
Other responsibilities include: 
1. Obtaining a randomization code from the electronic system prior to the index 
procedure, including day of procedure; 
2. Ensuring appropriate device cartridges are available and in the OR suite on 
procedure day;  
3. Providing necessary procedure information in a blinded fashion to the study 
coordinator for eCRF entry. 
  
6.3.2 
Study devices 
All study devices will be blinded by coverage with a sterile drape. For subjects randomized to 
DrugSorb-ATR, the unblinded perfusionist will monitor flow to ensure it stays within the 
protocol dictated range.  
Subjects randomized to standard of care without DrugSorb-ATR (i.e., control) will have a 
sham device in the operating room. The sham device is identical in appearance to an active 
DrugSorb-ATR cartridge. Sham devices are sealed, inactive, pre-assembled device sets 
containing liquid to mimic a primed, ready to use, device. They are permanently sealed and 
cannot be put online with the perfusion circuit. Sham devices are marked “Not for human 
use” and cannot be opened, and they will not support flow, as they are glued/sealed shut. 
These devices are clamped like the DrugSorb-ATR device, but line connections are not made 
to the CPB circuit. Once installed, the sham device is covered with a sterile drape, and tubing 
lines approximate the positioning of the real DrugSorb-ATR device.  
Assembly of the blind space may be required in advance should the OR personnel be in the 
workspace during set-up, to preserve knowledge of treatment allocation. The FCS and/or 
unblinded perfusionist ensures the blind is maintained prior to, throughout, and post-surgery. 
Of note, the sham device and blinding scheme discussed above is identical to the model used 

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in STAR-T, which is an ongoing IDE study already approved by the FDA.  
6.3.3 
Unblinding Procedure 
It is the intention of this study to unblind both the subject and the site study personnel at the 
completion of the overall study. This will occur after all necessary 30-day follow-up 
assessments are completed and all the data have been collected and verified for all subjects, 
and the clinical database has been “locked”, or write-protected from further changes. If the 
subject develops a condition within the 30-day follow-up window, the subject and team will 
be unblinded only if doing so is necessary to make informed decisions about clinical care, 
or in the possibility of an unanticipated adverse device effect (UADE). 
 
Any subject that is unblinded prematurely for any reason shall continue to be followed in 
accordance with the protocol evaluations outlined. A subject is NOT automatically considered 
to be withdrawn if unblinding occurs earlier than anticipated.  
 
If the site investigator believes there is reason to unblind either themselves or the subject (e.g., 
significant change in subject’s health status related to the possible use of the device), the site 
will contact the Sponsor to discuss the subject’s circumstances, at which time the Sponsor, if 
in agreement with the site’s request, may approve release of the blinding information by the 
unblinded Sponsor designee.   
6.4. 
Field Clinical Specialists 
Support by a Field Clinical Specialist (FCS), as designated by the Sponsor, may be offered to assist 
with set up of the blind and provide guidance during the procedure. In instances where the Sponsor-
designated FCS has previously observed set-up of the investigational device and has found the 
unblinded perfusionist(s) skilled and competent to manage study procedures, a waiver of FCS 
assistance may be granted. All such waivers of FCS assistance will be documented and retained in the 
study file.  
 
The FCS will observe and proctor the unblinded perfusionist as he or she assembles the DrugSorb-
ATR cartridge and peripheral FDA-approved components as specified in the IFU. The unblinded 
perfusionist is responsible for the final hookup to the hospital perfusion apparatus. The Sponsor FCS 
will be available through-out the procedure to provide additional support to the perfusionist as needed. 
This approach is consistent with site expectations for study support and will further ensure study 
subject safety in a novel device trial. In addition, the presence of the FCS will likely reduce variability 
in study related procedures and ensure their timely execution (i.e., serial blood sampling for drug 
levels). 
 
6.5. 
Device Quality Complaints: Deficiencies, Malfunctions, and Observations 
If there is a device deficiency, malfunction, or other observation with the DrugSorb-ATR device (i.e., 
device quality complaint) the Investigator (or designee) is required to complete the Device 
Deficiency/Observation eCRF and to notify the Sponsor immediately and indicate if the observation 
resulted in an adverse event and indicate if complications are related to the device, procedure, or 
underlying disease. If the device quality complaint is associated with an SAE, SADE, or UADE, the 
Investigator will be required to enter the adverse event within 24hrs of awareness, and this 
information will be transferred to the Contract Research Organization (CRO) and Sponsor through 
automated notification. 
In the event of any suspected device problem, the device shall be returned to the Sponsor for analysis. 

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Instructions for returning the investigational device are included in the Study Reference Manual. If the 
investigator cannot determine the cause of the event, it should be classified as unknown. 
7. STUDY OVERSIGHT 
7.1. 
Data and Safety Monitoring Board (DSMB)  
This is an independent committee that will be charged with ensuring the safety of the subjects 
enrolled in the clinical study. The Data Safety Monitoring Board (DSMB) will be comprised of four 
members: three clinicians and one biostatistician with relevant clinical/medical experience with the 
indication/disease under clinical investigation. The membership of the committee will be independent 
of the investigative sites and study sponsor to reduce potential for perception of bias and to remain 
free of potential conflicts of interest. The policies and procedures governing the DSMB will be 
provided in a Charter that will be reviewed and ratified by the membership within a reasonable 
timeframe relative to the enrollment of the first few subjects entering the study. 
Included in the charter will be a mission statement, operating procedures, proposed monitoring 
criteria, time points for interim analysis, and proposed stopping rules if appropriate. There will be at 
least 4 DSMB meetings during the trial: a kick-off meeting of the DSMB in proximity of the start of 
enrollment, and 3 safety reviews scheduled at 33% study completion, 70% study completion 
(corresponding to the Interim Analysis), and a final review after database lock. The DSMB will meet 
at a minimum once per 6 months if a meeting is not already triggered by the above scheduled 
enrollment timeframes. Written recommendations from the DSMB will be provided to the study 
sponsor following each safety review meeting. The DSMB will operate under the auspices of an 
academic research organization. 
7.2. 
Clinical Events Committee (CEC) 
An independent group of physicians that are not involved in the clinical investigations will act as the 
Clinical Events Committee (CEC). The CEC will be responsible for the review and adjudication of 
study effectiveness and safety endpoints that occur within 30 days post-operation according to 
standardized definitions. Policies and procedures governing the work of the CEC and the definitions 
used in the adjudication process will be provided in the CEC Charter, which will be developed prior 
to the start of study enrollment. The CEC will operate under the auspices of an academic research 
organization. 
7.3. 
Executive Committee 
This committee shall serve as overall governance of the trial and will be comprised of clinicians with 
relevant clinical/medical experience within the indication/disease under clinical investigation and who 
also have significant experience in overseeing clinical studies. The Executive Committee shall 
provide advice to the Sponsor regarding the conduct and any necessary adjustments to the trial 
protocol and/or study execution. The Executive Committee will also advise the Sponsor in the case 
that any decisions are necessary in response to recommendations provided by the independent Data 
and Safety Monitoring Board. 
7.4. 
Central Laboratory 
A central laboratory shall be utilized to analyze some of the blood samples collected in this study. The 
sample size and shipping requirements are provided to the sites in the Study Laboratory Manual. All 
sites will be trained on the collection, preparation, and shipping for central laboratory samples.  
8. STUDY MONITORING 

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The CRO will monitor and manage the data for the investigational study on behalf of the Sponsor, 
CytoSorbents, Inc. A study-specific Monitoring Plan will be created to ensure protocol compliance 
and adherence to applicable regulatory requirements. The monitoring process will begin with site 
initiation activities and continue until completion of the study closeout visit. Clinical monitors will 
verify subject data and ensure compliance is consistent with Good Clinical Practice (GCP), clinical 
protocol and other study requirements, according to the guidelines per the Monitoring Plan, set forth 
in the CROs monitoring Standard Operating Procedures (SOPs), and 21 CRF Part 812.  
8.1. 
Monitor Training 
The designated monitors and/or representatives of the Sponsor will be trained to monitor study 
progress including but not limited to the protocol and eCRFs, and per the Monitoring Plan.  
8.2. 
Site/Investigator Training 
The Sponsor is responsible for providing training to the Investigator and appropriate clinical site 
personnel on the following topics:  
• 
Protocol 
• 
Electronic case report form (eCRF) data entry and management 
• 
Procedure/Laboratory/other testing requirements 
• 
DrugSorb-ATR device 
8.3. 
Site Monitoring 
Completed eCRFs will be verified by the monitor both in person at the investigational sites and 
remotely at regular intervals throughout the study. The Investigator will allow the monitor and/or 
representative of the Sponsor, and any regulatory body to review and inspect the study files, subject 
eCRFs, subject medical records and other related study documents as required. All eCRFs will be 
reviewed for completeness and clarity. Missing or unclear data will be investigated by the monitor 
and will be retrieved, clarified, and entered by study personnel as necessary throughout the study. 
CytoSorbents, Inc., or their authorized representative may request additional documentation from the 
Investigator such as physician procedure notes or physician written summaries when adverse events 
are observed and reported.  
8.4. 
Regulatory Agency Inspection  
If an Investigator is contacted by a regulatory agency regarding this study, the Investigator will notify 
the Sponsor or its designee immediately. The Investigator and research coordinator must be available 
to respond to reasonable requests and queries made during the inspection process. The Investigator 
must provide the Sponsor or designee with copies of all correspondence that may affect the review of 
the current trial (e.g., Form FDA 483, Inspectional Observations and Warning Letters). The Sponsor 
may provide needed assistance in responding to regulatory audits.  
9. STUDY ASSESSMENTS AND PROCEDURES 
An outline of study assessments, procedures, labs, and associated time windows is given in the 
Schedule of Assessments (Table 6 in Appendix 4). Subjects will be evaluated through the Follow-up 
evaluation at 30 days post-operation. Assessments and procedures that are recorded as Standard of 
Care (SOC) within the Schedule of Assessments are outside of the CIP and are optional. They may 
be recorded if they are performed in accordance with SOC at the particular institution. Failure to 
record an assessment/procedure that is listed as SOC will not be a violation of protocol. Required 
assessments and procedures (not denoted as SOC) that are not completed or that are completed 
outside of the specified windows will be recorded as a protocol deviation (Section 13.2, 13.3).  

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Reference Section 4.3 for the full list of study endpoints. These endpoints require assessment of 
clinical events and/or treatments, blood product transfusions, drainage volume, and laboratory 
parameters. Definitions of analysis populations and description of statistical analyses of endpoints are 
briefly described in Section 11 and will be detailed in the Statistical Analysis Plan (SAP) for the 
study. 
9.1. 
Procedures and Assessments by Study Phase 
Subjects are considered enrolled in the study at the time which consent or assent (in the case of a 
proxy providing permission for an incapacitated subject) to participate in the study is provided.  
Details on the consent process are provided in Section 15.3 and the ethics of consenting non-
vulnerable and vulnerable (incapacitated) populations are detailed in Appendix 3.  
Subjects who do not meet study entry (inclusion/exclusion) criteria are screening failures and will exit 
the study. Treated subjects will be followed up through 30 days after the surgical procedure.   
The start of the investigation is defined as the date of consent to enroll the first prospective subject. 
The end of the investigation is defined as the date of the last subject’s last contact or assessment 
(whether scheduled or unscheduled). 
The investigation is divided operationally into 6 phases: 
• 
Screening Phase – the period between the time consent/assent is provided for study 
participation and the start of the surgical procedure with CPB  
• 
Pre-CPB Phase – the period within 2 hours before start of the operation with CPB (time of 
skin incision). Note: The Pre-CPB Phase may overlap with the Screening phase. 
• 
Operation Phase – the start of the surgical procedure (defined as skin incision) until chest 
closure. 
• 
Post-CPB Phase – the period from the end of CPB up to admission to the Intensive Care Unit 
(ICU). Blood sampling for drug removal obtained in the post-CPB phase should be drawn as 
soon as possible following the end of CPB, and no later than 30min after the subject has been 
disconnected from the CPB circuit. 
• 
Post-operation Phase – from admission to the ICU through Day 29 or the point of discharge 
from hospitalization, whichever is sooner.  Discharge from hospitalization means the date of 
initial discharge from the hospital in which the cardiothoracic surgery was completed (i.e., 
index procedure) irrespective of discharge to home care, secondary care or other rehabilitation 
unit. 
• 
Day 30 Evaluation Post-Cardiothoracic Surgery – The subject status on postoperative day 30 
will be evaluated by telephone contact, in-person follow-up visit, or review of medical 
records. Assessment of mortality (i.e., vitals status), blood product transfusions, and other 
adverse events will be performed. 
An overview of the investigation design is shown in Figure 5. 

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* Pre-CPB phase may overlap with the Screening Phase. 
Figure 5. Investigation Schematic 
9.1.1. 
Screening Phase and the Pre-CPB Phase 
The Screening Phase through the Pre-CPB Phase is the period bound by the time that consent is 
provided for study participation and the start time of CPB. Subjects are qualified for study 
participation by confirmation of meeting all the inclusion and none of the exclusion criteria. 
Each enrolled subject will be assigned a unique Subject Number consisting of a Site Number assigned 
by the Sponsor or designee, and a number which is sequentially assigned to all subjects screened at 
the investigation sites (e.g., XXX-YYY, where XXX is the site number and YYY is the subject 
number). The Subject Number will be used as a subject identification for each subject throughout the 
investigation. 
Screening and pre-CPB assessments should be completed as detailed in Table 6. As discussed in 
Section 1.1, all subjects undergoing CABG or with recent coronary stent placement (within prior 6 
months) should have aspirin continued going into surgery. An overview of antithrombotic and 
anticoagulation management for study subjects is provided in Appendix 4, Table 5. During 
Screening, if consented subjects enter the Operation Phase without post-consent clinical chemistry, 
cardiac troponin, hematology, or coagulation tests to record, the last pre-consent laboratory values 
MAY be used. 
Pre-randomization stratification 
Pre-randomization stratification will be performed on three levels (see Section 6.1 for details):  
1. By DOAC type (either apixaban or rivaroxaban); 
2. By study site; 
3. By the planned surgical procedure: 
• 
Isolated CABG (irrespective of number of grafts); or 
• 
All other cardiothoracic procedures requiring CPB.  
 
Randomization 
Subjects will be prospectively randomized in a one to one (1:1) fashion to either the control arm 
(SOC) or to the investigation arm (SOC + DrugSorb-ATR), as detailed in Section 6.2.  
Post-Operation Phase 
Post-op Day 30 
Evaluation  
Period between the 
time consent is 
provided for study 
participation and 
start of the surgical 
procedure  
Period within 2hrs 
of start of 
operation with 
CPB (i.e., time of 
skin incision) 
Period from 
skin incision to 
chest closure  
Period from the 
end of the CPB 
up to admission 
to the ICU 
From admission to the ICU 
through Day 29 (or until 
hospital discharge) 
Subjects will be 
followed up on 
Day 30 after the 
surgical procedure  
Post-CPB 
Phase 
Operation 
Phase 
Pre-CPB* 
Phase 
Screening 
Phase 

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9.1.2. 
Operation Phase  
The Operation Phase will be initiated at the time of first incision. During the Operation Phase, the 
subject will either undergo standard CPB, or CPB + DrugSorb-ATR according to randomization.  
Subjects randomized to the control arm will receive standard of care in which a sham device will be in 
place parallel to the CPB circuit, but through which no blood will circulate. Refer to Section 6.3 for 
details. 
In the treatment arm, DrugSorb-ATR treatment will initiate with the start of CPB and continue 
through the end of CPB. Per the IFU and under the guidance of a Field Clinical Specialist, the 
DrugSorb-ATR cartridge will be placed into a parallel bypass circuit to the main blood flow in a 
standard CPB circuit and primed for use in preparation for the Operation Phase. Throughout the 
treatment session, the DrugSorb-ATR setup will be monitored for blood leaks, flow changes, and/or 
clots. Any adverse device events and/or device observations must be recorded by indicating the 
location of leaks and/or by recording the size of any clots present. DrugSorb-ATR treatment flow 
rates will be controlled utilizing a roller clamp placed on the distal, superior line above the DrugSorb-
ATR prior to returning to the reservoir. Flow rate will be measured using a Sponsor provided 
Transonic® (or equivalent) ultrasonic flow meter and probe, placed on the inlet line below the 
DrugSorb-ATR device. The blood flow rate through the device will be adjusted to 500mL/min 
± 100mL/min. 
During the operation phase, arterial blood gas analysis will be obtained at the following time periods: 
within 30min pre-CPB, 30 ± 15 min into CPB, within 30 minutes post-CPB, and upon admission to 
the ICU. Activated clotting time will be obtained once at 30 ± 15 minutes into CPB, and once within 
30 minutes post-protamine administration. All other assessments including monitoring of transfusions, 
will be performed as detailed in Table 6 of Appendix 4. Intraoperative transfusions will be 
administered at the discretion of the investigator in accordance with standard institutional practice. 
9.1.3. 
Postoperative phase through 30-day evaluation 
Subjects will undergo scheduled study procedures as indicated in the Schedule of Assessments in 
Appendix 4 until the point of discharge from index hospitalization. A Follow-up Evaluation will be 
performed 30 days after the index operation for vital status/mortality check. This can be done via 
telephone contact, in-person follow-up visit, or review of medical records. 
Postoperative Antithrombotic Management: 
Approaches to antiplatelet and anticoagulation management during the study are listed below and 
summarized in Table 5. All subjects on preoperative aspirin should be maintained on the same 
therapy through-out the study. Additionally: 
1. Any ACS subjects or those with recent coronary stent placement who cannot discontinue 
DAPT (i.e., clopidogrel, ticagrelor, etc.) for the recommended preoperative washout period 
will be excluded from study participation. Initiation of DAPT in the postoperative period is at 
the discretion of the investigator, or per their institutional protocols. 
2. Timing of resumption for DOAC therapy in the postoperative period will be at the discretion 
of the investigator, based on the indication for anticoagulation and the anticipated bleeding 
risk.  
 
Postoperative anticoagulation for venous thromboprophylaxis in all subjects should be administered 
according to standardized institutional protocols. 

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9.2. 
Safety and Tolerability Assessments 
9.2.1. 
Adverse Events 
Throughout the study, the Investigator or designee will determine adverse event (AE) occurrences. 
AE definitions, assignment of severity/seriousness/causality, and procedures for reporting SAEs, 
SADEs, and UADEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the Informed Consent Form 
(assent if signed by the legally authorized representative, or consent if signed by the individual) to the 
postoperative day 30 assessment. Subjects will be observed for any signs or symptoms and if possible, 
asked about their condition by open questioning, such as “How have you been feeling since you were 
last asked?”, at least once each day while in hospital and at each investigation visit. Subjects will also 
be encouraged to spontaneously report AEs occurring at any other time during the investigation. 
If an AE occurs, appropriate diagnostic and therapeutic measures are to be taken and the investigation 
treatment may be discontinued if deemed clinically necessary. Follow-up evaluations of the subject 
are to be performed until the subject recovers or until the clinical Investigator considers the situation 
to be no longer clinically significant. 
Adverse events are monitored and recorded on the AE form of the eCRF. In absence of a specific 
diagnosis, an individual AE form must be filled in for each sign or symptom. Changes from baseline 
laboratory values which are abnormal values and that are classified as clinically significant by the 
investigator (e.g., requiring medical intervention) must be recorded as AEs. 
Persistent AEs will be entered once in the eCRF until they are resolved; a new event must be 
documented if deterioration occurs. These AEs will be carefully monitored. If an AE is still not 
resolved at the end of the investigation, this will be documented as “ongoing.” For recurrent AEs (i.e., 
AEs of the same nature, but with a different date of onset), an individual AE form must be completed 
for each of them. 
Bleeding event AEs 
All bleeding events are to be recorded as AE/SAEs by the Investigator or designee. Volume of blood 
loss and necessary transfusions will be documented in the corresponding eCRFs where applicable. In 
some cases, these events may contribute to the subject’s UDPB class. [35] Classifications are based 
on criteria/events occurring within the first postoperative day (as presented in Table 1) and will be 
determined based on the relevant data entered within the eCRFs.  
Of note, UDPB counts transfusions of PRBCs, platelets, FFP, and Cryoppt beginning at chest closure. 
While intra-operative transfusions of these blood products prior to chest closure will be documented, 
they will not be counted as part of the UDPB classification or contribute to the primary endpoint. 
Preoperative transfusions are not counted in the UDPB classification. Transfusions of PCC and 
rFVIIa are counted beginning at the start of the procedure for UDPB. [35] Measurement of CTD 
volume begins at chest closure for UDPB classification. All subjects with events meeting criteria for 
UDPB classification of moderate, severe, or massive bleeding (Classes 2, 3 or 4) will be referred to 
the CEC for adjudication of UDPB bleeding class. Bleeding events occurring beyond the first 
postoperative day (i.e., not eligible for UDPB classification) will be adjudicated by the CEC for 
clinical severity. Details on the process for adjudication and relevant definitions are provided in the 
CEC Charter. 
Postoperative Ischemic Events: 
Postoperative ischemic events occurring during the index hospitalization will be captured as safety 

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endpoints in this study. This is with the intent of evaluating any potential risk for ischemic rebound in 
the setting of rapid antithrombotic drug removal. Postoperative ischemic events include myocardial 
infarction (MI), stroke, and urgent coronary revascularization. Of note, given the occasional 
complexities of distinguishing ischemic from hemorrhagic stroke (i.e., ischemic with hemorrhagic 
conversion), all postoperative strokes occurring during the index hospitalization will be captured 
within the safety endpoint.  
All reported safety events occurring within 30 days of the study procedure that meet programed 
criteria for cardiac ischemia or stroke will be submitted to the CEC for endpoint adjudication. All 
coronary revascularization procedures (regardless of open or percutaneous) that occur post-index 
procedure and during the follow-up period will be adjudicated by the CEC for the potential safety 
endpoint of urgent coronary revascularization. Details on endpoint definitions, adjudication criteria, 
and all other CEC processes/procedures are detailed in the CEC charter.  
Venous Thromboembolic Events: 
Postoperative venous thromboembolic events (VTEs) occurring during the index hospitalization will 
also be captured as safety endpoints in this study. These include clinically significant deep vein 
thromboses and pulmonary embolism. The intent is to identify any potential risk for thrombotic 
rebound in the setting of rapid anticoagulant removal.  
All reported safety events occurring within 30 days of the study procedure that meet programmed 
criteria for VTE will be submitted to the CEC for endpoint adjudication. In addition to confirmation 
of VTE, the events will be evaluated by the CEC for clinical significance. Details on endpoint 
definitions, adjudication criteria, and all other CEC processes/procedures are detailed in the CEC 
charter. 
Postoperative Mortality or AEs Resulting in Death 
All deaths (including AEs resulting in death) that occur within 30 days of the study procedure will be 
adjudicated by the CEC for endpoint criteria. This includes assessment of the timing and nature of the 
mortality (cardiac vs. non-cardiac death). For the purposes of this study, fatal bleeding will be 
considered a type of cardiac death. Details on endpoint definitions, adjudication criteria, and all other 
CEC processes/procedures are detailed in the CEC charter. 
Safety Reporting to the FDA 
The Sponsor will provide safety reports (of adverse events, including relatedness to the device, 
severity, outcome/resolution, and all deaths) to the FDA for each set of 20 subjects enrolled. These 
reports are independent of the required annual reports for all IDEs. 
The Sponsor will perform ongoing safety evaluations of any deaths as they occur in the study and 
share the information with the agency as requested. Specifically, if four or more of the 20 study 
subjects within each reporting set die within 72 hours of the device therapy, the Sponsor will send an 
immediate report of those deaths to the FDA for review.  
9.2.2. 
Medical History 
Medical history will be obtained at Screening and should include demographic information (date of 
birth, biologic sex, race, ethnicity) and subject’s medical and surgical history. The medical history 
must be documented in the subject's eCRF. 
9.2.3. 
Clinical Laboratory Evaluations 

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Blood samples will be collected and documented by the Investigator (or designee) for all clinical 
laboratory evaluations at the times indicated in the Schedule of Assessments in Appendix 4. Local 
clinical laboratory assessments (including clinical chemistry, hematology, and coagulation tests) are 
listed in Appendix 2. The handling and management of these samples will be per institutional 
protocols. Of note: if multiple sets of labs are obtained for a subject within the same post-operative 
day (either as part of standard institutional protocols, or due to changes in the subject’s clinical 
picture), the lab assessments obtained at the time which most closely approximates those listed in 
Table 6: Schedule of Assessments should be the values entered into the EDC for study purposes.  
Instructions for the collection and storage of study samples that will be analyzed by the Central 
Laboratory are provided in the Study Laboratory Manual. 
9.2.4. 
Vital Signs 
Supine blood pressure, pulse rate, respiratory rate, oxygen saturation, and body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 4. Vital signs may also be 
performed at other times if judged to be clinically appropriate, or if the ongoing review of the data 
suggests a more detailed assessment of vital signs is required. 
All measurements will be performed singly and repeated once if outside the relevant clinical reference 
range. 
9.2.5. 
Physical Examination 
Body mass index will be calculated using the subject’s body weight and height at the time of 
screening and documented with other demographic information (Schedule of Assessments, Appendix 
4). A physical exam will be performed and documented at the time of screening/subject enrollment. 
Physical exams performed as part of standard of care on the day of screening but occurring prior to 
signing of informed consent may be documented as the screening PE. A physical exam will be 
repeated on the day of the procedure if the day of the procedure is different than the day of screening.  
9.2.6. 
Other Assessments: Blood Products and Blood Loss 
Intraoperative and postoperative blood loss and chest drainage volumes (chest drainage includes 
output from all chest and mediastinal tubes) will be measured and documented at the times indicated 
in the Schedule of Assessments in Appendix 4. Cell Saver will not be included in the calculation of 
blood product transfusions, as this is volume that would normally be given back as part of standard of 
care. Chest tube drainage will be recorded in the corresponding Chest Tube Drainage eCRF for at 
least 24hrs post-operation, unless unable to do so (i.e., subject death prior to 24hrs). Volume of blood 
loss not coming from chest/mediastinal drainage will be documented separately, in the corresponding 
Blood Loss (Non-Chest Drainage) eCRF where applicable. Blood products received by the subject 
will be recorded in the corresponding Transfusion eCRF. 
9.3. 
Blood Sampling for Drug Removal 
Blood samples for the analysis of plasma apixaban and rivaroxaban concentrations will be collected at 
the times indicated in the Schedule of Assessments in Appendix 4 and will be stored until analysis. A 
pre-CPB sample will be obtained prior to the start of CPB and may be performed up to 2 hours prior 
to skin incision. While the subject is on CPB, serial samples will be drawn at 30-minute intervals 
following initiation of CPB, through the first 2 hours of CPB. Sampling times will be at 30 (±15) 
minutes, 60 (±15) minutes, at 90 (±15) minutes, and at 120 (±15) minutes of CPB time. A post-CPB 
sample will be obtained as soon as possible following the end of CPB, and no later than 30min after 
the subject has been disconnected from the CPB circuit.  

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If the total CPB time required for the procedure is <120min (2hrs), the serial sampling will only be 
performed through the required duration of CPB. For procedures requiring >120min (2hrs) of CPB 
time, serial sampling will not extend beyond this time point, as the incremental change is expected to 
be minimal compared to the post-CPB value. Processing, storage, and shipping instructions for these 
blood samples will be provided by the Sponsor (or designee) to the investigation sites and detailed in 
the Study Laboratory Manual. Samples will be stored and analyzed at a designated bioanalytical 
laboratory using a validated assay. Any residual samples will be destroyed at the completion of the 
final investigation report or if the subject withdraws assent/consent to use the sample for the research 
purposes of the investigation. 
10. CONCOMITANT MEDICATIONS 
Medication history and concomitant medications will be recorded in the eCRF. The medication 
history will include all acute and chronic prescription and over-the-counter medications taken during 
the 30 days prior to Screening. Medication history will be repeated on the day of the procedure if 
different from the day of screening. 
All medications administered during the Screening, Pre-CPB, Intraoperative, Post-CPB, and during 
the Postoperative Phases must be collected. Unless medically necessary, concomitant medications 
should be withheld two hours prior to and during therapy with the investigational device. This is to 
reduce risk of unintended removal and inadequate delivery of these medications. 
Study subjects may, in addition to apixaban and rivaroxaban, also be receiving other antithrombotic 
medications during their current hospitalization that could contribute to bleeding. The use of 
antithrombotic medications will be reviewed during the screening period. Certain agents and the 
timing of administration could confound the results of the study and are therefore listed as prohibited 
medications (see Appendix 5 for details).  Subjects on prohibited medications at the time of surgery 
cannot be randomized. Each antithrombotic medication is categorized as allowed or prohibited in the 
study, and the reason for this categorization is provided.  
Prior and concomitant medications will be coded using the latest version of the WHO Drug 
Dictionary, based on Anatomical Therapeutic Chemical classification and Preferred Name.  
There are no protocol-specified prohibited medications during the Postoperative phase of the study.   
11. STATISTICAL CONSIDERATIONS 
General statistical considerations: descriptive summaries will be presented using mean with standard 
deviation (SD), median, minimum and maximum for continuous variables and as count and percent of 
subjects for categorical variables. Inferential statistical tests will be two-sided and use alpha (α) of 
0.05 as a critical value, unless noted otherwise. Statistical analysis will be carried out using SAS 
Version 9.4 or later and/or R software language. 
11.1. 
Statistical Power and Sample Size Determination 
Overall study sample size is designed to provide adequate power for the primary effectiveness 
endpoint, at both the interim and final analysis, the key secondary endpoints, and selected secondary 
endpoints.  
As noted above (Section 6.2), to maintain the balance between sites in terms of numbers of subjects 
randomized, study sites will be capped at randomizing a maximum of 15% of the overall study sample 
(i.e., 18 subjects). For sites with a total enrollment consisting of only one type of DOAC drug as per 
chance, the randomization cap will be replaced by a maximum of 10% of the overall study sample 

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(i.e., 12 subjects). 
The null hypothesis for the primary composite endpoint is represented by: 
H0: The distributions of the components are the same in the two treatment groups 
The alternative hypothesis for the primary composite endpoint is represented by: 
 
HA: For at least one component, the distribution is different between the treatment groups 
 
The null hypothesis for the first key secondary endpoint is represented by: 
𝐻𝐻0: 𝜋𝜋 𝐷𝐷𝐷𝐷= 𝜋𝜋 𝑆𝑆𝑆𝑆𝑆𝑆 
The alternative hypothesis for the first key secondary endpoint is represented by: 
𝐻𝐻𝐴𝐴: 𝜋𝜋 𝐷𝐷𝐷𝐷≠𝜋𝜋 𝑆𝑆𝑆𝑆𝑆𝑆 
where 𝜋𝜋1,𝐷𝐷𝐷𝐷 and 𝜋𝜋1,𝑆𝑆𝑆𝑆𝑆𝑆 are the pre-CPB vs. post-CPB mean percent changes in blood apixaban levels 
with DrugSorb-ATR (DS) and Control (SOC), respectively. The second key secondary endpoint null 
and alternative hypotheses take the same form as the first key secondary endpoint but substituting 
rivaroxaban for apixaban. 
The null hypothesis for the first secondary endpoint is represented by: 
𝐻𝐻0: 𝜋𝜋 𝐷𝐷𝐷𝐷= 𝜋𝜋 𝑆𝑆𝑆𝑆𝑆𝑆 
The alternative hypothesis for the first secondary endpoint is represented by: 
𝐻𝐻𝐴𝐴: 𝜋𝜋 𝐷𝐷𝐷𝐷≠𝜋𝜋 𝑆𝑆𝑆𝑆𝑆𝑆 
where 𝜋𝜋𝐷𝐷𝐷𝐷 and 𝜋𝜋 𝑆𝑆𝑆𝑆𝑆𝑆 are the mean 24-hour CTD volumes with DrugSorb-ATR (DS) and Control 
(SOC), respectively. The following additional secondary endpoints, for which power is formally 
allocated (see below), take the same form of null and alternative hypotheses as above: platelet 
transfusions (mean number of units) and pRBC transfusions (mean number of units). 
Approximately 120 combined DOAC subjects meeting the study inclusion criteria (Section 4.4.1) will 
be randomized in a 1:1 ratio to the treatment and control arms. A combined DOAC population is 
planned for analysis in the current study since apixaban and rivaroxaban share the same mechanism of 
action, same indications for use, same risk for post-surgical bleeding outcomes, have been shown in 
ex vivo testing to have nearly identical removal rates when treated with the study device, and are 
therefore considered exchangeable.  
In terms of the composite primary effectiveness bleeding endpoint, while bleeding is known to be of 
significant risk in patients on both apixaban and rivaroxaban undergoing CT surgery without 
preoperative washout, literature quantifying postoperative bleeding outcomes is limited in this 
specific population. However, published real-world use experience from the Asklepios Klinik St. 
Georg research group (Hamburg, Germany) has demonstrated highly similar treatment effects for 
intraoperative CytoSorb removal of ticagrelor and rivaroxaban in patients undergoing emergent CT 
surgery. [12] The difference between treatment and control groups regarding postoperative blood loss 
(in the form of 24hr chest tube drainage volume), reoperation rates for bleeding, and transfusion 
volumes were comparable between the ticagrelor and rivaroxaban cohorts. Thus, for the purpose of 
this study, we will anticipate the same treatment effects for DrugSorb-ATR therapy in subjects 

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undergoing CT surgery (within 36 hours of last DOAC dose) as were utilized for the STAR-T trial 
(which enrolled subjects undergoing CT surgery within 48 hours of last ticagrelor dose). The 
difference in timing between last drug dose and start of surgery for the DOAC vs. ticagrelor studies is 
necessary due to the difference in recommended washout periods between the DOACs and ticagrelor. 
Because of exchangeability between apixaban and rivaroxaban, the anticipated proportions of 
individual DOACs expected in the trial (ranging from 40% - 60%, reflective of real-world use 
patterns), are not assumed to impact power or sample size. Assuming a 5% dropout rate, a total of 114 
subjects (57 per arm) are expected to be evaluable for effectiveness and safety. Sample size is based 
on published response rates for the primary effectiveness Win Ratio sub-components, as noted for 
rivaroxaban and ticagrelor (above) with a bridge to apixaban, and can be calculated via an iterative 
simulation process with programming code available in an appendix to Redfors et al. (2019). [16] As 
a sensitivity exercise, power was estimated under varying conditions where the ratios of apixaban to 
rivaroxaban subjects were allowed to range from 40% to 60%, for either drug, and under assumptions 
of +/-5% worse vs. better outcomes for apixaban as compared to rivaroxaban (see Table 3). Power for 
the study to reject a false null hypothesis is formally estimated where apixaban is assumed equally 
comparable to rivaroxaban, at a subject ratio of 50:50 (see bold results in Table 3, below). 
 
 

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Table 3. Win Ratio Effect Size Assumptions with Power and Sample Size Estimates Under Varying 
Conditions 
A:R* 
Com-
para-
bility 
Ratio 
A:R 
n Per 
Group 
Effect Size 
Power 
Component #1 
Component #2 
Component #3 
Fatal Bleeding 
UDPB (Class ≥2) 
24hr CTD 
Treatment 
Event 
Control 
Event 
Treatment 
Event 
Control 
Event 
Treatment 
Mean (SD) 
Control 
Mean (SD) 
A Has 
5% 
Higher 
Event 
Rate 
Than R 
Among 
Treated 
Subjects 
40:60 
Interim 
Analysis 
N=39 
3.06% 
3.00% 
24.79% 
40.50% 
489.6 (253) 
800 (253) 
88.1% 
40:60 
End of 
study 
N=56 
3.06% 
3.00% 
24.79% 
40.50% 
489.6 (253) 
800 (253) 
99.3% 
50:50 
Interim 
Analysis 
N=39 
3.07% 
3.00% 
24.91% 
40.50% 
492.0 (253) 
800 (253) 
87.1% 
50:50 
End of 
study 
N=56 
3.07% 
3.00% 
24.91% 
40.50% 
492.0 (253) 
800 (253) 
99.2% 
60:40 
Interim 
Analysis 
N=39 
3.09% 
3.00% 
25.03% 
40.50% 
494.4 (253) 
800 (253) 
86.0% 
60:40 
End of 
study 
N=56 
3.09% 
3.00% 
25.03% 
40.50% 
494.4 (253) 
800 (253) 
99.2% 
A = R 
Event 
Rate 
Among 
Treated 
Subjects 
40:60 
Interim 
Analysis 
N=39 
3.00% 
3.00% 
24.30% 
40.50% 
480 (253) 
800 (253) 
91.3% 
40:60 
End of 
study 
N=56 
3.00% 
3.00% 
24.30% 
40.50% 
480 (253) 
800 (253) 
99.5% 
50:50 
Interim 
Analysis 
N=39 
3.00% 
3.00% 
24.30% 
40.50% 
480 (253) 
800 (253) 
91.3% 
50:50 
End of 
study 
N=56 
3.00% 
3.00% 
24.30% 
40.50% 
480 (253) 
800 (253) 
99.5% 
60:40 
Interim 
Analysis 
N=39 
3.00% 
3.00% 
24.30% 
40.50% 
480 (253) 
800 (253) 
91.3% 
60:40 
End of 
study 
N=56 
3.00% 
3.00% 
24.30% 
40.50% 
480 (253) 
800 (253) 
99.5% 
A Has 
5% 
Lower 
Event 
Rate 
Than R 
Among 
Treated 
Subjects 
40:60 
Interim 
Analysis 
N=39 
2.94% 
3.00% 
23.81% 
40.50% 
470.4 (253) 
800 (253) 
93.6% 
40:60 
End of 
study 
N=56 
2.94% 
3.00% 
23.81% 
40.50% 
470.4 (253) 
800 (253) 
99.7% 
50:50 
Interim 
Analysis 
N=39 
2.93% 
3.00% 
23.69% 
40.50% 
468.0 (253) 
800 (253) 
94.2% 
50:50 
End of 
study 
N=56 
2.93% 
3.00% 
23.69% 
40.50% 
468.0 (253) 
800 (253) 
99.7% 
60:40 
Interim 
Analysis 
N=39 
2.91% 
3.00% 
23.57% 
40.50% 
456.6 (253) 
800 (253) 
94.7% 
60:40 
End of 
study 
N=56 
2.91% 
3.00% 
23.57% 
40.50% 
456.6 (253) 
800 (253) 
99.8% 
 

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* A, R = apixaban, rivaroxaban. 
Notes: n = number; UDPB = Universal Definition of Perioperative Bleeding; CTD = chest tube drainage (volume [mL]). 
             Component #1 minimum rates of 3.0% assumed as a conservative approach. 
             Component #2 rates based on Russo et al. (2019), however, with a discount applied to bring the Treatment arm up to ~40% 
reduction on the Control arm. [42] 
             Component #3 rates based on Hassan et al. (2019), however, with a discount applied to bring the Treatment arm up to ~40% 
reduction on the Control arm. [12] 
Using a Finkelstein – Schoenfeld test, a total of 57 subjects per arm ensures power of >99.2% for the 
primary effectiveness endpoint at the final analysis, using a two-sided alpha (α) of 0.05, and assuming 
an interim analysis for efficacy at 70% completion. [15] Power for each of the key secondary 
endpoints is estimated at 96.3% assuming a 40% ± 40% mean difference between treatment and 
control, where N=29 subjects receiving apixaban with N=29 corresponding controls along with 
parallel numbers of subjects receive rivaroxaban and corresponding control, based on a two-sample t-
test assuming equal variance and a two-sided alpha of 0.05. For the 24-hour CTD secondary endpoint, 
assuming a treatment arm volume of 480 ± 253 mL and control arm volume of 800 ± 253 mL  [12] [a 
discount is applied (see Table 3 for details) to bring the Active arm up to ~40% reduction on the 
Control arm], power is similarly estimated at >99.9%. Power for comparisons of platelet transfusions 
between the treatment arm (0.32 ± 0.9 units) and control arm (1.6 ± 2.2 units) [43] is estimated at 
98.0%, based on a two-sample t-test assuming unequal variance and a two-sided alpha of 0.05. 
Similarly, power for PRBC transfusions between the treatment arm (1.3 ± 2.1 units) and control arm 
(4.4 ± 5.7) [43] is estimated at 96.7%. Sample size and power for all secondary endpoints were 
calculated using PASS 2021 (NCSS, LLC. Kaysville, UT, USA, ncss.com/software/pass). 
11.2. 
Analysis Populations 
Enrolled subjects include all subjects who provide informed assent/consent. Enrolled subjects who do 
not meet criteria for study eligibility are deemed screening failures and will exit the study. 
The Intent-to-Treat (ITT) Population will include all enrolled (assented/consented) subjects who are 
randomized.  
 
The modified Intent-to-Treat (mITT) Population will include all randomized subjects who undergo 
the index surgical procedure and receive a study device (whether DrugSorb-ATR or sham). The main 
primary analyses of the trial will be performed in the mITT Population.  
 
Baseline demographic and clinical variables will be summarized for each of the treatment groups for 
the ITT and mITT populations. So long as the ITT and mITT populations are not identical, the ITT 
subjects who do not fall within the mITT population will be presented in a listing, including the 
reasons for why they did not receive a study device. 
The Per Protocol (PP) Population will include all mITT subjects who have no major protocol 
violations. Analysis of the primary efficacy endpoint will be performed in the PP population as a 
sensitivity analysis. 
 
The Safety Analysis (SA) Population will include all enrolled subjects who are treated or attempted 
treatment with a study device. “Attempted treatment” refers to any subject(s) who initiate treatment 
with a study device (whether DrugSorb-ATR or sham) during the index procedure but experience 
early discontinuation of treatment due to device deficiency, clinical judgement on the part of the 
investigator, adverse event, or other rationale. All safety analyses will be performed in the Safety 
Analysis population.          
11.3. 
Effectiveness Analysis 
The primary effectiveness endpoint will be evaluated using the Win Ratio method of analysis for a 

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hierarchical composite endpoint based on the Finkelstein-Schoenfeld test (Finkelstein and Schoenfeld, 
1999; Pocock, et al., 2012) with three components ranked in order of clinical importance: a) fatal 
bleeding events occurring within 48hrs post-index procedure, b) moderate, severe, or massive 
perioperative bleeding events according to the Universal Definition of Perioperative Bleeding in 
Cardiac Surgery (UDPB) classification ≥2, and c) 24-hour chest tube drainage (mL) following 
surgery. [14] [15] The Win Ratio assigns “wins”, losses”, or “ties” in sequential comparisons between 
treatment and control arm subjects according to the hierarchical order of the components of the 
primary composite endpoint.  
 
 There are two key advantages to the Win Ratio method of analysis. First, the hierarchical assessment 
of the individual components of the composite endpoint according to their clinical significance. 
Second, the opportunity for different types of components, such as categorical versus continuous, to 
all be included thereby capturing all available information from each component to increase statistical 
power.[15] A Win Ratio along with a two-sided 95% CI will be estimated, and a Win Ratio greater 
than 1.0 favors the treatment arm; when the lower bound of a two-sided 95% confidence interval (CI) 
around the ratio exceeds 1.0, the treatment is shown to be statistically superior to control at alpha = 
0.05.[16] The primary effectiveness analysis will use a combined DOAC population to evaluate the 
difference between the SOC (control) arm and the DrugSorb-ATR (investigational) arm. 
The key secondary effectiveness endpoints are drug removal endpoints, namely the percent change in 
pre-CBP vs. post-CPB apixaban and rivaroxaban levels as measured by liquid 
chromatography/tandem mass spectrometry (LC/MS-MS). Blood samples for drug removal analyses 
will be collected and analyzed by a central core laboratory. 
Change from baseline in blood concentration of apixaban or rivaroxaban is defined as:  
pre-CPB [apixaban]blood - post-CPB [apixaban]blood *100% 
pre-CPB [apixaban]blood 
 
and 
 
pre-CPB [rivaroxaban]blood - post-CPB [rivaroxaban]blood *100% 
pre-CPB [rivaroxaban]blood 
 
Benchtop studies of drug removal by DrugSorb-ATR (data on file, CytoSorbents Corporation) 
demonstrate concentration and time dependent absolute drug removal, which are nearly identical for 
both apixaban and rivaroxaban. Based on these benchtop studies, a conservative estimate of 40% 
reduction in blood concentration of DOAC between pre- and post- DrugSorb-ATR removal is 
expected, with a standard deviation of 40%, in the treatment arm. Minimal change is expected in the 
control arm. A two-sample t-test will be used to evaluate the difference between treatment arms. Due 
to highly variable baseline drug levels in the study population, percent change from baseline will be 
analyzed as opposed to observed values.  
Additional secondary endpoints include 24-hour CTD (volume [mL]), total platelet transfusions 
during the index hospitalization (volume [mL] and units), and total PRBC transfusions during the 
index hospitalization (volume [mL] and units). Twenty-four-hour CTD (mL) will be assessed via two-
sample t-test for mean difference. In the event the assumptions for a two-sample t-test are not met, a 
nonparametric test such as a Mann-Whitney test will be employed, with median and range values 
provided in the output. An additional analysis of 24-hour CTD will compare the frequency of subjects 
falling into volume categories (i.e., <500 mL, 500 to <750 mL, 750 to <1000 mL, 1000 to <1250 mL, 
1250 to <1500 mL, and  ≥1500 mL), and will use a Fisher-Freeman-Halton exact test to compare 
treatment groups. The transfusion endpoints will all be analyzed using two-sample t-tests for mean 
differences, and Fisher-Freeman-Halton exact tests for units. In the event the assumptions for a two-
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median and range values provided in the output. The remaining Win Ratio component parts will also 
be included as secondary endpoints: proportions of fatal perioperative bleeding events will be 
assessed via Fisher’s exact test; and proportions of UDPB events (by category) will be assessed via a 
Fisher-Freeman-Halton exact test. All surgical re-exploration for excessive bleeding, including those 
events occurring beyond the timeframe captured within the UDPB component of the primary endpoint 
will be captured as a secondary endpoint. Time to re-exploration will be considered.  
 
Type I error (alpha, α) will be preserved from inflation due to multiplicity across the primary 
effectiveness, key secondary, and secondary endpoints via a hierarchical closed testing step-down 
approach. Only if preceding endpoints are declared statistically significant at the alpha 0.05 level, can 
further endpoints also be declared significant. The order of hierarchical testing will follow the order of 
primary, key secondary, and secondary endpoints as listed in the paragraph above, namely: the 
primary endpoint will be tested first, followed by the first key secondary endpoint (percent change in 
pre-CPB vs. post-CPB blood apixaban levels), followed by the second key secondary endpoint 
(percent change in pre-CPB vs. post-CPB blood rivaroxaban levels), followed by the first secondary 
endpoint (24-hour CTD), second secondary endpoint (platelet transfusions), and lastly the third 
secondary endpoint (pRBC transfusions).  
11.4. 
Subgroup Analysis 
Results comparing the two treatment arms based on the components of primary effectiveness 
endpoints will be contrasted across clinically meaningful subgroups according to the following 
factors:  
• 
DOAC type (apixaban vs. rivaroxaban), 
• 
Planned surgery type (CABG-alone vs. all other types of CT surgery)  
• 
EuroScore II score (<7% vs. ≥7%),  
• 
STS Risk score (<4% [low], 4-8% [intermediate], ≥8% [high]),  
• 
Left ventricular ejection fraction (LVEF) [≥50% (normal), 40-49% (mild dysfunction), 30-
39% (moderate dysfunction), <30% (severe dysfunction)]  
• 
Baseline thrombocytopenia (platelet count <150,000 µ/L vs. ≥150,000 µ/L),  
• 
Age group (<65 vs ≥65 years old),  
• 
Biologic sex (F vs. M),  
• 
History of MI (Y vs. N), and  
• 
History of stroke (Y vs. N).  
 
For the fatal bleeding events occurring within 48hrs post-index operation, and moderate, severe, or 
massive bleeding events components, a logistic regression will be utilized with treatment, group and 
their interaction included in the model. Details will be provided in the SAP.  
11.5. 
Exploratory endpoints 
Other exploratory endpoints include: 
• 
Area under the concentration time curve (AUC), using the trapezoidal approach, for 
intraoperative apixaban or rivaroxaban pharmacokinetic (PK) concentration 
• 
Operative time (measured from start of skin incision to completion of chest closure) 
• 
Duration of ICU stay 
• 
Duration of hospital stay 
• 
30-day hospital re-admissions 
 
Details on methods of analysis for exploratory endpoints will be provided in the SAP. 

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11.6. 
Interim Analysis 
An interim analysis with unblinded efficacy assessment is planned once 70% of evaluable subjects 
(n=40 per group) have completed the primary effectiveness assessment, including follow-up period. 
All data for the interim primary effectiveness endpoint will be fully adjudicated by the CEC prior to 
analysis. The interim evaluation will be performed with possible early stopping for efficacy on the 
basis of a Lan-DeMets O’Brian-Fleming spending function, which generates group-sequential 
boundaries that resemble O’Brian-Fleming boundaries, with experiment-wise error preserved at 0.05. 
[44, 45] Based on simulation results, a Win Ratio Z-value boundary of 2.44 would need to be crossed, 
corresponding to a two-sided p-value of 0.0148. Should the interim efficacy boundary not be crossed, 
a total alpha of 0.0148 would be spent at the interim, plus 0.0352 spent at the final analysis. In this 
case, at the final analysis a Win Ratio Z-value of 2.00 would need to be crossed, corresponding to a p-
value of 0.0456, to declare a statistically significant Win Ratio result favoring the treatment arm. The 
estimated probability of stopping due to efficacy at the interim is >88.1%. 
 
To maintain study blinding, the interim analysis will be conducted by an independent unblinded 
statistician separate from the day-to-day operational team with appropriate experience. Enrollment 
will not be paused during the interim analysis. Interim analysis results will be shared only with the 
DSMB, which will make a decision to either stop the study early due to overwhelming efficacy or 
continue until the final analysis. The FDA will be immediately notified of any decision by the DSMB 
to halt or terminate the study early. Should the study stop early, a final analysis will also take place 
that will include any additional subjects who were treated and followed-up during the conduct of the 
interim analysis. 
 
To prevent potential operational bias resulting from the interim analysis, the clinical personnel at sites 
may not be informed of the interim results. Details on the interim analysis methodology will be 
provided in the SAP.  
11.7. 
Treatment of Missing Data 
Every effort will be taken to obtain data entry compliance of all critical fields during the study. The 
study assumes 5% of the primary effectiveness and safety data will be missing. Reasons for missing 
data will be collected and a distribution of the prognostic factors in subjects with and without missing 
data will be compared to identify any confounding factors. Sensitivity analyses will be conducted to 
assess the sensitivity of the results to assumptions underlying the missingness mechanism. Details will 
be provided in the SAP.  
11.8. 
Safety Analysis 
The incidence of all AEs occurring after the start of the CPB procedure will be summarized by 
treatment group using frequency and percentage. AEs that occur following informed consent but prior 
to the start of CPB will not be included in this safety analysis but will be provided in a listing. Within 
the Safety Analysis, AEs will be summarized by severity and relationship to the study device as 
determined by the Investigator (or designee). Discontinuations due to AEs, and SAEs will be 
summarized. All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®) according to system organ class and preferred term, prior to database lock. 
Observed values for clinical laboratory test data and vital signs, along with change from baseline 
results, will be summarized by collection time point. A summary of clinically notable values will be 
provided. 

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Safety results will be further analyzed by clinically meaningful subgroups according to the following 
risk stratification criteria: age group, gender, history of prior MI, prior stroke, prior hypertension, 
prior hyperlipidemia, prior diabetes, and prior tobacco use. Details will be provided in the SAP. 
 
Listings will be provided of all safety endpoint data. 
Further details regarding presentation and analysis of safety data will be detailed in the SAP.   
11.9. 
Device Malfunctions/Deficiencies 
A summary of device malfunctions/deficiencies will be provided by treatment arm. All 
malfunctions/deficiencies will be listed. 
11.10. Disposition and Baseline Characteristics 
Number and percentage of subjects discontinuing prematurely from the study will be provided by 
treatment group and by reason discontinued. All data for background and demographic variables will 
be summarized and listed by treatment group and subject. Relevant medical history, current medical 
conditions, and incidence of prior and concomitant medications will be summarized by treatment 
group as well as listed. 
12. DATA HANDLING AND RECORD KEEPING 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 Section 4.9 and regulatory and institutional requirements for the protection 
of confidentiality of subjects. As part of participating in a manufacturer-sponsored study, each site 
will permit authorized representatives of the sponsor(s), the sponsor’s designee, and regulatory 
agencies to examine (and when required by applicable law, to copy) clinical records for the purposes 
of quality assurance reviews, audits, and evaluation of the study safety and progress.  
Source data are all information, original records of clinical findings, observations, or other activities 
in a study necessary for the reconstruction and evaluation of the trial.  
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  
12.1. 
Data Management Procedures 
Electronic Case Report Forms (eCRFs) will be used to collect all subject data during the course of the 
study, which are part of a database that meets 21 CFR Part 11 requirements. eCRFs must be fully 
completed for each subject and electronically signed by the Investigator when complete.  
Federal Regulations and Good Clinical Practice Guidelines require that Investigators maintain 
information in the study subject’s medical records that corroborate data collected on the eCRFs. In 
order to comply with these regulatory requirements, the following information should be maintained:  
• 
Medical history/physical condition of the study subject before involvement in the study 
sufficient to verify protocol entry criteria.  
• 
Dated and signed notes on the day of entry into the study including the study Investigator, 
study name, subject number assigned and a statement that consent was obtained. 
• 
Dated and signed notes from each study subject visit with reference to the CRFs for further 
information, if appropriate (for specific results of procedures and exams). 

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• 
Information related to adverse event(s). 
• 
Study subject’s condition upon completion of or withdrawal from the study. 
• 
Discharge summaries/procedure reports. 
12.2. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic Case 
Report Forms (eCRFs), investigation-related forms, investigation reports, or any related publications. 
Subject and Investigator personal data will be treated in compliance with all applicable laws and 
regulations. In the event the clinical investigation plan (CIP), investigation report, or investigation 
data are included in a public registry, all identifiable information from individual subjects or 
Investigators will be redacted according to applicable laws and regulations. 
The subject must be informed that his/her personal investigation-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be explained 
to the subject. The subject must also be informed that his/her investigation-related data may be 
examined by Sponsor or Contract Research Organization (CRO) auditors or other authorized 
personnel appointed by the Sponsor, by appropriate EC members, and by inspectors from regulatory 
authorities. 
12.3. 
Data retention 
Maintenance of study records should be obtained for a period of five (5) years after the latter of two 
occurrences: 
 
1. The date when the investigation is terminated or completed, or 
2. The date that the records are no longer needed to support a regulatory approval. 
 
These documents should be retained for a longer period, however if required by local regulations. No 
records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the Sponsor to inform the Investigator when these documents no longer need to be 
retained. 
12.4. 
Investigator Records 
Investigators will maintain complete, accurate, and current study records. Investigator records shall 
include the following materials: 
• 
Correspondence: All significant correspondence with another investigator, an IRB, the 
sponsor, a monitor, or FDA, including required reports. 
• 
Subject Records: Signed Informed Consent Forms, copies of supporting documents 
(laboratory reports, reports of diagnostic tests, medical records, etc.) and records of exposure 
of each subject to the device. Informed consent must comply with FDA regulations (21 CFR, 
part 50). 
• 
Clinical Investigational Plan/Protocol: A current copy of the Clinical Study Protocol and 
amendments including Instructions for Use of the DrugSorb-ATR device and copies of the 
eCRFs. 
• 
Institutional Review Board (IRB) Information: All information pertaining to IRB review 
and approval of this clinical study including a copy of the IRB letter approving the clinical 
study, a blank Informed Consent Form approved by the IRB, and certification from the IRB 
Chairman that the IRB complies with FDA regulations (21CFR, part 56), and that the IRB 
approved the clinical study protocol. 
• 
Investigator Agreements: Copies of the signed Investigator, Sub-Investigator Agreements 

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with accompanying curriculum vitae. Signed Protocol pages. 
• 
Study Documents: Including Investigational Device Accountability logs (including device 
shipment list/packing lists), Screening and Enrollment logs, and Site Visit logs 
• 
Other: Any other records that may be required by applicable state or federal laws. 
12.5. 
Investigator Reports 
The Investigator will prepare and submit the designated reports listed in Table 4. 
Table 4. Responsibilities for Preparing and Submitting Reports 
Type of Report 
Prepared by the Investigator 
for: 
Time of Notification/Report 
Completion 
Enrollment Notification eCRF 
Sponsor 
Within 24 hours of the subject 
signing the ICF 
SAE/SADE/UADE eCRF 
Sponsor 
Within 24 hours of knowledge or 
as required by the IRB 
All other eCRFs 
Sponsor and IRB (as required) 
Within 10 business days (or as 
required by IRB for AE eCRFs) 
Device deficiency or device 
observation eCRF 
Sponsor 
Within 24 hours of knowledge 
Subject Death or withdrawal 
Sponsor and IRB (as required) 
Within 24 hours of knowledge 
Withdrawal of IRB or FDA 
Approval 
Sponsor 
Within 24 hours of knowledge 
Informed Consent Not Obtained 
Sponsor and IRB 
Within 24 hours of knowledge or 
as required by IRB 
Progress report 
Sponsor and IRB 
Annually 
Final summary report 
Sponsor, IRB, and FDA 
Within six months of study 
completion 
Other reports 
Sponsor and IRB and FDA 
As needed 

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13. QUALITY CONTROL AND ASSURANCE 
13.1. 
Site and Investigator Selection 
The Sponsor selects qualified investigators with appropriate experience at health care facilities with 
adequate resources to participate in this study. The investigational sites will be selected using 
combined current assessments of site and investigator qualifications.  
13.2. 
Protocol Deviations 
An Investigator is not allowed to deviate from the Protocol without the prior written approval of the 
Sponsor. Under emergency circumstances, deviations from the Protocol to protect the rights, safety 
and well-being of human subjects may proceed without prior approval of the sponsor and the IRB. 
Such deviations shall be documented and reported to the sponsor and the IRB (as required) as soon as 
possible.  
A protocol deviation is a failure to comply with the requirements specified within this clinical study 
protocol. Examples of protocol deviations may include enrollment of a study subject who does not 
meet all of the inclusion/exclusion criteria specified in the protocol, visits performed outside of the 
protocol specified visit window, and missed study visits. Each investigator shall conduct this clinical 
study in accordance with this clinical study protocol, regulatory body regulations, Good Clinical 
Practices, and any conditions of approval imposed by their IRB.  
All deviations are reviewed and assessed for their impact on subject safety by the Sponsor or 
designee. The PI and study staff are responsible for knowing and adhering to their IRB reporting 
requirements.  
The protocol deviations for this protocol consist of, but not limited to the following: 
• 
Failure to obtain subject’s informed consent prior to any study-related activities; 
• 
Failure to conduct protocol required clinical follow-ups; 
• 
Failure to conduct protocol required clinical follow-ups within time windows; and, 
• 
Failure to report serious adverse events according to protocol requirements. 
In the event of any deviation from the protocol, the Investigator will be notified of the site’s non- 
compliance. Corrective actions will be required, if necessary. Continued protocol deviations despite 
re-education of the study site personnel or persistent protocol deviation may result in termination of 
the site’s study participation. Subjects enrolled at these sites will continue to be followed per the 
clinical protocol.  
13.3. 
Protocol Deviation Process 
Investigators must report protocol deviations to the Sponsor within 10 working days of investigational 
site knowledge of the deviation by entering data into the protocol deviation log. Any protocol 
deviations that affect the rights, safety or well-being of the subject or the scientific integrity of the 
clinical investigation, including those which occur under emergency circumstances must be reported 
within 24 hours to the Sponsor and IRB if required by the IRB.  
13.4. 
Corrective/Preventative Action 
The Sponsor reserves the right to terminate an investigational site from the study for any of the 
following reasons: 

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• 
Repeated failure to complete Electronic Case Report Forms (eCRFs); 
• 
Failure to obtain Informed Consent; 
• 
Failure to report Serious Adverse Events within 24 hours of knowledge; 
• 
Loss of or unaccountable investigational device inventory; 
• 
Repeated protocol violations; 
• 
Failure to enroll an adequate number of subjects 
13.5. 
Data Quality Assurance 
The following data quality steps will be implemented: 
• 
All subject data relating to the investigation will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator 
is responsible for verifying that data entries are accurate and correct by electronically signing 
the eCRF.  
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• 
The Investigator must permit investigation-related monitoring, audits, and regulatory agency 
inspections and provide direct access to source data documents.  
• 
The Sponsor or designee is responsible for the data management of this investigation 
including quality checking of the data. Predefined, agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented.  
• 
An Investigation Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of subjects are being protected; and that the 
investigation is being conducted in accordance with the currently approved CIP and any other 
investigation agreements, ISO GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this investigation 
must be retained by the Investigator in the investigation site archive for at least 5 years after 
the end of the investigation unless local regulations or institutional policies require a longer 
retention period. No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or party without 
written notification to the Sponsor. 
14. TERMINATION OF STUDY OR STUDY SITE PARTICIPATION 
The Sponsor may terminate the study at any time. Reasons for study termination may include but are 
not limited to any of the following: 
• 
Adverse events unknown to date (i.e., not previously reported in any similar investigation or 
in market use with respect to their nature, severity, and/or duration). 
• 
Increased frequency, severity, and/or duration of known, anticipated, or previously reported 
AEs. 
• 
Medical or ethical reasons affecting the continued performance of the investigation. 
• 
Difficulties in the recruitment of subjects. 
• 
Cancellation of device development. 
If the study is terminated prior to the completion of expected enrollment for any reason, all 
participating centers will be notified within five working days. All subjects already enrolled will 
continue to be followed for the planned course of study described in this protocol. The study will be 
terminated following the final follow-up visit of the last enrolled subject. 

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In addition to the corrective actions listed in Section 13.4, the Sponsor reserves the right to terminate 
study site participation and remove appropriate study materials at any time. Specific instances that 
may precipitate such termination include but are not limited to the following: 
• 
Failure to meet minimum subject enrollment requirements 
• 
Failure to comply with protocol specified procedures and documentation 
• 
Failure to comply with Good Clinical Practice 
 
The site Investigator may also discontinue study participation with suitable written notice to the 
Sponsor.  
15. ETHICS/PROTECTION OF HUMAN SUBJECTS 
15.1. 
Statements of Compliance 
This clinical investigation shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, and 21 CFR Part 812, 50, 54, 56. The clinical investigation shall 
not begin until the required approval from the IRB has been obtained, if appropriate. Any additional 
requirements imposed by the IRB, or regulatory authority shall be followed.  
15.2. 
Institutional Review Board (IRB) 
Each participating institution must provide for the review and approval of this protocol and the 
associated informed consent documents and recruitment material by an appropriate IRB. Any major 
amendments to the protocol or consent materials must also be approved before they are placed into 
use.  
 
15.3. 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout an individual’s study participation. Discussion of risks and possible 
benefits of this therapy will be provided to the subjects and their families. Consent forms describing in 
detail the study interventions/products, study procedures, and risks are given to the subject and written 
documentation of informed consent is required prior to starting intervention/ administering study 
product.  
 
Consent may be provided by: 1) individual subject providing informed consent; 2) assent of a 
guardian, healthcare proxy, or welfare attorney on behalf of a subject without capacity to consent 
(vulnerable or incapacitated individual). Details of the process for obtaining and documenting 
informed consent are provided in Appendix 3. Failure to obtain informed consent prior to initiation of 
study treatments will need to be documented as a protocol deviation and be reported in accordance 
with regulations. 
15.4. 
Subject Confidentiality 
Confidentiality of data shall be observed by all parties involved at all times throughout the clinical 
investigation. All data shall be secured against unauthorized access.  
 
The privacy of each subject and confidentiality of his/her information shall be preserved in reports 
and when publishing any data. The Principal Investigator or institution shall provide direct access to 
source data during and after the clinical investigation for monitoring, audits, IRB review and 
regulatory authority inspections. As required, the Principal Investigator or institution shall obtain 

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permission for direct access to source documents from the subject, hospital administration and 
national regulatory authorities before starting the clinical investigation.  
16. PROTOCOL AMENDMENTS 
The Protocol, CRFs, ICF and other subject information, or other clinical investigation documents 
shall be amended as needed throughout the clinical investigation, and a justification statement shall be 
included with each amended section of the document. Proposed amendments to the Protocol shall be 
agreed upon between the Sponsor and Principal Investigator(s), or the coordinating investigator. The 
amendments to the Protocol and the subject’s Informed Consent Form shall be notified to, or 
approved by, the IRB and regulatory authorities as required. For non-substantial changes (e.g., minor 
logistical or administrative changes, change of monitor(s), telephone numbers, renewal of insurance) 
not affecting the rights, safety and well-being of human subjects or not related to the clinical 
investigation objectives or endpoints, a simple notification to the IRB and, where appropriate, 
regulatory authorities can be sufficient. The version number and date of amendments shall be 
documented. 
17. PUBLICATION POLICY 
CytoSorbents manages its clinical studies in an ethical and rigorously scientific manner, working with 
leading experts in the field, to clearly and publicly demonstrate the benefits, risks, and value of 
DrugSorb-ATR to caregivers and study subjects alike. The Sponsor accepts the obligation to facilitate 
publication of medically important clinical data in a timely, objective, accurate, and balanced manner, 
regardless of the outcome of this trial. To ensure that an accurate record of the study data is presented 
to the public, CytoSorbents understands the need to allow sufficient time for careful preparation, 
analysis, interpretation, and review of study data and reports prior to their dissemination. 
Safety and Efficacy Data generated for all prespecified primary and secondary endpoints, shall be 
compiled, analyzed, reviewed, and published in the following manner:  
• 
The Principal Investigator(s) and Sponsor shall compile and disseminate a clinical summary 
report that shall be disseminated to CytoSorbents (as Sponsor), all participating local and 
central IRBs, and the FDA. Data from this Summary Report shall also be published on the 
ClinicalTrials.Gov website simultaneously.  
• 
Following database closure, a study publication shall be submitted to a peer reviewed journal 
within 18 months of database closure. In the event that the study is terminated early, a 
publication of this data will be submitted within 12 months of database closure.  
 
 

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18. REFERENCES 
1. 
Eliquis (apixaban) Package Insert. 2012, Bristol-Meyers Squibb Co: Princeton, New Jersey. 
2. 
Xarelto (rivaroxaban) tablets (Package Insert). 2011, Janssen Pharmaceuticals: Titusville, New Jersey. 
3. 
Ziakas, P.D., et al., Medicare part D prescribing for direct oral anticoagulants in the United States: Cost, use and 
the "rubber effect". PLoS One, 2018. 13(6): p. e0198674. 
4. 
Inc., P., 2020 Pfizer Annual Report to Shareholders. 2021. 
5. 
Johnson, J., 2020 Annual Report. 2021. 
6. 
Doherty, J.U., et al., 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of 
Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology 
Clinical Expert Consensus Document Task Force. J Am Coll Cardiol, 2017. 69(7): p. 871-898. 
7. 
Erdoes, G., et al., International consensus statement on the peri-operative management of direct oral 
anticoagulants in cardiac surgery. Anaesthesia, 2018. 73(12): p. 1535-1545. 
8. 
Godier, A., et al., Predictors of pre-procedural concentrations of direct oral anticoagulants: a prospective 
multicentre study. Eur Heart J, 2017. 38(31): p. 2431-2439. 
9. 
Pernod, G., et al., Management of major bleeding complications and emergency surgery in patients on long-term 
treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on 
perioperative haemostasis (GIHP) - March 2013. Arch Cardiovasc Dis, 2013. 106(6-7): p. 382-93. 
10. 
Hassan, K., et al., Bleeding Complications After Use of Novel Oral Anticoagulants in Patients Undergoing 
Cardiac Surgery. Ann Thorac Surg, 2018. 105(3): p. 702-708. 
11. 
Koertge, A., et al., Extracorporeal Hemoperfusion as a Potential Therapeutic Option for Critical Accumulation of 
Rivaroxaban. Blood Purif, 2018. 45(1-3): p. 126-128. 
12. 
Hassan, K., et al., Cytosorb Adsorption During Emergency Cardiac Operations in Patients at High Risk of 
Bleeding. Ann Thorac Surg, 2019. 108(1): p. 45-51. 
13. 
Mendes, V., et al., Cytosorb(®) hemoadsorption of apixaban during emergent cardio-pulmonary bypass: a case 
report. Perfusion, 2020: p. 267659120967827. 
14. 
Pocock, S.J., et al., The win ratio: a new approach to the analysis of composite endpoints in clinical trials based 
on clinical priorities. Eur Heart J, 2012. 33(2): p. 176-82. 
15. 
Finkelstein, D.M. and D.A. Schoenfeld, Combining mortality and longitudinal measures in clinical trials. Stat 
Med, 1999. 18(11): p. 1341-54. 
16. 
Redfors, B., et al., The win ratio approach for composite endpoints: practical guidance based on previous 
experience. Eur Heart J, 2020. 41(46): p. 4391-4399. 
17. 
Bjørnstad, J.L., et al., Operative survival in patients with acute aortic disease in the era of newer oral 
anticoagulants. Open Heart, 2020. 7(2). 
18. 
Lippi, G., et al., Oral anticoagulants around the world: an updated state-of-the art analysis. Annals of Blood, 
2018. 3. 
19. 
Zhu, J., et al., Trends and Variation in Oral Anticoagulant Choice in Patients with Atrial Fibrillation, 2010-2017. 
Pharmacotherapy, 2018. 38(9): p. 907-920. 
20. 
Tafur, A.J., et al., Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation Study. J 
Am Heart Assoc, 2020. 9(19): p. e017316. 
21. 
Schumer, E.M., et al., Emergency Coronary Artery Bypass Grafting: Indications and Outcomes from 2003 through 
2013. Tex Heart Inst J, 2016. 43(3): p. 214-9. 
22. 
Fox, V., et al., Direct oral anticoagulants and cardiac surgery: A descriptive study of preoperative management 
and postoperative outcomes. J Thorac Cardiovasc Surg, 2021. 161(5): p. 1864-1874.e2. 
23. 
Dixon, B., et al., The association of blood transfusion with mortality after cardiac surgery: cause or confounding? 
(CME). Transfusion, 2013. 53(1): p. 19-27. 
24. 
Christensen, M.C., et al., Increased chest tube drainage is independently associated with adverse outcome after 
cardiac surgery. J Cardiothorac Vasc Anesth, 2012. 26(1): p. 46-51. 
25. 
Cuker, A., et al., Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J 
Hematol, 2019. 94(6): p. 697-709. 
26. 
KCENTRA (Prothrombin Complex Concentrate (Human)) Product Insert. 2013, CSL Behring GmbH: Marburg, 
Germany. 
27. 
ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) Package Insert. 2018, Portola Pharmaceuticals 
Inc.: San Francisco, CA. 

Clinical Investigation Plan (CIP)  
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 CIP Reference Number: 2021-02 
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28. 
Connolly, S.J., et al., Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N 
Engl J Med, 2019. 380(14): p. 1326-1335. 
29. 
Mueck, W., et al., Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for 
the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost, 2008. 
100(3): p. 453-61. 
30. 
Frost, C., et al., Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa 
inhibitor, in healthy subjects. Br J Clin Pharmacol, 2013. 76(5): p. 776-86. 
31. 
Ferrandis, R., et al., Periprocedural Direct Oral Anticoagulant Management: The RA-ACOD Prospective, 
Multicenter Real-World Registry. TH Open, 2020. 4(2): p. e127-e137. 
32. 
Kreutz, R., et al., Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban 
and twice-daily apixaban: a randomized crossover study. J Thromb Haemost, 2017. 15(10): p. 2017-2028. 
33. 
Barnes, G.D. and E. Mouland, Peri-Procedural Management of Oral Anticoagulants in the DOAC Era. Prog 
Cardiovasc Dis, 2018. 60(6): p. 600-606. 
34. 
Kaneko, T., M. Yammine, and S.F. Aranki, New oral anticoagulants--what the cardiothoracic surgeon needs to 
know. J Thorac Cardiovasc Surg, 2014. 148(5): p. 1794-1801.e1. 
35. 
Dyke, C., et al., Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg, 
2014. 147(5): p. 1458-1463.e1. 
36. 
Kinnunen, E.M., et al., Clinical significance and determinants of the universal definition of perioperative bleeding 
classification in patients undergoing coronary artery bypass surgery. J Thorac Cardiovasc Surg, 2014. 148(4): p. 
1640-1646.e2. 
37. 
Engelman, D.T., et al., Guidelines for Perioperative Care in Cardiac Surgery: Enhanced Recovery After Surgery 
Society Recommendations. JAMA Surg, 2019. 154(8): p. 755-766. 
38. 
Kirklin JW, B.-B.B., Cardiac Surgery. 1986, New York: John Wiley & Sons. 
39. 
Christensen, M.C., et al., Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc 
Surg, 2009. 138(3): p. 687-93. 
40. 
Despotis, G.J., et al., Factors associated with excessive postoperative blood loss and hemostatic transfusion 
requirements: a multivariate analysis in cardiac surgical patients. Anesth Analg, 1996. 82(1): p. 13-21. 
41. 
Liu, W., et al., Impact of major bleeding on the risk of acute kidney injury in patients undergoing off-pump 
coronary artery bypass grafting. J Thorac Dis, 2018. 10(6): p. 3381-3389. 
42. 
Russo, J.J., et al., Ischemic and bleeding outcomes after coronary artery bypass grafting among patients initially 
treated with a P2Y(12) receptor antagonist for acute coronary syndromes: Insights on timing of discontinuation of 
ticagrelor and clopidogrel prior to surgery. Eur Heart J Acute Cardiovasc Care, 2019. 8(6): p. 543-553. 
43. 
Hansson, E.C., et al., Coronary artery bypass grafting-related bleeding complications in patients treated with 
ticagrelor or clopidogrel: a nationwide study. Eur Heart J, 2016. 37(2): p. 189-97. 
44. 
Lan, K.K.G. and D.L. DeMets, Discrete Sequential Boundaries for Clinical Trials. Biometrika, 1983. 70(3): p. 
659-663. 
45. 
O'Brien, P.C. and T.R. Fleming, A multiple testing procedure for clinical trials. Biometrics, 1979. 35(3): p. 549-
56. 
 
 

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19. APPENDICES 
 
 

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Appendix 1: Adverse Event Reporting 
An adverse event (AE) is any untoward medical occurrence (signs, symptoms, abnormal laboratory 
findings) in a subject regardless of relationship to the device or procedure. Throughout the study, the 
Investigator or designee will determine adverse event (AE) occurrences. All AEs that occur starting 
from subject enrollment through follow-up will be reported. As a matter of semantics, AEs that are 
new onset or worsen in severity after the start of the cardiopulmonary bypass procedure are 
considered Treatment-emergent AEs. This term does not include adverse events occurring prior to the 
start of CPB but after the signing of the ICF (assent or consent). As previously discussed in Section 
11.6, only the treatment-emergent AEs will be included in the safety analysis. This will be further 
detailed in the SAP. 
 
Each adverse event is considered to be either anticipated or unanticipated as described below. The 
site is required to report the classes of adverse events that occur in the study (AE, SAE, and 
UADE) as described further below. 
Severity Assessment 
The Investigator will assess each adverse event for severity in accordance with the following 
categories: mild, moderate, severe, life-threatening, or death. 
The severity assessment is distinct from the seriousness assessment (see definition of SAE below). 
Serious Adverse Events 
A serious AE (SAE) is defined as any untoward medical occurrence that meets one or more of the 
following criteria: 
• 
led to death; 
• 
led to a life-threatening illness or injury; 
• 
led to in-patient hospitalization or prolongation of existing hospitalization; 
• 
led to disability or permanent damage to a body structure or body function; 
• 
led to fetal distress, fetal death, congenital anomaly, or birth defect; 
• 
required medical or surgical intervention to prevent permanent impairment or damage; or 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
Definition of Hospitalization 
Adverse events requiring hospitalization or extended hospitalization should be considered serious. In 
general, hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. Planned 
hospitalization for pre-existing condition, or a procedure required by the Clinical Investigation Plan, 
without a serious deterioration in health is not considered a serious adverse event. 
 
Serious AEs occurring after 30 days post-operation are to be reported to the Sponsor if, in the 
judgment of the Investigator, there is an association between the event and the previous use of the 
device under investigation. 
Causality Assessment 

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The Investigator will assess each adverse event for relationship to the following (causality), and 
relationship classified as unrelated, unlikely related, possibly related, probably related, or definitely 
related: 
Investigational Treatment/Device: An investigational device/treatment-related adverse 
event is one which in the judgment of the Investigator, results as a consequence of the 
investigational device/treatment. Clinical judgement in conjunction with the relevant 
documents, such as the Investigator’s Brochure and the Clinical Investigational Plan shall be 
applied in the determination of whether the AE might be related to the device/treatment. The 
presence of confounding factors, such as concomitant medication/treatment, the natural 
history of the underlying disease, other concurrent illness or risk factors shall be considered.  
 
Surgical Procedure: The investigator will distinguish between the events potentially related 
to CPB and the investigational device from those related to the underlying surgical 
procedures. A procedure-related adverse event is one which, in the judgment of the 
Investigator, results as a consequence of the subject's surgical procedure and is not specific to 
the investigational device/treatment used or the associated CPB circuit. Complications 
occurring during a procedure are considered not related to the device if the complication 
would have been applied to the subjects in the absence of the investigational device 
use/application. Adverse events that have previously been determined to be related to the 
investigational device should not also be assessed as being related to the surgical procedure. 
 
Causality assessment will also be performed during CEC adjudication of relevant events. Guidelines 
for CEC causality assessments are provided in the CEC charter. 
 
Action Taken for Adverse Events 
The Investigator or designee will record the action taken for the AE within the electronic Case Report 
Form (eCRF) in accordance with the following categories: treatment interrupted, treatment 
withdrawn, medication, procedure/intervention, transfusion, other/unknown, or none. 
Outcome  
The Investigator or designee will record the outcome of the AE within the electronic Case Report 
Form (eCRF) in accordance with the following categories: resolved without sequelae, resolved with 
sequelae, ongoing, or resulted in mortality. 
Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have AEs. Any subject who has 
an ongoing AE that is related to the investigational medical device at the 30-day Follow-up 
Evaluation will be followed up, where possible, until resolution or stabilization. This will be 
completed at the Investigator’s (or designee’s) discretion. Any subject who has an ongoing AE that is 
not related to the investigational medical device at the 30-day Follow-up Evaluation can be closed out 
as ongoing at the Investigator’s discretion. 
Adverse Device Effect:  
An adverse device effect (ADE) is an AE related to the use of an investigational medical device. This 
definition includes AEs resulting from insufficient or inadequate instructions for use, deployment, 
installation, or operation, or any malfunction of the investigational medical device. The definition also 
includes any event resulting from use error or from intentional misuse of the investigational medical 

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device. These events can be classified as either serious or not serious in accordance with the definition 
for SAEs above. Serious adverse device effects are also commonly referred to by the abbreviation 
SADE. 
Unanticipated Adverse Device Effect:  
An unanticipated adverse device effect (UADE) is any adverse device effect which by its nature, 
incidence, severity or outcome has not been identified in the current version of the risk analysis 
report. These events can be classified as either serious or not serious in accordance with the definition 
for SAEs above. In the event of a possible UADE, the subject blind may be broken as per Section 
6.3.3 above. This will enable confirmation of relationship between the adverse event and device 
exposure and facilitate appropriate safety procedures as well as regulatory reporting per guidelines.   
Anticipated Adverse Events/Device Related Adverse Events 
A variety of complications are expected to occur in subjects undergoing CPB and cardiothoracic 
surgery, regardless of whether DrugSorb-ATR is used. These may include, but are not limited to:  
Serious, but less common, risks:  
• 
Bleeding during or after the surgery including bleeding in relation to anticoagulation  
• 
Blood clots that can cause heart attack, stroke, or lung problems  
• 
Heparin-induced thrombocytopenia  
• 
Bypass induced thrombocytopenia  
• 
Reduction in platelets  
• 
Infection, including pneumonia  
• 
Organ injury including:  
- 
Respiratory damage causing breathing problems or failure to wean from the 
ventilator  
- 
Cardiac dysrhythmias/arrhythmias  
- 
Kidney injury or renal failure 
- 
Cognitive impairment  
• 
Death 
 
Less serious, but more common risks and adverse events:  
• 
Low-blood pressure  
• 
Nausea and/or vomiting  
• 
Hypothermia and/or Chills  
• 
Allergic response to device materials  
• 
Reduction in platelet count  
• 
Reduction in white blood cell count  
• 
Reduction in proteins (albumin, total protein)  
• 
Coagulation within device  
• 
Heparin-induced thrombocytopenia  
 
 

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Potential Adverse Device Events Directly Related to DrugSorb-ATR:  
• 
Removal of drugs and hormones  
• 
Allergic response to device materials  
• 
Reduction in platelet count  
• 
Reduction in white blood cell count  
• 
Reduction in proteins (albumin, total protein) which may increase with CPB duration.  
• 
Reductions in serum calcium (as a consequence of reductions in albumin)  
• 
Coagulation within device 
• 
Infection 
• 
Blood loss 
• 
Hemolysis 
• 
Device leakage 
• 
Circuit leakage 
• 
Death  
Investigator Reporting: 
The Investigator at each participating center is ultimately responsible for reporting adverse events to 
the Sponsor or its designee. The information to be reported on the adverse event should include the 
start date of the adverse event, treatment, resolution, and assessment of both the seriousness and the 
relationship to the investigational device. The Investigator (or designee) is required to complete the 
adverse event eCRF at each study visit if an adverse event occurs. One adverse event eCRF must be 
completed for each adverse event. The timing of mandatory Investigator reports is provided in Table 
4.  
If there is a device malfunction or other observation, the Device Observation CRF requires the 
Investigator to indicate if the observation resulted in an adverse event and indicate if complications 
are related to the device, procedure or underlying disease.  
Sponsor Reporting:  
Reports will be provided to the FDA as required under §812.150. The details will be provided in the 
Study Reference Manual for the trial. 

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Appendix 2: Clinical Laboratory Evaluations 
 
Clinical chemistry: 
Hematology: 
Alanine aminotransferase a 
Albumin a 
Alkaline phosphatase a 
Aspartate aminotransferase a 
Blood urea nitrogen 
Calcium 
Ionized Calcium a 
Chloride 
Creatinine 
Direct bilirubin a  
Gamma-glutamyl transferase a 
Glucose 
Potassium  
Sodium 
Total bilirubin a 
Total protein a 
Hematocrit  
Hemoglobin 
Platelet count 
Red blood cell count 
White blood cell (WBC) count 
Differential a 
 
Coagulation tests: 
Other, including cardiac biomarkers 
Coagulation Panel: 
Activated partial thromboplastin time 
International normalized ratio 
Prothrombin time 
Fibrinogen a  
 
Point of Care Test(s): 
Activated clotting time (ACT) [refer to 
Schedule of Assessments for specific timing of 
sampling]  
Serum pregnancy testb 
Cardiac troponin (cTn)c 
a Performed only if part of routine standard of care. Sponsor agrees to forego the data if the assessments are not performed and recorded  
b Performed in serum at Screening for all females of childbearing potential. Pre-consent test results done during the current admission MAY 
be used. Pre-consent test results done before the current admission MAY NOT be used. 
c Performed in serum Screening for all females of child-bearing potential. Post-op testing will be per institutional standard of care, or as 
indicated by symptoms and concern for perioperative myocardial infarction 
 
 

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Appendix 3: Regulatory and Ethical Considerations 
This investigation will be conducted in accordance with the Clinical Investigation Plan (CIP) and with 
the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and 21 CFR Part 812, 50, 54, 56. 
• 
Applicable International Organization for Standardization (ISO) ISO14155 Clinical 
investigation of medical devices for human subjects — Good clinical practice, Good Clinical 
Practice (GCP) Guidelines. 
The CIP, CIP amendments, Informed Consent Form (ICF) along with associated information sheets, 
and other relevant documents must be submitted to an Ethics Committee (EC) by the Investigator and 
reviewed and approved by the EC and regulatory authority before the investigation is initiated.  
Any substantial CIP amendments, likely to affect the safety of the subjects or the conduct of the study, 
will require EC, IRB, and regulatory authority approval before implementation of changes made to 
the study design, except for changes necessary to eliminate an immediate hazard to investigation 
subjects or any non-substantial changes, as defined by regulatory requirements.  
Informed Consent for Non-vulnerable Populations 
Subjects will be given an opportunity to ask questions about the investigation prior to providing 
consent for participation. Written documentation of informed consent is required prior to starting the 
intervention/administering the study product. Consent forms will be IRB-approved, and the subject 
will be asked to read and review the document. The subject should have the opportunity to discuss the 
study with their surrogates or think about it prior to agreeing to participate unless study timeframes do 
not allow for such discussions. The subjects may withdraw consent at any time throughout the course 
of the trial. 
A copy of the signed Informed Consent Form will be given to the subject, and another will be 
maintained in the subject’s records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in the study. 
When informed consent of the subject is not possible because of the subject’s medical condition, the 
informed consent of the legally authorized representative, if present, shall be requested (see the below 
section on Informed Consent for Vulnerable Populations).  
If informed consent is not obtained prior to any research procedures being conducted, the 
investigative site must notify the Sponsor and IRB within 24 hours of knowledge of the incident. 
If new information becomes available, that can significantly affect a subject’s future health and 
medical care, this information shall be provided to the subject(s) affected in written form. If relevant, 
all affected subjects shall be asked to confirm their continued informed consent in writing. 
Informed Consent for Vulnerable Populations  
Considering the nature of the clinical investigation as well as the clinical investigation population, is it 
likely that potential subjects may not be able to give voluntary written informed consent in advance of 
the procedure (vulnerable individual lacking capacity). A personal legally authorized representative 
(preferably the nearest relative or healthcare proxy) of the subject shall be consulted in the event the 
subject is unable to consent for themselves and this person will be the one responsible for assenting to 

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the subject participation in the clinical investigation.  After the procedure is completed, the consent of 
the subject will be obtained as soon as the subject has recovered capacity. Upon regaining capacity, 
those subjects who do not wish to consent, may request that all data obtained under the assent be 
withdrawn from the study database.  
Informed Consent for Subjects Unable to Read or Write 
Informed consent shall be obtained through a supervised oral process if the subject or legally 
authorized representative is unable to read or write. An independent witness shall be present 
throughout the process. The written Informed Consent Form and any other information shall be read 
aloud and explained to the prospective subject and his/her legally authorized representative and, 
whenever possible, shall sign and personally date the Informed Consent Form. The witness also signs 
and personally dates the Informed Consent Form attesting that the information was accurately 
explained, and that informed consent was freely given. 
Disclosure 
All information provided regarding the investigation, as well as all information collected and/or 
documented during the course of the investigation, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written permission 
from the Sponsor. 
 
 

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Appendix 4: Study Schedules 
Table 5. Schedule of Antithrombotic and Anticoagulation Management 
Time period 
Screening/ 
preoperative 
period 
Operation 
Postoperative 
day 1 
>1-day 
post-
operation 
30-day 
follow-up 
Subjects with ACS or coronary stent placement within the previous 6 months 
Aspirin 
X 
X 
Xa 
X 
 
X 
P2Y12 inhibitor 
Prohibited 
Prohibited 
 
SOC ---------------------------- SOC 
Apixaban or rivaroxaban 
Xb 
 
Xc 
Xc 
 
Xc 
Thromboprophylaxis 
 
 
SOC ---------------------------------------------------- SOC 
All other subjects 
Aspirin 
 
SOC -------------------------------------------------------------------------- SOC 
P2Y12 inhibitor 
Prohibited 
Prohibited 
 
SOC ---------------------------- SOC 
Apixaban or rivaroxaban 
Xb 
 
Xc 
Xc 
 
Xc 
Thromboprophylaxis 
 
 
SOC -----------------------------------------------------SOC 
a Subjects not previously on Aspirin in the preoperative setting should be initiated on Aspirin therapy at 6 hours post-op, per institutional 
protocols 
b Last dose is within 36 hours of operation start as per the study inclusion criteria.  
c Timing of apixaban and/or rivaroxaban resumption (or any other form of therapeutic anticoagulation) in the postoperative period is at 
the discretion of the treating physician. Known thrombotic risk must be weighed against anticipated bleeding risk when making this 
decision. 
SOC = per institutional protocols 

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Table 6: Schedule of Assessments 
Study Procedures 
Screening 
Pre-CPB 
Operation 
Post-CPB 
Post-Operation 
Follow-up 
Visit/End of 
Study/Early 
Termination 
Timepoint 
Up to 36 
hours before 
Operation 
Within 
2 hours before 
start of 
operation (i.e., 
skin incision) 
From chest 
incision to 
chest closure 
Within 
30min after 
end of CPB 
ICU Admission  
POD 
1 
POD 
2 
POD 
3 
POD 
4 
POD 
5-29 
POD30 
+ 5 days 
Informed consent/authorization a 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographic information  
X 
 
 
 
 
 
 
 
 
 
 
EuroScore II 
X 
 
 
 
 
 
 
 
 
 
 
STS Risk Score 
X 
 
 
 
 
 
 
 
 
 
 
Last pre-operation dose of DOAC (date, time, 
and dosage) 
X 
 
 
 
 
 
 
 
 
 
 
Medication history within 30 days of study 
enrollment 
X r 
 
 
 
 
 
 
 
 
 
 
Physical exam, height, weight b 
X r 
 
 
 
 
 
 
 
 
 
 
Planned surgical procedure c 
X 
 
 
 
 
 
 
 
 
 
 
Drug removal blood sampling d 
 
X 
X 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
 
X 
X 
X 
X 
X 
X s 
X 
EKG e 
X 
 
 
 
SOC t  
SOC t  
SOC t  
SOC t  
SOC t  
SOC t  
 
Pregnancy test f 
X 
 
 
 
 
 
 
 
 
 
 
Cardiac troponin (cTn) g 
X 
 
 
 
SOC t 
SOC t 
SOC t 
SOC t 
SOC t 
SOC t 
 
Hematology g 
X 
 
 
 
X 
X 
X 
X 
X 
X u 
 
Clinical chemistry g 
X 
 
 
 
X 
X 
X 
X 
X 
X u 
 
Coagulation tests g 
X 
 
 
 
X 
X 
X 
X 
X 
X u 
 
Vital signs h 
X 
 
 
 
SOC 
X 
X 
X 
X 
X s 
SOC 
CPB duration i 
 
 
X 
 
 
 
 
 
 
 
 
DrugSorb-ATR flow rate & flow duration i 
 
 
 
 
 
 
 
 
 
 
 
Surgical procedure type j 
 
 
X 
 
 
 
 
 
 
 
 
Activated Clotting Time (ACT) k 
 
 
X 
X 
 
 
 
 
 
 
 
Arterial Blood Gas (ABG) l 
 
 
X 
X 
X 
 
 
 
 
 
 

Clinical Investigation Plan (CIP)  
CONFIDENTIAL 
 
 CIP Reference Number: 2021-02 
Version 2.1 
STAR-D  
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Study Procedures 
Screening 
Pre-CPB 
Operation 
Post-CPB 
Post-Operation 
Follow-up 
Visit/End of 
Study/Early 
Termination 
Timepoint 
Up to 36 
hours before 
Operation 
Within 
2 hours before 
start of 
operation (i.e., 
skin incision) 
From chest 
incision to 
chest closure 
Within 
30min after 
end of CPB 
ICU Admission  
POD 
1 
POD 
2 
POD 
3 
POD 
4 
POD 
5-29 
POD30 
+ 5 days 
Blood products m 
X--------------------------------------------------------------------X 
X 
X 
X 
X 
X s 
 
Operation blood loss and drainage m 
 
 
X 
 
 
 
 
 
 
 
 
Post-Operation chest tube drainage 
 
 
 
X-------------------------------------X 
 
 
 
 
 
Post-Op blood loss & bleeding m 
 
 
 
 
X 
X 
X 
X 
X 
X s 
X 
Daily assessment 
 
 
 
 
 
X 
X 
X 
X 
X s 
 
Adverse events n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ventilation and mechanical support o 
 
 
 
 
X 
X 
X 
X 
X 
X s 
 
FiO2 p  
 
 
 
 
X 
X 
X 
X 
X 
X s 
 
Vasopressor requirements q 
 
 
 
 
X 
X 
X 
X 
X 
X s 
 
Abbreviations: AE = adverse event; CPB = cardiopulmonary bypass; D = day; h = hour; eCRF = electronic case report form; ICF = Informed Consent Form; ICU = Intensive Care Unit; POD = post-operative 
day; SOC = standard of care. 
a Authorization or informed consent must be obtained at Screening (see Appendix 3) 
b Body mass index will be calculated from the subject’s height and weight measurements obtained at Screening or from the values in the medical record in the current hospital admission. 
c Pre-randomization stratification will be performed based on the planned surgical procedure; changes in the planned surgical procedure should be updated within the IxRS system whenever possible to avoid 
any unintended protocol deviation. 
d Blood samples will be collected for the determination of plasma DOAC concentration at a designated bioanalytical laboratory using a validated assay. The pre-CPB blood sample will be drawn prior to the start 
of cardiopulmonary bypass and can be up to 2hrs prior to skin incision. The post-CPB blood sample will be drawn as soon as possible following the end of CPB, and no later than 30min after the subject has 
been disconnected from the CPB circuit. During the procedure, while the subject is on CPB, serial sampling will be obtained q30±15min up through 2hrs of CPB. If the procedure requires a CPB time of <2hrs, 
then sampling will be q30±15min only up through completion of the CPB. 
e Baseline EKG is required on file within the subject’s medical record pre-op but does not need to have been performed within 36hrs of surgery.  
f In all females of childbearing potential. Performed in serum. Pre-consent test results done during the current admission MAY be used. Pre-consent test results done before the current admission MAY NOT be 
used. 
g Refer to Appendix 2 for a list of evaluations in the hematology, clinical chemistry, cardiac biomarker, and coagulation tests. During Screening, if consented subjects enter the Operation Phase without 
post-consent evaluation of hematology, clinical chemistry, or coagulation tests to record, the last pre-consent laboratory values MAY be used. Intraoperative ACT is documented in the ACT log, and not 
recorded in the Coagulation Test eCRF. 
h Vital signs include supine blood pressure, pulse rate, respiratory rate, oxygen saturation, and body temperature. 
i Duration of CPB = time from the start of CBP to end of CPB, which may differ from duration of operation. Flow rate and flow duration for the device will be recorded q30±5min while patient is on CPB; flow 
rates are not mandated while subject is on hypothermic circulatory arrest (HCA).  
j Details regarding the surgical type will be recorded.  Delayed sternal closure will be recorded. Re-exploration/re-thoracotomy will be recorded according to the same schedule as AEs and documented in the 
re-operation eCRF. 
k ACT will be obtained once at 30min into CPB ±15min, and once within 30min post-protamine administration (post-CPB) 
l During the operation phase, arterial blood gas analysis will be obtained at the following time periods: within 30min pre-CPB, 30±15min into CPB, within 30min post-CPB, and upon admission to the ICU 

Clinical Investigation Plan (CIP)  
CONFIDENTIAL 
 
 CIP Reference Number: 2021-02 
Version 2.1 
STAR-D  
Page 76 of 77 
m Blood product administration will be monitored and recorded from the point of consent through discharge. Cell Saver will not be included as blood product administration.  Blood loss and bleeding events will 
be monitored and recorded through follow-up, and drainage will be monitored from chest closure to 12h post-op (for UDPB class) and continued from 12hr post-op through at least 24h post-operation. 
Measurement of drainage after 24h and through time of chest/mediastinal drain removal will be per SOC. 
n All AEs will be recorded from point of authorization to participate in the study through the 30-day Follow-up. If an AE occurs, appropriate diagnostic and therapeutic measures are to be taken and the 
investigation treatment may be discontinued if deemed clinically necessary. Follow-up evaluations of the subject are to be performed until the subject recovers or until the clinical Investigator considers the 
situation to be no longer clinically significant. Serious AEs occurring after 30 days post-operation are to be reported to the Sponsor if, in the judgment of the Investigator, there is concern for potential 
association between the event and the use of the DrugSorb-ATR device.  
o If subject is intubated/requires mechanical ventilatory support, the maximum ventilation and mechanical support requirements will be recorded for each day.  
p Documented in the ABG eCRF; only required if the subject is intubated or on mechanical ventilatory support 
q The maximum vasopressor dosage will be recorded each day. 
r Physical exam performed on the day of screening as part of standard of care but occurring prior to signing of informed consent may be used for the screening PE. The physical exam and review of concomitant 
medication history will be repeated on the day of the procedure, if the day of the procedure is different than the day of screening 
s Assessments completed daily through hospital discharge.    
t In the advent of any cardiac ischemic AEs, EKG (to assess for Q waves) and cTn must be obtained. EKG will be provided as source documentation for CEC adjudication. cTn will be documented within the 
laboratory eCRF for CEC event adjudication 
u Through postoperative day 5 only. 

Clinical Investigation Plan (CIP)  
CONFIDENTIAL 
 
 CIP Reference Number: 2021-02 
Version 2.1 
STAR-D  
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Appendix 5: Antithrombotic Medications Allowed/Disallowed in the Preoperative Period 
Aspirin – allowed 
 
Ticagrelor – any use within 7 days disallowed (as may have confounding effects on bleeding) 
 
Clopidogrel – any use within 7 days disallowed (as may have confounding effects on bleeding) 
 
Prasugrel – any use within 7 days disallowed (as may have confounding effects on bleeding) 
 
Cangrelor – any use within 4 hours of (or during) the index procedure is disallowed (as may have 
confounding effects on bleeding) 
 
Argatroban – any use within 4 hours of (or during) the index procedure is disallowed 
 
Bivalirudin – any use within 2 hours of (or during) the index procedure is disallowed 
 
Heparin – allowed 
 
Low molecular weight heparin (e.g., enoxaparin) and fondaparinux – allowed 
 
Dabigatran and edoxaban – any use within 5 days is disallowed, as it may have confounding effects 
on bleeding 
 
Warfarin – any use within 7 days disallowed (as may have confounding effects on bleeding) 
 
Tirofiban – any use within 8 hours disallowed as may have confounding effects on bleeding 
(restoration of platelet function normally occurs within approximately 4 hours)1  
 
Eptifibatide – any use within 8 hours disallowed as may have confounding effects on bleeding 
(restoration of platelet function normally occurs within approximately 4 hours)1 
 
Abciximab – any use within 5 days disallowed as may have confounding effects on bleeding 
(restoration of platelet function normally occurs within approximately 72 hours)1 
 
References (for this appendix only): 
1. Schrör K, Weber AA. Comparative Pharmacology of GP IIb/IIIa Antagonists. J Thromb Thrombolysis. 
15:71–80.