Safe, Timely Antithrombotic Removal-Ticagrelor (STAR-T): Double-blind Randomized Study of Reduction in Bleeding by Ticagrelor Removal Via Intraop Use of DrugSorb-Antithrombotic Removal (ATR) in Cardiac Surgery Patients <2 Days of Drug Stop
Phase: NA
Conditions: Hemorrhage, Surgical, Blood Loss, Surgical, Blood Loss, Postoperative, Hemorrhage Postoperative
Sponsor: CytoSorbents, Inc

STAR-T 
Version 5.1  
TITLE PAGE 
Clinical Investigation Plan 
Safe and Timely Antithrombotic Removal - Ticagrelor (STAR-T): A 
Prospective, Multi-center, Double-blind, Randomized, Study to Evaluate 
Reduction in Postoperative Bleeding by Removal of Ticagrelor with the 
Intraoperative use of the DrugSorb-ATR Device in Patients Undergoing 
on-pump Cardiothoracic Surgery within Two Days of Ticagrelor 
Discontinuation. 
Clinical Investigation Plan Status: Final 
Clinical Investigation Plan Version 5.1 Date: 26-May 2023 
Investigational Medical Device: DrugSorb-ATR 
Global Trade Item Number: 01230000006002 
  
CytoSorbents Clinical Investigation Plan Reference Number: 2021-01 
 
 
 
 
Sponsor: 
CytoSorbents, Inc. 
305 College Road East 
Princeton, New Jersey 08540  
 
 
 
Sponsor Signatory: 
Efthymios Deliargyris, MD, FACC, FESC, FSCAI 
 
Chief Medical Officer 
 
Information described herein is confidential and may be disclosed only with the express written 
permission of the Sponsor. 
 
 
 
 
 
 

STAR-T 
Version 5.1  
SIGNATURE PAGE – SPONSOR APPROVAL 
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. 
 
SPONSOR APPROVAL 
I have read the Clinical Investigation Plan and approve it: 
 
 
_
                           May 26, 2023_____ 
Efthymios Deliargyris, MD, FACC, FESC, FSCAI 
 
Date 
Chief Medical Officer 
 
BRIEF PROTOCOL REVISION HISTORY 
Version 
Date 
Brief Description of Changes 
Final 
3-15-2021 
Original Submission 
1.1 
4-12-2021 
The following sections were updated to address requests by the 
agency: 
• 
Inclusion/Exclusion Criteria 
• 
Potential Investigational Device Risks 
• 
Addition of a Secondary Endpoint: Re-exploration for 
excessive bleeding  
• 
Maintaining the Study Blind 
• 
Schedule of Events 
1.2 
4-15-2021 
Revised wording in 9.2.6 and Table 6 
1.3 
5-19-2021 
Labeling for the DrugSorb device has been updated to reflect 
current trademark status more accurately (DrugSorb® to 
DrugSorb)  
 
The following sections and subsections were updated to address 
suggestions by the agency: 
• 
Study Design 
• 
Primary Effectiveness Endpoint 
• 
Addition of an exploratory endpoint: AUC for 
intraoperative ticagrelor PK analysis 
• 
Blood Sampling for Drug Removal 
• 
Data Safety and Monitoring Board (DSMB) 
• 
Statistical Considerations 
 
The following sections were updated to provide additional 
guidance for investigators:  
• 
Study Justification 
• 
Subject Randomization 

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• 
Field Clinical Engineers 
• 
Unblinding Procedure 
• 
Bleeding Event AEs 
• 
Unanticipated Adverse Device Events 
1.3 
7-6-2021 
Update on the timing of blood sampling for the drug removal 
endpoint: the post-CPB sample should be collected as soon as 
possible following the end of CPB, and no later than 30min after 
the subject has been disconnected from the CPB circuit 
2.0 
12-12-2021 
Updates have been made to the protocol wording and details to 
ensure clarity and consistency in the following sections: 
• 
Synopsis 
• 
Sections: 1, 4, 6, 7, 9, 11 
• 
Table 6 
• 
Figures 3 and 5 
• 
Appendix 2 
 
Number of allowed study sites increased from 20 to 30. 
 
Statistical Considerations (Section 11) has been adjusted to correct 
typographical errors, better match sister study (STAR-D, 
G210263), describe stratified Win Ratio analysis, and add more 
conservative stopping boundaries for the pre-specified interim 
analysis.  
3.0 
01-21-2022 
• 
Language around inclusion criteria #3 has been updated 
to allow enrollment of patients undergoing CT surgery 
with CPB “within two days following ticagrelor 
discontinuation (date of last dose = day 0).” 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 where relevant 
• 
All references to prior eligibility timeframe of “48hrs 
since last ticagrelor dose” have been updated to “within 
two days of ticagrelor discontinuation” through-out the 
protocol to ensure consistency with the above 
• 
Language around exclusion criteria #1 has been revised to 
exclude those patients who are undergoing 
“cardiothoracic surgery occurring 3 or greater following 
ticagrelor discontinuation.” This update has been made 
within the protocol Synopsis and Section 4.4.2 Exclusion 
Criteria 
• 
The screening period described in Table 6 (Schedule of 
Assessments) has been updated to “Up to two days prior 
to the day of operation,” to maintain consistency with the 
revised Inclusion Criteria #3 
• 
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, with supplemental 
analysis to be performed on the ITT population. This 
language has been updated in the protocol Synopsis and 
Section 11.2 Analysis Populations accordingly 
4.0 
08-10-2022 
• 
Geographic location of study sites has been updated to 
include both the US and Canada (Synopsis and Section 
1.1) 
• 
The term “response rate” has been revised to “effect size” 
in Section 11.1 Statistical Power and Sample Size 
Determination  
• 
Additional clarifying language added around the ITT, 

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mITT, PP, and Safety Populations, and their planned 
analysis (Synopsis and Section 11.2) 
• 
Language around stratification of the Win Ratio analysis 
by study site and surgery type has been removed from 
Section 11.3 Effectiveness Analysis 
• 
Language around planned subgroup analyses has been 
moved to a separate section (Section 11.4 Subgroup 
Analysis) 
• 
Typographic error has been corrected in Section 11.6 
Treatment of Missing Data 
• 
Language incorrectly referring to subgroup analysis of 
safety results in Section 11.7 Safety Analysis has been 
removed 
4.1 
09-16-2022 
• 
The following sections/subsections were updated to 
clarify safety analysis as proposed by the Agency in their 
response to the STAR-T IDE: Synopsis and Section 11.7  
• 
The following sections/subsections were updated to 
address primary hypothesis proposed by the Agency in 
their response to the STAR-T IDE: Section 11   
• 
Updates were made to Executive Committee membership 
(Study Organization) 
• 
Updates were made to include abbreviations for per 
population and safety analysis (List of Abbreviations) 
5.0 
04-02-2023 
• 
The interim analysis will not be performed. Mention of 
the interim analysis has been removed from the synopsis, 
from the DSMB oversight duties, and Section 11.5, 
Interim Analysis has been deleted. 
• 
The planned enrollment is increased to up to 140 subjects. 
• 
Table 6 (Schedule of Assessments) in Appendix 4 has 
been modified to specify that certain assessments (vital 
signs), laboratory testing (hematology, clinical chemistry 
and coagulation panel), and other assessments related to 
mechanical ventilation, FiO2 and vasopressor 
requirements will only be scheduled as part of the trial 
through postoperative day 2. These tests are optional 
beyond post-operative day 2, and may be recorded if they 
are performed in accordance with SOC at the particular 
institution.  
• 
Clarifications have been added and typographical errors 
have been fixed.  
5.1 
05-26-2023 
• 
Updates were made to Executive Committee membership 
(Study Organization) 
• 
Addition of  Exclusion Criterion #15 for performance of 
Acute Normovolemic Hemodilution (ANH) (Synopsis 
and Section 4.4.2 Exclusion Criteria) 
• 
The actual number of patients reflecting the 15% site 
enrollment cap (i.e., 18 subjects) has been removed 
(Sections 6.2 and 11.1) 

STAR-T 
Version 5.1  
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 
 
 
 
 
 
 
 
 
 
 
 

STAR-T 
Version 5.1  
SYNOPSIS 
Title of investigation: Safe and Timely Antithrombotic Removal - Ticagrelor (STAR-T): A Prospective, 
Multicenter, Double-blind, Randomized, Study to Evaluate Reduction in Postoperative Bleeding by 
Removal of Ticagrelor with the Intraoperative use of the DrugSorb-ATR Device in Patients Undergoing 
on-pump Cardiothoracic Surgery within Two Days of Ticagrelor Discontinuation. 
 
Objectives: 
• 
To demonstrate reductions in postoperative bleeding complications with the intraoperative use of 
DrugSorb-ATR in patients undergoing cardiothoracic surgery within two days of ticagrelor 
discontinuation. 
• 
To demonstrate reductions in ticagrelor blood levels ([ticagrelor]) 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: 
Ticagrelor is a reversibly-binding inhibitor of the platelet P2Y12 receptor, antagonizing the activation of 
P2Y12 by ADP. [1] Ticagrelor is indicated to reduce thrombotic cardiovascular events in patients with acute 
coronary syndrome (ACS). [1]  As with all antithrombotics, the predominant safety concern with ticagrelor is 
the risk of bleeding. For patients on ticagrelor requiring cardiothoracic surgery, the 2011 ACCF/AHA 
guidelines for CABG recommend discontinuing ticagrelor at least 5 days before elective surgery, and at least 
24 hours prior to urgent surgery. [2] [3] Nonetheless, the PLATO study showed that up to 5% of patients on 
ticagrelor may require  cardiac surgery before the recommended washout period. [4] In those patients, very 
high rates of major bleeding were observed especially if the surgery occurred within two days of ticagrelor 
discontinuation.[5, 6] Likewise, patients on ticagrelor initially deemed stable enough to attempt washout 
before cardiothoracic surgery may still experience clinical deterioration and therefore benefit from urgent 
surgery before complete washout. Currently, there is no intervention available to address this significant 
unmet medical need from ticagrelor-induced surgical bleeding in the patients who proceed to surgery before 
complete washout. 
 
The DrugSorb-Anti Thrombotic Removal (ATR) device has high affinity for binding hydrophobic small 
molecules and drugs (~5-kDa to 60-kDa). Data on drug removal capabilities of the device have previously 
been published in Europe under the name CytoSorb®. However, DrugSorb-ATR is the appropriate name 
whenever reference is being made to the device’s specific use in the indication of antithrombotic drug 
removal (ATR), unless citing previously published data. In such cases the name CytoSorb® will be used to 
remain consistent with the literature.   
 
Ticagrelor is rapidly and efficiently removed from whole blood by DrugSorb hemoadsorption. An early 
benchtop experiment published by Angheliou et. al. demonstrated peak ticagrelor removal rate of 94-99% 
during 3-10hr recirculating experiments. [7] Additional preclinical studies have demonstrated that the bulk 
of ticagrelor removal from blood happens early with >60% removal in the first 60 minutes and 
approximately 80% removal by 90 minutes of DrugSorb-ATR hemoadsorption (unpublished data). 
 
A retrospective case-series study from Asklepios Klinik St. Georg (Hamburg, Germany) evaluated the use of 
the CytoSorb® device in (primarily ACS) patients on ticagrelor undergoing emergent cardiothoracic surgery 
with cardiopulmonary bypass (CPB). Patients on ticagrelor 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 in patients managed with CytoSorb® compared with the control 
cohort.[8] No device-related adverse events (AEs) or device malfunctions/deficiencies were reported. Since 
January 2020, the CytoSorb® device has CE mark approval for the removal of ticagrelor during surgery 
requiring cardiopulmonary bypass (CPB). 
 
Thus, as a result of these preclinical and clinical findings, the Sponsor proposes to conduct a prospective, 
multi-center, double-blind, randomized, clinical trial to demonstrate that DrugSorb-ATR use during CPB 
significantly reduces postoperative bleeding complications and efficiently removes ticagrelor in patients 
undergoing cardiothoracic surgery within two days of ticagrelor discontinuation, while demonstrating a 

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favorable safety profile.  
 
Hypothesis:  
In patients undergoing cardiothoracic surgery on CPB within two days of ticagrelor discontinuation, 
intraoperative ticagrelor removal with DrugSorb-ATR will significantly reduce postoperative bleeding 
complications. 
Endpoints: 
Primary Effectiveness Endpoint: 
• 
Perioperative bleeding complications, assessed by the ranked composite of:  
1) Fatal perioperative 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 Endpoint:  
Change in blood ticagrelor levels ([ticagrelor]) pre- vs. post-CPB measured by liquid 
chromatography/tandem mass spectrometry (LC/MS-MS) 
 
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 ticagrelor pharmacokinetic (PK) 
concentration  
• 
Duration of index operation (minutes); 
• 
Length of ICU stay; 
• 
Length of hospital stay; 
• 
30-day hospital readmissions. 
 
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 
• 
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 the DrugSorb-ATR device to reduce postoperative bleeding as measured by a composite 
endpoint of: fatal perioperative bleeding (occurring within 48hrs of the index operation), moderate, severe, 
or massive bleeding (UDPB ≥2), and 24-hour chest tube drainage in patients undergoing cardiothoracic 
surgery requiring CPB within two days of ticagrelor discontinuation. Subjects will be randomized in a 1:1 
ratio to either standard of care (SOC) alone (control arm) or standard of care plus intraoperative ticagrelor 
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 device in the investigational arm, with the entire set-up covered by a drape to maintain the 

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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) site, and b) 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 confounding effects arising 
from differing institutional practices and from procedure-specific CPB duration (i.e., device exposure – 
treatment duration) and bleeding risk. 
Number of subjects: 
Up to 140 subjects will be randomized into the study (70 into each arm).  
 
Number of sites: 
Approximately 30 investigational sites in the US and Canada 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 within two days of ticagrelor discontinuation (last day of 
completed ticagrelor treatment = day 0): 
• CABG alone 
• Valve repair or replacement 
• Combination surgery (i.e., CABG + valve operation) 
• Aortic surgery 
Exclusion criteria: 
1. Cardiothoracic surgery occurring 3 days or greater following ticagrelor discontinuation  
2. Heart-lung transplant procedures 
3. Procedures for ventricular assist device (i.e., implant or revision of LVAD or RVAD) 
4. Any of the below conditions that pose a known risk for bleeding: 
• Heparin induced thrombocytopenia 
• Peri-operative platelet count < 50,000 µ/L 
• Hemophilia 
• INR > 1.5 
5. Prohibited concomitant antithrombotic medications (reference Appendix 5 of study protocol); 
6. Acute sickle cell crisis 
7. Known allergy to any of the device components 
8. Subjects with active (untreated) systemic infection  
9. Subjects with a history of major organ transplantation and those currently receiving 
immunosuppressive medication (corticosteroids excluded) or who are profoundly immune 
suppressed 
10. Women of childbearing potential with a positive pregnancy test performed during the current 
admission or who are breast-feeding 
11. Subjects with life expectancy of <30 days (not inclusive of the critical condition that is requiring 
the cardiac operation under study) 
12. Inability to comply with the requirements of the study protocol 
13. Treatment with an investigational drug or device within 30 days prior to surgery 
14. Subjects with previous enrollment in this trial 
15. Subjects in whom acute normovolemic hemodilution (ANH) is used perioperatively 
 

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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: 
The DrugSorb-ATR device is a sorbent-filled hemoperfusion cartridge that is able to efficiently adsorb 
ticagrelor 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 the DrugSorb-
ATR device. 
Statistical methods: 
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 perioperative bleeding events (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.[9] [10] 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 key secondary effectiveness endpoint is the pre-CBP vs. post-CPB change in ticagrelor blood levels as 
measured by liquid chromatography/tandem mass spectrometry [drug removal endpoint]. Change in each 
subject’s blood concentration of ticagrelor ([ticagrelor]) from immediately before to immediately after 
CPB will be collected and analyzed by a central core laboratory. 
 
Change from baseline in blood concentration of ticagrelor is defined as:  
 
               pre-CPB [ticagrelor]blood - post-CPB [ticagrelor]blood  *100% 
pre-CPB [ticagrelor]blood 
 
Based on existing benchtop evidence, a conservative estimate of 40% reduction in blood concentration of 
ticagrelor 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. We anticipate that drug removal data from clinical use in 
this application will become available during the course of the study and we plan to validate the above 
assumption based on the in vivo data. 
 
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. 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.  

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Sample Size 
Up to 140 subjects will be randomized in a 1:1 ratio to the treatment and control arms.  Sample size is based 
on assumed response rates for the primary effectiveness Win Ratio sub-components, and can be calculated 
via an iterative simulation process with programming code available in an appendix to Redfors et al. 
(2019).[11] With a Finkelstein-Schoenfeld test, total of 57 subjects per arm ensures power of >99.7%, using 
a two-sided alpha (α) of 0.05. With this same per arm sample size, power for the key secondary endpoint is 
estimated at >99.9%, 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. 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. 
 
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 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 in the mITT population. 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 supplemental analysis. 
 
The Safety Analysis (SA) Population will include all enrolled subjects who are treated with a study device.  
 
Safety Analysis 
All the safety endpoints will be analyzed in the SA population. Additional safety analyses will be conducted 
on the mITT and PP Population if they are different from the SA population.   
 
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). The primary role of the DSMB is to 
oversee the safety of subjects enrolled in the study. 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 who are not involved in the clinical investigation will act as the Clinical 
Events Committee (CEC) under the direction of 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. 
 
STUDY ORGANIZATION 

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Sponsor:  
CytoSorbents, Inc. 
 
Executive Committee: 
• 
U.S. Principal Investigators: 
O Michael Mack, MD (Baylor Scott & White Health) 
O C. Michael Gibson, MD (Beth Israel Deaconess Medical Center) 
• 
Canada Principal Investigator: 
O Richard Whitlock, MD (McMaster University) 
• 
Members: 
O David Schneider, MD (University of Vermont Medical Center) 
O Frank Sellke, MD (Brown University; Rhode Island Hospital and The Miriam 
Hospital) 
O Vinod Thourani, MD (Piedmont Heart Institute) 
o C. David Mazer, MD (St. Michael’s Hospital- Toronto) 
o James Demetrios Douketis, MD (McMaster University; St. Joseph’s Healthcare 
Hamilton) 
o Efthymios Deliargyris, MD (CytoSorbents, Inc.) 
 
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 
 
 
 

STAR-T 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SIGNATURE PAGE – SPONSOR APPROVAL .....................................................................2 
SIGNATURE PAGE – INVESTIGATOR AGREEMENT ......................................................5 
SYNOPSIS .................................................................................................................................6 
STUDY ORGANIZATION .....................................................................................................10 
TABLE OF CONTENTS .........................................................................................................12 
LIST OF TABLES AND FIGURES........................................................................................15 
LIST OF ABBREVIATIONS ..................................................................................................16 
1. 
INTRODUCTION ...........................................................................................................18 
1.1. 
Background and Clinical Need ..............................................................................18 
1.2. 
Preclinical Data Informing Study Design ..............................................................19 
1.3. 
Clinical Data Informing Study Design ..................................................................20 
1.4. 
Device Background and Nomenclature .................................................................20 
1.5. 
Study Design ..........................................................................................................20 
2. 
DRUGSORB -ATR DESCRIPTION AND INTENDED USE .....................................21 
2.1. 
Description of the DrugSorb-ATR Device and Principle of Operation ..............21 
2.2. 
Treatment Conditions.............................................................................................22 
2.3. 
Device Accountability ...........................................................................................23 
2.4. 
Use of the Investigational Device ..........................................................................23 
2.5. 
Investigational Device/Procedures Training ..........................................................23 
3. 
STUDY JUSTIFICATION ..............................................................................................24 
4. 
INVESTIGATIONAL PLAN ..........................................................................................27 
4.1. 
Study Objective(s) .................................................................................................27 
4.2. 
Study Design ..........................................................................................................27 
4.3. 
Study Outcomes .....................................................................................................28 
4.3.1. 
Primary Effectiveness Endpoint: .................................................................28 
4.3.2. 
Key Secondary Effectiveness Endpoint: .......................................................28 
4.3.3. 
Additional Secondary Effectiveness Endpoints: ..........................................28 
4.3.4. 
Exploratory Endpoint(s): .............................................................................28 
4.3.5. 
Primary Safety Endpoint: ............................................................................28 
4.3.6. 
Additional Safety Endpoints: .......................................................................28 
4.4. 
Subjects and Selection of Study Population ..........................................................28 
4.4.1. 
Inclusion Criteria: ........................................................................................29 
4.4.2. 
Exclusion Criteria: .......................................................................................29 
4.4.3. 
Informed Consent & Enrollment Procedures:..............................................29 
4.4.4. 
Subject Withdrawal/Discontinuation: ..........................................................30 
5. 
POTENTIAL RISK/BENEFIT ........................................................................................31 
5.1. 
Potential Investigational Device Risks ..................................................................31 

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5.2. 
Potential Benefits ...................................................................................................31 
5.3. 
Risk Mitigation ......................................................................................................31 
6. 
STUDY TREATMENT ...................................................................................................33 
6.1. 
Pre-randomization Stratification ............................................................................33 
6.2. 
Subject Randomization ..........................................................................................34 
6.3. 
Blinding..................................................................................................................34 
6.3.1. 
6.3.1  Maintaining the Study Blind ..............................................................35 
6.3.2. 
Study devices ...............................................................................................36 
6.3.3. 
Unblinding Procedure ..................................................................................36 
6.4. 
Field Clinical Engineers .........................................................................................36 
6.5. 
Device Quality Complaints: Deficiencies, Malfunctions, and Observations ........37 
7. 
STUDY OVERSIGHT.....................................................................................................37 
7.1. 
Data and Safety Monitoring Board (DSMB) .........................................................37 
7.2. 
Clinical Events Committee (CEC) .........................................................................38 
7.3. 
Executive Committee .............................................................................................38 
7.4. 
Central Laboratory .................................................................................................38 
8. 
STUDY MONITORING .................................................................................................38 
8.1. 
Monitor Training ....................................................................................................38 
8.2. 
Site/Investigator Training ......................................................................................38 
8.3. 
Site Monitoring ......................................................................................................38 
8.4. 
Regulatory Agency Inspection ...............................................................................39 
9. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................39 
9.1. 
Procedures and Assessments by Study Phase ........................................................39 
9.1.1. 
Screening Phase and the Pre-CPB Phase .....................................................40 
9.1.2. 
Operation Phase ...........................................................................................41 
9.1.3. 
Postoperative phase through 30-day evaluation ..........................................42 
9.2. 
Safety and Tolerability Assessments .....................................................................42 
9.2.1. 
Adverse Events ............................................................................................42 
9.2.2. 
Medical History ...........................................................................................43 
9.2.3. 
Clinical Laboratory Evaluations ..................................................................43 
9.2.4. 
Vital Signs ....................................................................................................44 
9.2.5. 
Physical Examination...................................................................................44 
9.2.6. 
Other Assessments: Blood Products and Blood Loss ..................................44 
9.3. 
Blood Sampling for Drug Removal .......................................................................44 
10. CONCOMITANT MEDICATIONS ...............................................................................45 
11. STATISTICAL CONSIDERATIONS.............................................................................45 
11.1. Statistical Power and Sample Size Determination .................................................45 
11.2. Analysis Populations ..............................................................................................46 
11.3. Effectiveness Analysis ...........................................................................................47 
11.4. Subgroup Analysis .................................................................................................48 

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11.5. Treatment of Missing Data ....................................................................................49 
11.6. Safety Analysis ......................................................................................................49 
11.7. Device Malfunctions/Deficiencies .........................................................................49 
11.8. Disposition and Baseline Characteristics ...............................................................49 
12. DATA HANDLING AND RECORD KEEPING ...........................................................49 
12.1. Data Management Procedures ...............................................................................50 
12.2. Subject Data Protection..........................................................................................50 
12.3. Data retention .........................................................................................................50 
12.4. Investigator Records ..............................................................................................51 
12.5. Investigator Reports ...............................................................................................51 
13. QUALITY CONTROL AND ASSURANCE .................................................................52 
13.1. Site and Investigator Selection ...............................................................................52 
13.2. Protocol Deviations ................................................................................................52 
13.3. Protocol Deviation Process ....................................................................................52 
13.4. Corrective/Preventative Action ..............................................................................52 
13.5. Data Quality Assurance .........................................................................................53 
14. TERMINATION OF STUDY OR STUDY SITE PARTICIPATION ............................53 
15. ETHICS/PROTECTION OF HUMAN SUBJECTS .......................................................54 
15.1. Statements of Compliance .....................................................................................54 
15.2. Institutional Review Board (IRB) ..........................................................................54 
15.3. Informed Consent Process .....................................................................................54 
15.4. Subject Confidentiality ..........................................................................................54 
16. PROTOCOL AMENDMENTS .......................................................................................55 
17. PUBLICATION POLICY ...............................................................................................55 
18. REFERENCES ................................................................................................................56 
19. APPENDICES .................................................................................................................57 
Appendix 1: Adverse Event Reporting ..............................................................................57 
Appendix 2: Clinical Laboratory Evaluations ...................................................................61 
Appendix 3: Regulatory and Ethical Considerations .........................................................62 
Appendix 4: Schedule of Assessments ..............................................................................64 
Appendix 5: Antithrombotic Medications Allowed/Disallowed .......................................68 
 
 
 

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LIST OF TABLES AND FIGURES 
Table 1. Bleeding Class According to the Universal Definition of Perioperative 
Bleeding in Adult Cardiac Surgery ..............................................................................26 
Table 2. Risks and Mitigation Strategies ...........................................................................32 
Table 3. Win Ratio Effect Size Assumptions with Power and Sample Size Estimates .....46 
Table 4. Responsibilities for Preparing and Submitting Reports .......................................51 
Table 5. Schedule of Antithrombotic and Anticoagulation Management .........................64 
Table 6: Schedule of Assessments .....................................................................................65 
 
Figure 1: Removal of Ticagrelor From Whole Bovine Blood Ex Vivo ............................20 
Figure 2. DrugSorb-ATR Device ....................................................................................21 
Figure 3. DrugSorb-ATR Integration in the Cardiopulmonary Bypass Circuit ..............22 
Figure 4. Comparison of Natural Washout (Onset-Offset Study) versus 
CytoSorb®/DrugSorb-ATR Washout (In-vitro test) From Cmax ................................25 
Figure 5. Investigation Schematic ......................................................................................40 

STAR-T 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACS 
Acute coronary syndrome 
ADE 
Adverse device effect 
ADP 
Adenosine diphosphate 
AE 
ANH 
Adverse event 
Acute normovolemic hemodilution 
ATR 
Anti-Thrombotic Removal 
AUC 
Area under the concentration time curve 
CABG 
Coronary artery bypass grafting 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CPB 
Cardiopulmonary bypass 
CIP 
Clinical investigation plan 
CRO 
Contract Research Organization 
Cryoppt 
Cryoprecipitate 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
EC 
Ethics committee 
ECG 
Electrocardiogram 
FDA 
US Food and Drug Administration 
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 
PCC 
Prothrombin complex concentrates 
PK 
Pharmacokinetic 
PLATO 
Platelet Inhibition and Patient Outcomes 
PLT 
Platelet concentrates 
PP 
Per Protocol 
PRBC 
Packed red blood cells 
RCT 
Randomized controlled trial  
rFVIIa 
Recombinant activated factor VII 

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SA 
Safety Analysis 
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 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 

STAR-T 
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1. INTRODUCTION 
1.1. 
Background and Clinical Need 
Ticagrelor is a reversibly binding inhibitor of the platelet P2Y12 receptor, antagonizing the activation 
of P2Y12 by adenosine diphosphate (ADP). Ticagrelor is indicated to reduce thrombotic 
cardiovascular events in patients with acute coronary syndrome (ACS). [1] As with any drug that 
inhibits platelet function, the predominant safety concern with ticagrelor is the heightened risk of 
bleeding. For patients on ticagrelor requiring cardiac or cardiothoracic surgery, the 2011 ACCF/AHA 
guidelines recommend discontinuing ticagrelor at least 5 days before elective CABG, and at least 24 
hours before urgent CABG. [2]  
The pivotal study of Platelet Inhibition and Patient Outcomes (PLATO) study compared ticagrelor to 
another P2Y12 receptor antagonist, clopidogrel, administered with aspirin and other standard therapy 
in patients with ACS for the prevention of major adverse cardiovascular events. [4] In the PLATO 
study approximately 10% of the study population required coronary artery bypass grafting (CABG) 
surgery and approximately half of those patients had CABG before the recommended washout period. 
These patients experienced very high rates of serious postoperative bleeding, especially if the 
operation was within two days of ticagrelor discontinuation. [4] Importantly, studies in this setting 
have shown that platelet transfusions are inefficient in reversing the antiplatelet action of ticagrelor 
and limiting the excess bleeding risk, which is consistent with the drug labeling. [3] [12]  
In contrast to ticagrelor that requires washout before surgery, aspirin is continued during coronary 
artery bypass grafting (CABG) in standard-of-care practices at United States (US) and Canadian 
centers.  The rationale is that although there is some evidence that aspirin increases the risk of 
bleeding in CABG patients, on balance the protective benefits are generally thought to outweigh the 
bleeding risk. Practice guidelines from the ACCF and AHA in 2011 therefore recommend not 
discontinuing aspirin in patients undergoing CABG. [2] Indeed, the above guidelines recommend that 
if aspirin was not initiated pre-operatively, it should be initiated (100mg-325mg) within six hours 
postoperatively and continued indefinitely to improve graft patency and reduce risk of adverse 
cardiovascular events. 
 
The effects of ticagrelor in combination with aspirin versus aspirin alone on bleeding in CABG 
patients can be estimated from observational studies that investigated the timing of ticagrelor 
discontinuation and bleeding in CABG patients.  In the SWEDEHEART registry, patients who 
underwent CABG ≤24 hours following ticagrelor discontinuation (with aspirin continued) had an 
incidence of major bleeding [Bleeding Academic Research Consortium-CABG (BARC-4) definition] 
of approximately 38%.[13] This incidence was reduced to <10% in those undergoing surgery 4-5 days 
after ticagrelor discontinuation. Data from PLATO showed that >65% of patients who underwent 
CABG within 24 hours of ticagrelor discontinuation experienced major, life-threatening, or fatal 
CABG-related bleeding (PLATO definition). In contrast, patients who underwent CABG 4-5 days 
after discontinuation of ticagrelor had an incidence of major/life-threatening/fatal bleeding of 
27.8%.[5] It can be inferred from this that dual antiplatelet therapy with ticagrelor and aspirin has a 
large impact on bleeding that is greatly reduced if standard recommended wash-out durations are 
followed (time taken for offset of action of ticagrelor). Similar results from review of the European 
Multicenter Registry on Coronary Artery Bypass Grafting (E-CABG) are detailed in Section 3. 
Currently, there are no available interventions to address the significant unmet medical need in 
patients whose clinical condition necessitates cardiothoracic surgery before adequate washout of 
ticagrelor can occur. It is for this reason, DrugSorb- ATR has been designated a Breakthrough 
Device by the FDA. 

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1.2. 
Preclinical Data Informing Study Design 
Preclinical studies have shown that ticagrelor is rapidly and efficiently removed from whole blood by 
CytoSorb® hemoadsorption. Of note, DrugSorb-ATR is identical to the CytoSorb® device but with 
an updated name (refer to Section 1.4 for details). To maintain consistent nomenclature with that used 
in published data, the device will be referred to by its historic name CytoSorb® in the discussions of 
preclinical and clinical data informing study design.  
Human Whole Blood Experiments 
Removal of ticagrelor from human whole blood ex vivo by CytoSorb® hemoadsorption has been 
shown in a model using approximately 500 mL of blood obtained from healthy volunteers. [7] The 
blood was placed in a one-liter perfusion bag and was anticoagulated with heparin and mixed with 
18.1 mg of ticagrelor. The blood-drug mix was then allowed to equilibrate for 30 minutes at room 
temperature under gentle agitation of the bag to achieve a starting drug concentration of 70 μmol/L 
(36.2 μg/mL). This high drug concentration was reportedly chosen to provide a large dynamic range 
to study changes in drug concentration over the time course of the experiment. Using a standard 
infusion pump, blood was then circulated from the bag through the CytoSorb® device at a flow rate of 
17 mL/min, a rate that circulates 500 mL every 29 minutes, and then back to the bag. (Note: for 
comparison, a 60 kg human with an estimated total blood volume of 4.7 L will circulate this total 
blood volume through the CytoSorb® device every 16 minutes at a flow rate of 300 mL/min). The 
reservoir bag underwent continual gentle agitation to mix reservoir blood with returned blood. Blood 
samples to assay for the concentration of ticagrelor were drawn from the reservoir bag every hour 
after start of flow through the CytoSorb® device, up to 10 hours. Concentrations of ticagrelor were 
determined using tandem liquid chromatography mass spectrometry. The results showed that >99% of 
the ticagrelor was removed from human whole blood ex vivo within the first 3 hours of CytoSorb® 
hemoadsorption. 
Bovine Whole Blood Experiments 
Studies were conducted to evaluate the removal of ticagrelor from bovine whole blood ex vivo by 
CytoSorb® and were similar in design to the human whole blood experiments described above. 
Approximately 800 mL of bovine whole blood was used for the study. The starting concentration of 
ticagrelor was 1.15 μg/mL, a concentration representative of plasma drug levels in humans following 
standard dosing of ticagrelor. The pump circulated blood through the CytoSorb® device at a rate 
similar to the rate used in humans. Blood samples to assay for the concentration of ticagrelor were 
drawn from the reservoir bag at specific intervals after start of flow through the CytoSorb® device. 
Concentrations of ticagrelor were determined using tandem liquid chromatography mass 
spectrometry. The results (Figure 1) showed that approximately 80% of the ticagrelor was removed 
from bovine whole blood ex vivo within 90 minutes of CytoSorb® hemoadsorption. 

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Figure 1: Removal of Ticagrelor From Whole Bovine Blood Ex Vivo 
1.3. 
Clinical Data Informing Study Design 
To date, over 120,000 CytoSorb® treatments have been performed globally. Approximately 10% of 
the treatments have been intra-operative on cardiopulmonary bypass (CPB) including a significant 
number for the removal of ticagrelor and rivaroxaban that are both CE mark approved. Overall, the 
device has a favorable safety profile. 
A retrospective case-control series from Asklepios Klinik St. Georg (Hamburg, Germany) evaluated 
the use of the CytoSorb® device in patients on ticagrelor undergoing emergent cardiothoracic surgery 
with CPB. A historical cohort of patients who underwent standard surgery on CPB but without the use 
of CytoSorb® was compared to the cohort of patients who received CytoSorb® hemoadsorption during 
CPB. Results showed significant reductions in multiple measures of postoperative bleeding with the 
intra-operative use of CytoSorb® that included blood products transfused, 24-hr chest tube drainage 
volume, rate of surgical re-exploration, length of ICU and total hospital stay. [8] Importantly, no 
device-related adverse events (AEs), unanticipated adverse device events (UADEs) or device 
malfunctions were reported. 
1.4. 
Device Background and Nomenclature 
The DrugSorb-ATR device is identical to the CytoSorb® device discussed in the above preclinical 
and clinical data. The only difference between the two devices is a name change which was 
implemented to more closely align the device name with its intended use. As such, for the purposes of 
this study, the device will hereafter be referred to as DrugSorb-ATR whenever reference is being 
made to its use in the indication of antithrombotic drug removal. 
1.5. 
Study Design 
The STAR-T study is designed to demonstrate reductions in postoperative bleeding complications 
with the intraoperative use of DrugSorb-ATR in patients undergoing cardiothoracic surgery within 
two days of ticagrelor discontinuation. These patients have been demonstrated in the literature to be at 

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greatest risk for bleeding complications (refer to Section 3 for details). The study also aims to 
establish the safety of intraoperative DrugSorb-ATR use in the target population.  
 
The mechanism of action is removal of ticagrelor from active circulation through hemoadsorption 
while the patient is on cardiopulmonary bypass. Thus, the change in total blood concentration of 
ticagrelor following CPB will be measured as a key secondary endpoint. To do so, patient blood 
samples will be obtained during the pre-operative and immediate post-CPB time periods for ticagrelor 
concentration testing. This will allow comparison of clinical outcomes with presence or absence of 
reduction in circulating drug concentration. Serial sampling (every 30 min) for quantification of serial 
changes in blood ticagrelor levels will also be obtained through the first 2 hours of therapy on CPB. 
This supplemental drug removal data will be analyzed as an exploratory endpoint. Additional 
outcome measures to be evaluated include those that are documented as part of routine care, and are 
detailed in Section 4.3.  
. 
2. DRUGSORB -ATR DESCRIPTION AND INTENDED USE 
2.1. 
Description of the DrugSorb-ATR Device and Principle of Operation 
The DrugSorb-ATR device is a sorbent-filled hemoperfusion cartridge (Figure 2). 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 
end-cap 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 
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 2. DrugSorb-ATR Device 
 
The polymer in the DrugSorb-ATR device is effective at binding small molecules with molecular 

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moieties contained in ticagrelor. Ticagrelor easily passes 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.  
The DrugSorb-ATR device is designed for use in extracorporeal circuits. For this investigation, the 
device will be incorporated as a shunt in the standard CPB circuit (Figure 3), in accordance with the 
device Instructions For Use (IFU). 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. 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. Upon completion of the surgical procedure, the entire circuit 
containing the device is flushed with saline, which is consistent practice with all CPB circuits, and the 
blood in the circuit is delivered back to the patient. 
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 flow through the device and 
therefore treatment may be terminated before the end of CPB.     
The intraoperative use of anticoagulants (e.g., heparin) will be used in this investigation as per the 
standard procedures of each clinical institution and in accordance with the IFU. 
 
Figure 3. DrugSorb-ATR Integration in the Cardiopulmonary Bypass Circuit 
2.2. 
Treatment Conditions 

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In addition to the DrugSorb-ATR device, the following will be provided by the Sponsor: 
• 
IFU of the device 
• 
Training from a Field Clinical Engineer to provide guidance on incorporating and using the 
device within a CPB circuit 
• 
A transonic (or equivalent) flow detector 
• 
Disposable connector and tubing sets to connect the investigational device to the CPB circuit 
• 
Standard roller clamp 
• 
Disposable hemostats 
2.3. 
Device Accountability  
The procedures for the accountability of investigational devices should follow the specifications 
below: 
• 
Access to investigational devices shall be controlled and the investigational devices shall be 
used only in the clinical investigation and according to the Clinical Investigation Plan (CIP). 
• 
The Sponsor or its designees shall keep records to document the physical location of all 
investigational devices from shipment of investigational devices to the investigation sites, use 
of the investigational devices, and either return or disposal. 
• 
The Principal Investigator or an authorized designee shall keep records documenting the 
receipt, use, return, and disposal of the investigational devices, which shall include: 
o the date of receipt 
o identification of each investigational device (lot number and serial number) 
o the expiry date, if applicable 
o the date or dates of use 
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 the DrugSorb-ATR device is for the removal of ticagrelor as an 
adjunct to the standard of care in subjects undergoing cardiothoracic surgery requiring CPB within 
two days of ticagrelor discontinuation and will only be used as specified by this clinical protocol.  
2.5. 
Investigational Device/Procedures Training 
The DrugSorb-ATR device is easily integrated in a standard heart-lung machine CPB circuit. In this 
study, as described in the Instructions for Use (IFU), one DrugSorb-ATR cartridge will be placed in 
a bypass circuit connected between the oxygenator and cardiotomy reservoir as shown in Figure 3, 
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. In standard subjects, flow rates through the DrugSorb-ATR device should be 
maintained at 500 ± 100mL/min. In subjects on 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 device should not exceed 700mL/min at any point during the procedure. 
The circuit containing the DrugSorb-ATR device will be connected prior to the start of the 
procedure. Blood flow through the DrugSorb-ATR device will commence when the subject goes on 
CPB. Use of the DrugSorb-ATR device will stop at the end of CPB. Once the CPB procedure is 

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complete the hemoperfusion session will be ended, the circuit flushed with saline or drained by 
gravity, with the return of blood in the circuit back to the subject, per the hospital protocol. 
DrugSorb-ATR device training for the device users involved in this study will occur prior to 
DrugSorb-ATR device use and will be documented in a training log. 
3. STUDY JUSTIFICATION 
Ticagrelor is the first FDA-approved, orally administered platelet inhibitor that reversibly antagonizes 
the P2Y12 adenosine diphosphate (ADP) receptor on platelets. Ticagrelor is also recommended as part 
of dual anti-platelet therapy with aspirin, prior to percutaneous coronary intervention (PCI) and stent 
placement to reduce the risk of in-stent thrombosis. [1]  
 
The most common adverse effect of ticagrelor is the increased risk of unwanted, serious, and 
potentially fatal bleeding from spontaneous events (e.g., gastrointestinal bleed, intracranial 
hemorrhagic stroke), major trauma, and/or unscheduled, emergent or urgent surgeries with high 
bleeding risk. Currently, there are no approved agents to either prevent or treat bleeding related to 
ticagrelor-induced platelet dysfunction. Held et. al. evaluated bleeding events in patients from the 
PLATO study who required CABG 7 days of last ticagrelor dose (nearly 50% of which underwent 
surgery 3 days since taking the drug). Within this population 81.3% experienced major bleeding 
events based on the PLATO study definitions; bleeding in accordance with the TIMI major criteria 
occurred in 59.3% of these patients, and 43.7% experienced CABG-related life threatening or fatal 
bleeding. [5] Most of the major bleeding events occurred within the first 24 hours after surgery. Data 
from the European Multicenter Registry on Coronary Artery Bypass Grafting (E-CABG) 
demonstrated that occurrence of major perioperative bleeding per Universal Definition of 
Perioperative Bleeding in Cardiac Surgery (UDPB) criteria was most significant in patients 
undergoing cardiac surgery 2 days after last ticagrelor dose. [6] These patients experienced a 17.7% 
incidence of severe or massive bleeding by UDPB criteria, as compared to just 7.7% in patients 
waiting 3 days after last ticagrelor dose before undergoing surgery. With a propensity-score matched 
cohort the difference was 16.0% vs 2.7%, respectively (p = 0.003). [6] Of note, incidence of even 
moderate bleeding events is strongly influenced by timing of last ticagrelor dose prior to surgery. As 
seen within the CAPITAL Registry dataset, patients had a 40.5% incidence of at least moderate 
bleeding (UDPB 2) when undergoing CABG <72hrs after last ticagrelor dose. This was compared to 
<20% incidence of such bleeding events in patients who were able to wait for longer wash-out 
periods. [14] 
 
In patients with significant postoperative bleeding, current standards of care utilize blood product 
transfusions as part of the management strategy. However, blood products – including transfusion of 
platelets – have not been demonstrated to be particularly effective in addressing ticagrelor-induced 
bleeding. [15] Thus, the recommended strategy to reverse ticagrelor-induced platelet dysfunction and 
reduce the risk of bleeding is to discontinue ticagrelor therapy 5 days prior to elective cardiac 
surgery, to allow effective drug “wash out.” [2] However, patients with emergent or urgent 
cardiovascular conditions (e.g., acute ascending aortic dissection, left main or multi-vessel coronary 
disease not amenable to PCI, or complications of PCI) cannot generally wait for this wash out period, 
and require emergent or urgent surgery, otherwise risking permanent injury, disability, or death. In 
such cases, the impaired platelet reactivity caused by ticagrelor is often associated with significant 
blood loss and associated morbidity, with no currently approved therapies to treat it.  
 
Integration of a DrugSorb-ATR device into the CPB circuit to remove ticagrelor from patients 
undergoing urgent surgery provides an option for clinicians to accelerate ticagrelor wash-out and 
reduce bleeding risk. Figure 4 compares the natural washout of a single dose of ticagrelor, as 
measured in the ONSET-OFFSET trial (Husted et. al), to the accelerated removal with CytoSorb® 

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(i.e., DrugSorb-ATR) using a simulated CPB circuit with bovine blood at comparable starting Cmax 
values. [16] These in vitro data demonstrate that DrugSorb-ATR removal of ticagrelor is 
substantially faster than natural washout. Levels of P2Y12 receptor modification (and therefore platelet 
activity) closely follow plasma levels of ticagrelor due to the rapid on/off receptor kinetics of the 
drug. [1] Thus, it is hypothesized that ticagrelor removal by the DrugSorb-ATR device will 
significantly reduce postoperative bleeding. As discussed above, this effect would be most meaningful 
in those patients undergoing cardiac surgery within two days of ticagrelor discontinuation, since those 
are the patients at highest risk of major bleeding complications.  
 
 
Figure 4. Comparison of Natural Washout (Onset-Offset Study) versus CytoSorb®/DrugSorb-
ATR Washout (In-vitro test) From Cmax 
 
Primary Effectiveness Endpoint: The composite primary endpoint of the trial was specifically 
constructed to assess the ability of the DrugSorb-ATR device to reduce the full spectrum of 
postoperative bleeding in patients on ticagrelor undergoing cardiothoracic surgery with CPB within 
two days following the day of last dose. 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. [9] [10] The three components are: a) fatal perioperative 
bleeding events, 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). Accordingly, the composite primary endpoint will capture the full spectrum of 
postoperative bleeding ranging from catastrophic fatal bleeding to excess chest tube drainage. 
 
The fatal perioperative bleeding events included in the primary effectiveness endpoint are those that 
occur within 48 hours of the index procedure. This window will focus on the fatal bleeding events that 
occur in temporal proximity to the index procedure and may therefore be modifiable by the 
intervention. In keeping with standard clinical practice, study subjects with ACS or recent coronary 
stent placement will be re-started on ticagrelor (or the treating physician’s choice agent for DAPT) 
during postoperative day 1 if there is no concern for bleeding (Section 9.1.3). This increases the 
probability that fatal bleeding occurring >48 hours post-op is independent of DrugSorb-ATR 

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effectiveness, and rather due to therapeutic drug levels from re-initiation of antithrombotic therapy.   
 
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. [17] 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 (starting from moderate, up through severe-
massive) is correlated with higher 30-day mortality rate, thus making the standardized definition both 
a useful descriptive tool as well as a predictor of clinical outcome. [17]  
 
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 
No 
< 600 
0* 
0 
0 
No 
No 
No 
No 
1 
No 
601-800 
1 
0 
0 
No 
No 
No 
No 
2 
No 
801-1000 
2-4 
2-4 
Yes 
Yes 
Yes 
No 
No 
3 
Yes 
1001-2000 
5-10 
5-10 
N/A 
N/A 
N/A 
No 
Yes 
4 
N/A 
>2000 
>10 
>10 
N/A 
N/A 
N/A 
Yes 
N/A 
Class 0 = Insignificant; Class 1 = Mild; Class 2 = Moderate; Class 3 = Severe; Class 4 = Massive  
PRBC = packed red blood cells; FFP = fresh frozen plasma; PLT = platelet concentrates; Cryoppt = Cryoprecipitate; PCCs = 
prothrombin complex concentrates = rFVIIa, recombinant activated factor VII; 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 measurements of postoperative blood loss are 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. [18]  
 
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 mediastinal re-exploration) that rely on rate and volume of chest 
tube drainage. [19] Postoperative CTD volume during the first 12 hours is included within the UDPB 
classification, however 24-hr CTD has also been identified as an important independent metric. 
Importantly, 24-hr CTD has been demonstrated to correlate with other clinical outcomes, including 
transfusion requirements and duration of hospital stay in linear regression models. [20, 21] Excessive 
24-hr CTD as defined by >1000 mL has been shown to be an independent predictor of postoperative 
acute kidney injury (odds ratio 1.40, p < 0.001). [22] 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]  
 

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Key Secondary Endpoint: Change in preoperative to postoperative ticagrelor concentration [drug 
removal] will be the key secondary endpoint that will investigate the ability of the DrugSorb-ATR 
device to successfully remove ticagrelor. Furthermore, this information will be helpful for 
establishing a relationship between ticagrelor removal and decreased postoperative bleeding (i.e., less 
drug = less bleeding).  
 
Pre-randomization stratification based on a) study site, and b) planned type of cardiothoracic 
operation will address potential confounding variables that may not be fully controlled in the 
randomization process. 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 includes combination cases 
(e.g., CABG + valve, double valve, etc.) and ascending aortic interventions. Compared to CABG-
alone, these operations have a significantly different profile in regards to bleeding risk and 
procedure/CPB duration. This distinction is also 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 the randomized, double-blind investigation outlined in this protocol will 
be to examine the ability of DrugSorb-ATR (a non-pyrogenic, sterile, single-use device designed to 
remove the small hydrophobic drug, ticagrelor) to reduce postoperative bleeding compared to current 
standard of care. Measurements of drug removal will also be performed to establish that bleeding 
reductions are related to reductions in ticagrelor levels. The safety of the device in this setting will be 
assessed by systematic capture of all AEs at the CGP level. 
4. INVESTIGATIONAL PLAN 
4.1. 
Study Objective(s)  
Patients undergoing cardiothoracic surgery within two days of ticagrelor discontinuation are at 
increased risk of bleeding complications due to platelet dysfunction. The DrugSorb-ATR 
hemoadsorption device removes circulating ticagrelor at rates much higher than normal washout, thus 
reducing platelet dysfunction, improving hemostasis, and reducing postoperative blood loss.  
The objectives of this study are as follows: 
• 
To demonstrate reductions in postoperative bleeding with the intraoperative use of 
DrugSorb-ATR in patients undergoing cardiothoracic surgery with CPB within two days of 
ticagrelor discontinuation; 
• 
To demonstrate reductions in ticagrelor blood levels [ticagrelor] 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 within two days  
ticagrelor discontinuation, the intraoperative use of the DrugSorb-ATR device will significantly 
reduce postoperative bleeding as measured by a ranked composite endpoint of clinically meaningful 
bleeding metrics: 1) fatal perioperative bleeding, 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  

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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 the DrugSorb-ATR device. 
4.3. 
Study Outcomes 
4.3.1. 
Primary Effectiveness Endpoint:  
• 
Ranked composite of perioperative bleeding events:  
1) Fatal perioperative bleeding (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 Endpoint: 
• 
Percent difference in pre-CPB vs. post-CPB blood ticagrelor levels as measured by liquid 
chromatography/tandem mass spectrometry [LC/MS-MS] (i.e., [ticagrelor]).  
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 ticagrelor 
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 
• 
Serious device-related adverse events 
4.4. 
Subjects and Selection of Study Population 

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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. 
4.4.1. 
Inclusion Criteria: 
1. Males and females aged ≥18 
2. Written full informed consent 
3. Undergoing cardiothoracic surgery with CPB within two days of ticagrelor discontinuation 
(last day of completed ticagrelor treatment = day 0) 
4.4.2. 
Exclusion Criteria: 
1. Cardiothoracic surgery occurring 3 days or greater following ticagrelor discontinuation 
2. Heart-lung transplant procedures 
3. Procedures for ventricular assist device (i.e., implant or revision of LVAD or RVAD) 
4. 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 > 1.5  
5. Prohibited concomitant antithrombotic medications (reference Appendix 5) 
6. Acute sickle cell crisis 
7. Known allergy to any of the device components 
8. Subjects with active (untreated) systemic infection 
9. Subjects with a history of major organ transplantation and those currently receiving 
immunosuppressive medication (corticosteroids excluded) or who are profoundly immune 
suppressed 
10. Women of childbearing potential with a positive pregnancy test performed during the current 
admission or who are breast-feeding 
11. Subjects with life expectancy of <30 days (not inclusive of the critical condition that is 
requiring the cardiac operation under study) 
12. Inability to comply with the requirements of the study protocol 
13. Treatment with an investigational drug or device within 30 days prior to surgery 
14. Subjects with previous enrollment in this trial 
15. Subjects in whom acute normovolemic hemodilution (ANH) is used perioperatively  
 
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 
investigation is applied to the subject, except when special circumstances described in Appendix 3 
apply. 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 

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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 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 informed consent form 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 (can be performed via telephone 
contact, in person visit, or review of medical records) 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. 
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 

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used in the analysis, following the intent-to-treat principle. In cases where particular analysis criteria 
are not met, for example for the per protocol (PP) 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 device that is incorporated into an extracorporeal CPB circuit. For the study 
described in this protocol, use of the DrugSorb-ATR device will be limited to the duration of CPB. 
The risk profile associated with the DrugSorb-ATR device 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 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 the DrugSorb-ATR device intra-operatively during 
cardiothoracic surgery to remove ticagrelor include: 
• 
Decrease in perioperative bleeding complications; including: 
• 
Decrease in perioperative 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 
• 
Decrease in mean operative time including time to hemostasis 
• 
Decrease in the amount of time on a mechanical ventilator 
• 
Decrease in hospital stay following surgery, including time in the ICU 
 
5.3. 
Risk Mitigation 
Mechanical and performance concerns have been reduced by extensive human, animal, and bench 
testing. The device materials have been shown to be biocompatible and acceptable for human use 

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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 Device 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 selective test is available, the treating physician is urged 
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 
time 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. 
Impairment of device function (DrugSorb-
ATR and CPB) in combination with parenteral 
nutrition (most notably: lipid emulsions) 
In case of need 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 latest two 
hours prior to the CPB-procedure. 

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Bleeding events due to necessary 
anticoagulation with CPB and DrugSorb-
ATR device 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 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. 
6. STUDY TREATMENT 
All treatments will be provided by trained professionals. Use of the DrugSorb-ATR Device will 
follow the instructions for use (IFU) under the guidance of a field clinical engineer. 
6.1. 
Pre-randomization Stratification 
Pre-randomization stratification will be performed on two levels, based on the rationale described 
below:  
1. By study site in order to control for differences in institutional protocols that could impact 
outcomes. These may include but are not limited to different institutional practices for 
drug and transfusion administration intra-op and post-op. Institutions may also differ in 
metrics utilized for clinical decision-making (e.g., delaying sternal closure, or surgical 
reoperation). 
2. By the intended surgical procedure in order to control for differing procedure-specific 

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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 intervention, and combination aortic + cardiac 
interventions.  
 
Of note, during the pre-procedure and intraoperative periods, the intended procedure may change due 
to factors that could not be adequately determined or 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. Subjects who have changes to their intended procedures 
on the day of surgery should progress through the study as in 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 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 device).   
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 study site (to account 
for different institutional protocols for bleeding and transfusion management), and type of surgery 
(isolated CABG – which generally has shorter CPB time, vs. all other cardiothoracic surgeries 
including combination cases – which generally require longer CPB times). 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 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. Sites may be allowed to 
randomize beyond the cap on a case-by-case basis in consultation with the sponsor, taking into 
account overall study goals, randomization balances between sites, and prior quality of data collected 
by the site. 
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 have an unblinded perfusionist to execute the necessary intraoperative study 
procedures. Extreme caution should be exercised by the perfusionist to prevent inadvertently 

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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 on CPB from view of the surgical staff. A Field Clinical Engineer (FCE), 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 FCE 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 device). 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.  
- 
Surgical team (including the surgeon, surgical assistant, circulating nurse, 
scrub tech, and other operating room staff); 
- 
Anesthesiologist and anesthesia team; 
- 
ICU staff; 
- 
Study coordinator. 
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. 
- 
Perfusionist; 
- 
Sponsor FCE. 
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 in the eCRFs and device accountability log. Other responsibilities include: 

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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 
the DrugSorb-ATR device, 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 device. 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 it. 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 FCE 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 
in REFRESH II, 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 a 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 
(significant change in subject’s health status related to the possible use of the device, 
withdrawal or discontinuation of study participation), 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 Engineers 

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Support by a Field Clinical Engineer (FCE), 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 FCE 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 FCE 
assistance may be granted. All such waivers of FCE assistance will be documented and retained in the 
study file.  
 
The FCE 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 Instructions for Use 
(IFU). The unblinded perfusionist is responsible for the final hookup to the hospital perfusion 
apparatus. The Sponsor FCE 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 FCE 
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. 
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, and proposed monitoring 
criteria. There will be at least 4 DSMB meetings in the course of the trial. A kick-off meeting of the 
DSMB in anticipation of the start of enrollment and 3 safety reviews scheduled after 40 patients have 
been enrolled, after 80 patients have been enrolled, 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.  

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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. 
7.3. 
Executive Committee 
This committee shall serve as overall governance of the trial and will comprise 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 with regard to 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 
The CRO will monitor and manage the data for the investigational study on behalf of the Sponsor, 
CytoSorbents, Inc. Some co-monitoring and remote data checking will also be done by qualified 
CytoSorbents personnel. 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 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 
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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  
In the event that 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 are given in the 
Schedule of Assessments 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) are optional and 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).  
Study outcomes will be assessed as part of blood products and drainage volume, laboratory 
parameters, and documentation of clinical events and/or treatments. Reference Section 4.3 for the full 
list of study endpoints. Definitions of analysis populations and description of statistical analyses 
endpoints is briefly described in Section 11 and 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 4.4.3 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 

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participation and the start of the surgical procedure with CPB  
• 
Pre-CPB Phase – the period within 2 hours of 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 30 min 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. 
 
 
 
 
 
 
 
* 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 
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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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 in on two levels (see Section 6.1 for details):  
1. By study site; 
2. By the planned surgical procedure: 
• 
Isolated CABG (irrespective of number of grafts); or 
• 
All other cardiothoracic procedures.  
 
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 device), as detailed in Section 6.2.  
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 Instructions for Use (IFU) and under the guidance of a Field Clinical 
Engineer, the DrugSorb-ATR device will be placed into a parallel bypass circuit to the main blood 
flow in a standard heart-lung machine circuit and primed for use in preparation for the Operation 
Phase. Throughout the treatment session, the DrugSorb-ATR device 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, also 
on the inlet line below the DrugSorb™-ATR device. The blood flow rate of the device will be 
adjusted to 500mL/min 100mL/min (minimum above 400mL/min is acceptable). 
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. Activated clotting time will be obtained once at 30 15min into CPB, and once within 30min 
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 practices but should follow Best Clinical 

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Practice Guidelines. 
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. Antiplatelet therapy in the postoperative setting is determined by whether or 
not the study subject had ACS or recent stent placement: 
1. Any ACS subjects who were not on aspirin in the preoperative setting should be initiated on 
aspirin at 6 hours post-op, per institutional protocols. In ACS subjects, or those with coronary 
stent placement within the prior 6 months, ticagrelor (or the treating physician’s choice P2Y12 
inhibitor for DAPT, in accordance with standard clinical guidelines) should be resumed on 
postoperative day 1 if there is no concern for bleeding. Otherwise, ticagrelor/DAPT should be 
resumed as soon as deemed safe by the surgeon when weighing benefits of improved graft or 
stent patency against risk of bleeding.  
2. In the remaining subjects, antithrombotic management should be per institutional protocols.  
 
Postoperative anticoagulation for venous thromboprophylaxis in all subjects should be administered 
according to standardized institutional protocols. 
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 
(ICF; assent or consent) 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 appropriate. 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 registered on the AE form of the eCRF. In absence of a specific 
diagnosis, an individual AE form has to 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. 

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Persistent AEs will be entered once in the eCRF until they are resolved or if a new event has to be 
documented due to deterioration. 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 has to be completed for each of 
them. 
Bleeding event AEs 
Bleeding events are to be recorded as AE/SAEs by the Investigator or designee and will be classified 
according to the Universal Definition of Perioperative Bleeding (UDPB) in adult cardiac surgery. [17]  
Classifications are based on criteria 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. Measurement of CTD volume begins at chest closure for UDPB classification. All bleeding 
event AEs classified as moderate, severe, or massive (Classes 2, 3 or 4) based on UDPB criteria will 
be referred to the CEC for adjudication of UDPB bleeding class. 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 
endpoints in this study. This is with the intent of evaluating any potential risk for ischemic rebound in 
the setting of ticagrelor 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.  
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. 
9.2.2. 
Medical History 
Medical history will be obtained at Screening and should include demographic information (date of 
birth, 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 clinical 
laboratory evaluations (including clinical chemistry, hematology, and coagulation tests) at the times 
indicated in the Schedule of Assessments in Appendix 4. Clinical laboratory evaluations are listed in 
Appendix 2. 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 24hrs, 48hrs, 
72hrs, etc., post-op 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 (Schedule of Assessments, Appendix 4). A physical exam (PE) 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. Cellsaver 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. 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 ticagrelor 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 cardiopulmonary bypass, and up to 2hrs pre-start of 
surgery (i.e., time of skin incision). While the subject is on CPB, serial samples will be drawn at 
3015min following initiation of CPB, at 60min, at 90min, and at 120min 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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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.   
Study subjects may, in addition to ticagrelor, 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. The type of agent 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 an alpha (α) 
critical value of 0.05, 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 
Up to 140 subjects meeting the study inclusion criteria (Section 4.4.1) will be randomized in a 1:1 
ratio to the treatment and control arms. As noted above (Section 6.2), in order 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.  Allowing for 5% dropouts, at total of 114 subjects (57 
per arm) are expected to be evaluable for effectiveness and safety. Sample size is based on assumed 
effect size for the primary effectiveness Win Ratio sub-components (Table 3), and can be calculated 
via an iterative simulation process with programming code available in an appendix to Redfors et al. 
(2019).[11] With a Finkelstein – Schoenfeld test, a total of 57 subjects per arm ensures power of 
>99.7% for the primary effectiveness endpoint at the final analysis, using a two-sided alpha (α) of 
0.05. [10] With this same per arm sample size, power for the key secondary endpoint is estimated at 
>99.9% assuming a 40% ± 40% mean difference between treatment and control, based on a two-

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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 [8] [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) [13] 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) [13] is estimated at 96.7%.  
Overall study sample size is designed to provide adequate power for the primary effectiveness 
endpoint, the key secondary endpoint, and succeeding three secondary endpoints. Sample size and 
power for all secondary endpoints were calculated using PASS 2021 (NCSS, LLC. Kaysville, UT, 
USA, ncss.com/software/pass).  
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. 
Table 3. Win Ratio Effect Size Assumptions with Power and Sample Size Estimates 
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) 
N=57 
3.0% 
3.0% 
24.3% 
40.5% 
480 (253) 
800 (253) 
>99.7% 
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. [14] 
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. [8] 
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 subjects who are randomized.  
 
The modified Intent-to-Treat (mITT) Population includes 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 in the mITT population. So 
long as the mITT and ITT 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 
supplemental analysis. 
 

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The Safety Analysis (SA) Population will include all enrolled subjects who are treated with a study 
device.           
11.3. 
Effectiveness Analysis 
The primary effectiveness endpoint will be evaluated using the Win Ratio method (Pocock, et al., 
2012) 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 in order of 
clinical importance: a) fatal perioperative 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. [9] [10] 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. [9] The estimated Win Ratio 
along with a two-sided 95% CI will be provided between the treatment and control arm. The details of 
the primary effectiveness analysis will be provided in the SAP. 
The key secondary effectiveness endpoint is a drug removal endpoint, namely the percent change in 
pre-CBP vs. post-CPB ticagrelor blood levels as measured by liquid chromatography/tandem mass 
spectrometry. Blood samples for drug removal analyses will be collected and analyzed by a central 
core laboratory. 
Change from baseline in blood concentration of ticagrelor is defined as:  
pre-CPB [ticagrelor]blood - post-CPB [ticagrelor]blood  *100% 
pre-CPB [ticagrelor]blood 
 
Benchtop studies of drug removal by the DrugSorb-ATR device (CytoSorbents, unpublished data) 
demonstrate concentration and time dependent absolute drug removal. Based on these benchtop 
studies, a conservative estimate of 40% reduction in blood concentration of ticagrelor 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 ticagrelor blood levels in the 
above benchtop studies, percent change from baseline will be analyzed as opposed to observed values. 
We anticipate drug removal data from other clinical studies in this application to become available 
during the course of the study and we plan to update the above assumption if necessary based on in 
vivo data. 
Additional powered 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. 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, a nonparametric test such as a Mann-Whitney test 
will be employed, with median and range values provided in the output. 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 

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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 taken into 
account.  
 
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 in the event that 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 key secondary endpoint (percent 
change in pre-CPB vs. post-CPB blood ticagrelor levels), followed by the first secondary endpoint 
(24-hour CTD), second secondary endpoint (platelet transfusions), and lastly (PRBC transfusions). 
Should all preceding statistical comparisons show results below their alpha cut-off values, further 
secondary endpoints will be evaluated: the proportion of fatal perioperative bleeding events, 
proportions of UDPB events (by category), and surgical re-exploration rates. 
Other exploratory endpoints include: 
• 
Area under the concentration time curve (AUC), using the trapezoidal approach, for 
intraoperative ticagrelor 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. 
Further details regarding summary and analysis of effectiveness data will be provided in the SAP. 
11.4. 
Subgroup Analysis 
The primary effectiveness endpoint will also be analyzed across the clinically meaningful subgroups, 
including but not limited to those outlined below:  
 
• 
Planned surgery type (CABG alone vs. all other types of surgery) 
• 
Key demographic factors including age (<65 vs  65 years old)  and sex (M/F) 
• 
EuroScore II score  
• 
STS Risk score (low, intermediate, high) 
• 
NYHA heart failure class (1, 2, 3, 4) 
• 
Left ventricular ejection fraction [according to the ACC classification: 50% (normal), 40-
49% (mild dysfunction), 30-39% (moderate dysfunction), <30% (severe dysfunction)]  
• 
Baseline thrombocytopenia (platelet count <150,000 /L, ≥150,000 /L) 
• 
Prior MI (Y/N) 
• 
Prior stroke (Y/N) 
• 
Prior hypertension (Y/N) 
• 
Prior hyperlipidemia (Y/N) 
• 
Diabetes mellitus (Y/N) 
• 
Chronic obstructive pulmonary disease/COPD (Y/N) 
• 
Current or prior tobacco use (Y/N) 
• 
Prior sternotomy (Y/N) 
• 
Drug removal  
 

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Additional details on subgroup analyses will be provided in the SAP.  
11.5. 
Treatment of Missing Data 
Every effort will be taken to obtain data entry compliance of all critical fields during the course of the 
study. The study assumes up to 5% of the data may 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.  
11.6. 
Safety Analysis 
All the safety endpoints will be analyzed in the SA Population. Additional safety analyses will be 
conducted on the mITT and PP Population if they are different from the SA population.  
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. 
All the safety data will be listed in the SA population. Further details regarding presentation and 
analysis of safety data will be detailed in the SAP.   
11.7. 
Device Malfunctions/Deficiencies 
A summary of device malfunctions/deficiencies will be provided by treatment arm. All 
malfunctions/deficiencies will be listed. 
11.8. 
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 

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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). 
• 
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 

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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 
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 

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completion 
Other reports 
Sponsor and IRB and FDA 
As needed 
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 

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The Sponsor reserves the right to terminate an investigational site from the study for any of the 
following reasons: 
• 
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 

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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. 
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 

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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 
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 the 
DrugSorb-ATR Device to caregivers and study subjects alike. We accept 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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19. REFERENCES 
1. 
Husted, S. and J.J. van Giezen, Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc 
Ther, 2009. 27(4): p. 259-74. 
2. 
Hillis, L.D., et al., 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery: executive summary: a 
report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice 
Guidelines. Circulation, 2011. 124(23): p. 2610-42. 
3. 
Brilinta (ticagrelor) Oral Tablets [package insert]. 2016, AstraZeneca Pharmaceuticals LP: Wilmington, 
Delaware. 
4. 
Wallentin, L., et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 
2009. 361(11): p. 1045-57. 
5. 
Held, C., et al., Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergoing coronary 
artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll 
Cardiol, 2011. 57(6): p. 672-84. 
6. 
Holm, M., et al., Bleeding in Patients Treated With Ticagrelor or Clopidogrel Before Coronary Artery Bypass 
Grafting. Ann Thorac Surg, 2019. 107(6): p. 1690-1698. 
7. 
Angheloiu, G.O., et al., Ticagrelor Removal From Human Blood. JACC Basic Transl Sci, 2017. 2(2): p. 135-145. 
8. 
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. 
9. 
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. 
10. 
Finkelstein, D.M. and D.A. Schoenfeld, Combining mortality and longitudinal measures in clinical trials. Stat 
Med, 1999. 18(11): p. 1341-54. 
11. 
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. 
12. 
Godier, A., G. Taylor, and P. Gaussem, Inefficacy of platelet transfusion to reverse ticagrelor. N Engl J Med, 
2015. 372(2): p. 196-7. 
13. 
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. 
14. 
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. 
15. 
Teng, R., et al., Effects of autologous platelet transfusion on platelet inhibition in ticagrelor-treated and 
clopidogrel-treated subjects. J Thromb Haemost, 2016. 14(12): p. 2342-2352. 
16. 
Husted, S.E., et al., Pharmacokinetics and pharmacodynamics of ticagrelor in patients with stable coronary artery 
disease: results from the ONSET-OFFSET and RESPOND studies. Clin Pharmacokinet, 2012. 51(6): p. 397-409. 
17. 
Dyke, C., et al., Universal definition of perioperative bleeding in adult cardiac surgery. J Thorac Cardiovasc Surg, 
2014. 147(5): p. 1458-1463.e1. 
18. 
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. 
19. 
Kirklin JW, B.-B.B., Cardiac Surgery. 1986, New York: John Wiley & Sons. 
20. 
Christensen, M.C., et al., Costs of excessive postoperative hemorrhage in cardiac surgery. J Thorac Cardiovasc 
Surg, 2009. 138(3): p. 687-93. 
21. 
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. 
22. 
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. 
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. 
Lan, K.K.G. and D.L. DeMets, Discrete Sequential Boundaries for Clinical Trials. Biometrika, 1983. 70(3): p. 
659-663. 
25. 
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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20. APPENDICES 
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. 

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Causality Assessment 
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, 

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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 
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 or not 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  
Potential Adverse Device Events Directly Related to DrugSorb-ATR:  

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• 
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   
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   
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 child-bearing 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 subjects. 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: Schedule of Assessments 
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 
Ticagrelor/P2Y12 
inhibitorb 
Xc 
 
Xd 
X 
 
X 
Thromboprophylaxis 
 
 
SOC ---------------------------------------------------- SOC 
All other subjects 
Aspirin 
SOC 
SOC 
SOC 
SOC 
 
SOC 
Ticagrelor/P2Y12 
inhibitorb 
Xc 
 
 
SOC----------------------------------SOC 
Thromboprophylaxis 
 
 
SOC -----------------------------------------------------SOC 
aSubjects not previously on Aspirin in the preoperative setting should be initiated on Aspirin therapy at 6 hours post-op, 
per institutional protocols 
bChoice of agent for postoperative DAPT is at the discretion of the treating physician, in accordance with standard clinical 
guidelines 
cTiming of last dose must be consistent with the study inclusion criteria 
dResumption of ticagrelor therapy should be within 24hrs post-op if there is no clinical concern for bleeding. Otherwise, if 
concern for bleeding exists, ticagrelor should be resumed as soon as deemed clinically safe in the judgement of the 
surgeon. Known benefit of ticagrelor in postoperative graft/stent patency must be weighed against bleeding risks 
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 2 days 
prior to the 
day of 
Operation 
Within 
2 hours before 
start of 
operation (i.e., 
skin incision) 
From chest 
incision to 
chest closure 
Within 30 
min after end 
of CPB 
ICU Admission  
POD 
1 
POD 
2 
POD 
3 
POD 
4 
POD 
5-29 
POD 30 
+ 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 ticagrelor (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 
Xu 
SOC 
SOC 
SOC  
 
Clinical chemistry g 
X 
 
 
 
X 
X 
Xu 
SOC 
SOC 
SOC  
 
Coagulation panel g 
X 
 
 
 
X 
X 
Xu 
SOC 
SOC 
SOC  
 
Vital signs h 
X 
 
 
 
SOC 
X 
X 
SOC 
SOC 
SOC s 
SOC 
CPB duration i 
 
 
X 
 
 
 
 
 
 
 
 
DrugSorb flow rate & flow duration i 
 
 
X 
 
 
 
 
 
 
 
 
Surgical procedure type j 
 
 
X 
 
 
 
 
 
 
 
 
Activated Clotting Time (ACT) k 
 
 
X 
X 
 
 
 
 
 
 
 

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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 2 days 
prior to the 
day of 
Operation 
Within 
2 hours before 
start of 
operation (i.e., 
skin incision) 
From chest 
incision to 
chest closure 
Within 30 
min after end 
of CPB 
ICU Admission  
POD 
1 
POD 
2 
POD 
3 
POD 
4 
POD 
5-29 
POD 30 
+ 5 days 
Arterial Blood Gas (ABG) l 
 
 
X 
X 
X 
 
 
 
 
 
 
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 
 SOC 
SOC 
SOC  
 
FiO2 p  
 
 
 
 
X 
X 
X 
SOC 
SOC 
SOC  
 
Vasopressor requirements q 
 
 
 
 
X 
X 
X 
SOC 
SOC 
SOC  
 
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, which may differ from the performed procedure. 
d Blood samples will be collected for the determination of plasma ticagrelor 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 the 2 days prior to the day of surgery. Post-op EKG is only mandated in the event 
of possible MI 
f In all females of child-bearing 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. Post-op cTn is only mandated in the event of possible MI  
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). Intraoperative ACT is documented in the ACT log, and not recorded in the 

Clinical Investigation Plan (CIP)  
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 CIP Reference Number: 2021-01 
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Coagulation Test eCRF. 
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 
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. 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 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 2 only. 

Clinical Investigation Plan (CIP)  
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 CIP Reference Number: 2021-01 
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Version 5.1 
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Appendix 5: Antithrombotic Medications Allowed/Disallowed 
Aspirin – allowed 
 
Ticagrelor – allowed 
 
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 
 
DOACs (e.g., apixaban, rivaroxaban, dabigatran and edoxaban) – any use within 5 days is 
disallowed, as it may have confounding effects on bleeding 
 
Warfarin – recent use disallowed unless INR < 1.5 as otherwise 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.