An In Vivo 24-Hour Recovery Study of Leukoreduced RBCs After Automated Separation of Whole Blood by the Reveos System and Storage for 42 Days
Phase: NA
Conditions: Device Validation of In-vivo Performance
Sponsor: Terumo BCT

CTS-5085_CIP_V3.0_2022_03_11, A
CIP - REVEOS
Document Type:
Simple Document
Document Subtype:
Record
Site(s):
Global
Affected Element:
Master or
Translation:
Is this an essential
design output (EDO)?
Electronic Signatures
Intention
User Name
Decision
Timestamp
Submit Document for Approval
Kathy Castillo
Approve
2022-03-11 23:03 GMT
Approve Document
James Kelley
Approve
2022-03-11 23:07 GMT
Approve Document
Anna Maria Neitenbach
Approve
2022-03-14 19:42 GMT
Approve Document
Jack Rhodes
Approve
2022-03-15 20:41 GMT
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Reveos Automated Blood Processing System 
Terumo Blood and Cell Technologies 
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 1 of 52 
CLINICAL INVESTIGATION PLAN 
Study Title: 
An In Vivo 24-Hour Recovery Study of Leukoreduced RBCs After 
Automated Separation of Whole Blood by the Reveos System and 
Storage for 42 Days 
Study Number: 
CTS-5085 
Study Device: 
The Reveos® Automated Blood Processing System (Reveos 
System) 
Legal Manufacturer: 
Terumo Blood and Cell Technologies 
10811 West Collins Avenue; Lakewood, CO 80215; USA 
Phone: +1 303-231-4832 
Sponsor: 
Terumo Blood and Cell Technologies  
10811 West Collins Avenue; Lakewood, CO 80215; USA 
Phone: +1 303-231-4832 
Sponsor Contact: 
James Kelley. MD, PhD 
Director of Global Medical Safety 
Phone: +1 720-232-1710 
Email: james.kelley@terumobct.com 
Lead Principal 
Investigator: 
Jose A. Cancelas, MD, PhD  
Hoxworth Blood Center 
University of Cincinnati 
3130 Highland Avenue; Cincinnati, OH 45267; USA 
Phone: +1 513-558-1324 
Email: Jose.Cancelas@uc.edu 
Funded By: 
Terumo Blood and Cell Technologies 
Version/Date: 
Version 3.0: 11 March 2022 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or 
under control of Terumo Blood and Cell Technologies and is provided to you in confidence 
as an Investigator, potential Investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Board/Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational device described 
in the protocol. You shall not disclose any of the information to others without written 
authorization from Terumo Blood and Cell Technologies, except to the extent necessary to 
obtain informed consent from those persons who may participate in the clinical trial or as 
required by law. Please refer to the Trial Master File and/or Clinical Trial Agreement for 
complete details regarding applicable confidentiality standards. 
The CTS contains additional Signature Pages
CTS-5085-3.0 Page 1 of 57
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CTS-5085_CIP_V3.0_2022_03_11, A, Approved, CIP - REVEOS

Reveos Automated Blood Processing System 
Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 2 of 52 
CLINICAL INVESTIGATION PLAN APPROVAL 
 
 
 
 
Name: 
Jose A. Cancelas, MD, PhD   
 
 
Title: 
Principal Investigator 
 
 
 
 
Signature: 
See Attached 
Date: 
 
 
 
 
 
 
Name: 
Moritz Stolla, MD, PhD 
 
 
Title: 
Principal Investigator  
 
 
 
 
 
 
Signature: 
See Attached 
Date: 
 
 
 
 
 
 
Name: 
James Kelley, MD, PhD 
 
 
Title: 
Director, Global Medical Safety and Clinical Affairs 
 
 
 
 
 
 
Signature: 
See Electronic Signature page 
Date: 
 
 
 
 
 
 
Name: 
William Coar, PhD  
 
 
Title: 
Consultant Statistician: Axio, a Cytel Company 
 
 
 
 
 
 
Signature: 
See Attached 
Date: 
 
 
 
 
 
 
Name: 
Jack Rhodes, BS 
 
 
Title: 
Clinical Affairs Manager, Global Clinical Affairs 
 
 
 
 
 
 
Signature: 
See Electronic Signature page 
Date: 
 
 
 
 
 
 
Name: 
Anna Maria Neitenbach, MD  
 
 
Title: 
Senior Clinical Research Lead, Global Clinical Affairs  
 
 
 
 
 
 
Signature: 
See Electronic Signature page 
Date: 
 
 
 
 
 
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Reveos Automated Blood Processing System 
Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 3 of 52 
DOCUMENT REVISION HISTORY 
 
 
Study Title: 
An In Vivo 24-Hour Recovery Study of Leukoreduced RBCs After Automated 
Separation of Whole Blood by the Reveos System and Storage for 42 Days 
Study Number: 
CTS-5085 
CIP Amendment 
Version and Date: 
Version 3.0 11 March 2022  
Replaces CIP 
Version and Date: 
Version 2.0: 11 August 2022 
Rationale: 
Typographical copy and paste errors were noted and corrected to align with FDA 
criteria for in vitro RBC quality metrics per Vostal presentation criteria (Reference # 
7). 
This change is reflected in sections 13.2, 13.3 and are detailed in the table below. 
Section(s) 
Used to Read: 
Now Reads (new wording bolded): 
Section 13 .2. Visit 2 
- Day 0, third last 
sentence in the 
section. 
 
Should LR-RBC Mass Recovery after 
filtration not meet recovery >85% or 
Leukoreduction not meet required FDA 
limit (< 5 x 106 WBC/per unit) LR-RBC 
unit will be discarded and the participant 
will be withdrawn from the study. 
Should LR-RBC Mass Recovery after 
filtration not meet recovery ≥ 85% or 
Leukoreduction not meet required FDA 
limit (< 5 x 106 WBC/per unit) LR-RBC 
unit will be discarded and the participant 
will be withdrawn from the study. 
Section 13.3 Visit 3 
(Day 42), 
REINFUSION -fifth 
paragraph 
Should LR-RBC not meet hemolysis 
requirement of < 1 % after storage, the 
units will not to be further processed and 
will be discarded. The participant will be 
withdrawn from the study before 
reinfusion 
Should LR-RBC not meet hemolysis 
requirement of ≤ 1 % after storage, the 
units will not to be further processed and 
will be discarded. The participant will be 
withdrawn from the study before 
reinfusion 
Section 13.3: Visit 3 
(Day 42): Procedures 
and data recorded 
from visit 3 (Day 42) 
Bullet 4 
Confirm of continued eligibility prior to 
reinfusion of radiolabeled cells (record 
current health status, current 
medications, negative RBC bacterial 
testing and/ or visual inspection, donor 
viral screen, hemolysis <1% of stored 
LR-RBC) 
Confirm of continued eligibility prior to 
reinfusion of radiolabeled cells (record 
current health status, current 
medications, negative RBC bacterial 
testing and/ or visual inspection, donor 
viral screen, hemolysis ≤1% of stored 
LR-RBC) 
The CTS contains additional Signature Pages
CTS-5085-3.0 Page 6 of 57
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Reveos Automated Blood Processing System 
Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 4 of 52 
SYNOPSIS 
Sponsor: 
Terumo Blood and Cell Technologies  
Study Title: 
An In Vivo 24-Hour Recovery Study of Leukoreduced RBCs After Automated 
Separation of Whole Blood by the Reveos System and Storage for 42 Days 
Study Number: 
CTS-5085 
Device 
Description: 
The Reveos® Automated Blood Processing System (Reveos system) is an automated 
whole blood processing system, not cleared for use in the United States.  The Reveos 
System has been available outside the United States since 2012 and is seeking United 
States Food and Drug Administration (FDA) 510(k) clearance as an automated whole 
blood processor.  
The Reveos System is an integrated manufacturing system that processes whole blood 
(WB) units into blood components and designed to minimize manual blood processing 
variables resulting from processing time, product and procedural variability. The Reveos 
System consists of the primary device (equipment) that uses centrifugal force to separate 
whole blood into its components, a disposable blood bag set to collect and store 
separated components, and a software program to manage the operations.  
The Reveos disposable blood bag set contains CPD (citrate phosphate dextrose) 
anticoagulant, additive solution formula 5 (AS-5), and a red blood cell (RBC) 
leukoreduction filter.  
The Reveos System can simultaneously process up to 4 whole blood units into 4 RBC 
units, 4 leukoreduced plasma units, and 4 interim platelet units (IPU). The CPD/AS-5 
RBC product is leukoreduced and may be stored up to 42 days. 
Intended Use: 
Intended Use of the Reveos Device  
The Reveos device is intended to automatically separate units of whole blood into blood 
components.  
Intended Use and Description of the Reveos Blood Bag Set  
The Reveos Blood Bag Set is intended to collect a unit of whole blood and to process the 
unit on the Reveos device, producing blood components.  
Intended Use of the Reveos System Manager Software  
The Reveos System Manager is a software application that manages Reveos procedures 
and processing data.  
Objectives: 
The primary objective of this study is to evaluate whether the LR-RBCs derived from 
whole blood and processed with the Reveos System meet FDA criteria for 24-hour 
recovery after 42-day storage. 
Primary Endpoint: 
The primary endpoint is the 24-hour in vivo RBC recovery after 42-day storage. 
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Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 5 of 52 
Study Design: 
This is a prospective, open-label, multicenter study to evaluate whole blood derived red 
blood cells processed using the Reveos System.    
The main objective is autologous in-vivo recovery of radiolabeled leukoreduced RBCs 
derived from whole blood processed using the Reveos System and stored for 42 days.    
DAY -14- 0    
Screening for all participants.      
DAY 0   
One (1) unit of whole blood (500mL +/- 10%) will be collected, and the whole blood unit 
will be processed with the Reveos System within 8 hours. The whole blood will be 
separated into three blood components: red blood cells, plasma and platelets.  RBCs will 
be leukoreduced with red blood cell (RBC) leukoreduction filter integrated into the 
Reveos Blood Bag Set.   
RBC mass recovery and leukoreduction post filtration will be measured.  
LR-RBC units will be stored at 1-6°C for 42 days. Plasma and platelet products will be 
discarded per site policy.     
DAY 42:      
Stored RBCs will be tested for hemolysis, in addition visual inspection and /or bacterial 
testing, and donor viral screens will be confirmed negative.   
Radiolabeling: An aliquot of 42-day stored autologous LR-RBCs will be radiolabeled 
with chromium-51 (51Cr).  An aliquot of freshly collected and prepared RBCs will be 
radiolabeled with technetium-99m (99mTc). The labeled aliquots will then be combined 
and infused to the autologous donor. Blood samples will be collected approximately at 5, 
7.5, 10, 12.5, 15, 20, and 30 minutes post infusion.    
DAY 43:   
Blood sample for 24-hour RBC recovery will be drawn. This visit concludes the study. 
Study Sites 
Planned: 
Hoxworth Blood Center, Cincinnati, OH and Bloodworks Northwest, Seattle, WA 
Study Duration: 
Approximately 57 days per participant 
Target Population: 
Healthy adult participant 
Number of 
Subjects Planned: 
24 evaluable participants (up to 50 enrolled).  
Inclusion Criteria: 
1. Healthy volunteers., of either gender 
2. Age 18 years or older. 
3. Normal health status as per AABB criteria for healthy donor. 
4. Able to commit to the study schedule. 
5. Meets the inclusion criteria defined by the Blood Center for whole blood donor. 
These criteria are based on FDA Regulations and AABB standards. Note: 
Participants who are deferred from volunteer community donations because of 
travel restrictions, piercings, tattoos or other reasons by PI approval may 
participate in the study, as products are re-transfused to the autologous donor. 
6. Participants of childbearing potential (either male or female) must agree to use 
medically acceptable method of contraception throughout of the study. 
7. Females of childbearing potential must be willing to take a pregnancy test prior 
to WB donation and infusion of radiolabeled RBCs. 
8. Signed and dated informed consent form. 
Exclusion Criteria: 
1. Pregnant or nursing females.  
2. Serum ferritin <12 ng/mL 
3. Has previously completed this study with evaluable data points.  
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Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 6 of 52 
4. Participation currently, or within the past 30 days, in another investigational 
trial that would potentially interfere with the analysis of this investigation (eg, 
pharmaceutical).  
5. As determined by the Investigator   
a. 
Has been diagnosed with a blood disorder(s) affecting RBC 
characteristics (eg, G-6PD).  
b. Reported history of RBC autoantibodies/autoimmune hemolytic 
anemia, RBC alloantibodies.  
c. 
Clinically significant acute or chronic disease  
d. Reported history of known hypersensitivity to technetium or 
chromium.   
e. 
Treatment with any medication as specified in site deferral list (based 
on AABB medication deferral list for blood donors).  
6. Other unspecified reasons that, in the opinion of the investigator make the 
subject unsuitable for enrollment.                
Statistical 
Methodology: 
Based on FDA criteria for in vivo RBC quality, the following criteria will be assessed: 
The mean 24-hour, post-transfusion, in vivo red cell recovery of at least 75% with a 
standard deviation of ≤ 9%, and the lower limit of a one-sided 95% confidence interval 
for the population proportion of successes is ≥ 70% where an individual success is 
defined to be a recovery of at least 75%.  If there are no more than 3 failures (ie, 3 
recoveries <75%), in an N of 24 or no more than 2 failures in an N of 20, than the lower 
limit of a 95% one-sided will be at least 70%. 
 
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Reveos Automated Blood Processing System 
Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 7 of 52 
TABLE OF CONTENTS 
1 
STATEMENT OF COMPLIANCE .........................................................................13 
2 
INTRODUCTION......................................................................................................14 
3 
DEVICE DESCRIPTION .........................................................................................14 
4 
INTENDED USE STATEMENT..............................................................................19 
5 
NONCLINICAL STUDIES.......................................................................................19 
6 
CLINICAL TRIAL EXPERIENCE .........................................................................19 
7 
RATIONALE FOR THE CURRENT STUDY .......................................................19 
8 
OBJECTIVES ............................................................................................................20 
8.1 
Primary Objective ............................................................................................20 
9 
ENDPOINTS ..............................................................................................................20 
9.1 
Primary Endpoint .............................................................................................20 
10 
INVESTIGATIONAL PLAN ...................................................................................20 
10.1 
Study Design ....................................................................................................20 
10.2 
Study Duration .................................................................................................21 
11 
STUDY POPULATION ............................................................................................22 
11.1 
Number of Participants and Selection..............................................................22 
11.2 
Inclusion Criteria .............................................................................................23 
11.3 
Exclusion Criteria ............................................................................................23 
12 
ENROLLMENT .........................................................................................................24 
12.1 
Recruitment and Pre-Screening .......................................................................24 
12.2 
Informed Consent Process ...............................................................................24 
12.3 
Participant Enrollment .....................................................................................25 
13 
STUDY PROCEDURES ...........................................................................................25 
13.1 
Visit 1 – (Day -14-0) ........................................................................................25 
13.2 
Visit 2 – Day 0 .................................................................................................26 
13.3 
Visit 3 (Day 42) ...............................................................................................28 
13.4 
Follow-Up Visits ..............................................................................................30 
13.4.1 
Visit 4 (Day 43) ................................................................................30 
13.5 
Long-Term Follow-Up.....................................................................................32 
13.6 
Participant Discontinuation/Termination .........................................................32 
14 
LABORATORY TESTS ...........................................................................................33 
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Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 8 of 52 
15 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ...33 
16 
ADVERSE EVENTS/EFFECTS ..............................................................................34 
16.1 
Potential Risks .................................................................................................34 
16.2 
Risk Mitigation ................................................................................................35 
16.3 
Potential Benefits .............................................................................................35 
16.4 
Adverse Event/Effect Definitions ....................................................................36 
16.4.1 
Adverse Event ...................................................................................36 
16.4.2 
Procedure Related Adverse Event ....................................................36 
16.4.3 
Serious Adverse Event ......................................................................36 
16.4.4 
Adverse Device Effect ......................................................................37 
16.4.5 
Unanticipated Adverse Device Effect ...............................................37 
16.5 
Adverse Event Recording ................................................................................37 
16.6 
Adverse Event Classification ...........................................................................38 
16.6.1 
Severity .............................................................................................38 
16.6.2 
Relationship ......................................................................................38 
16.7 
Adverse Event Follow-up ................................................................................39 
16.8 
Serious Adverse Event Reporting Requirements .............................................39 
16.9 
Medical Monitoring .........................................................................................40 
17 
DATA MONITORING COMMITTEE ...................................................................40 
18 
STUDY DEVICE DEFICIENCY .............................................................................40 
18.1 
Device Deficiencies .........................................................................................40 
18.2 
Device Accountability .....................................................................................41 
18.2.1 
Receipt of Study Device ...................................................................41 
18.2.2 
Storage ..............................................................................................41 
18.2.3 
Accountability ...................................................................................41 
19 
STATISTICAL PLAN ...............................................................................................42 
19.1 
Sample Size Rationale .....................................................................................43 
19.2 
Endpoints .........................................................................................................44 
19.2.1 
Primary Endpoint ..............................................................................44 
19.3 
Analysis Populations ........................................................................................45 
19.3.1 
Full Analysis Population ...................................................................45 
19.3.2 
Safety Analysis Population ...............................................................45 
19.3.3 
Evaluable Analysis Population .........................................................45 
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Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
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19.4 
Protocol Analysis Exclusions ..........................................................................45 
19.5 
Missing, Unused, and/or Spurious Data ..........................................................46 
19.6 
Interim Analysis ...............................................................................................46 
20 
STUDY MANAGEMENT .........................................................................................46 
20.1 
Ethics................................................................................................................46 
20.2 
Investigator Responsibilities ............................................................................46 
20.2.1 
Investigator Agreement .....................................................................46 
20.2.2 
Institutional Review Board ...............................................................46 
20.2.3 
Informed Consent..............................................................................47 
20.2.4 
Study Files and Record Retention.....................................................47 
20.3 
Sponsor Responsibilities ..................................................................................47 
20.3.1 
General Responsibilities ...................................................................47 
20.3.2 
Amendments to the Clinical Investigation Plan................................47 
20.4 
Joint Investigator-Sponsor Responsibilities .....................................................47 
20.4.1 
Access to Information for Monitoring and Auditing ........................47 
20.4.2 
Training .............................................................................................48 
20.5 
Collecting and Recording Data ........................................................................48 
20.5.1 
Source Documents ............................................................................48 
20.5.2 
Case Report Forms ............................................................................48 
20.5.3 
Data Queries......................................................................................49 
20.6 
Clinical Investigation Plan Compliance...........................................................49 
20.7 
Suspension or Termination of the Study ..........................................................49 
20.8 
Publication Policy ............................................................................................49 
21 
INVESTIGATOR SIGNATURE ..............................................................................51 
22 
REFERENCES ...........................................................................................................52 
 
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Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
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LIST OF TABLES 
Table 3-1  The composition of CPD ........................................................................................18 
Table 3-2  The composition of AS-5 .......................................................................................18 
Table 13-1  Schedule of Procedures ........................................................................................30 
Table 14-1  In vitro Tests .........................................................................................................33 
Table 16-1  Venipuncture Adverse Event Frequency ..............................................................34 
Table 19-1  Statistical Scenarios 1-5 Estimation of LR-RBC Evaluation Sample Size. .........43 
 
 
LIST OF FIGURES 
Figure 3-1  Reveos Equipment ................................................................................................15 
Figure 3-2  Reveos Device Rotor Compartment......................................................................16 
Figure 3-3  The Reveos blood bag set configuration ...............................................................17 
Figure 10-1  Study Flow ..........................................................................................................22 
Figure 13-1  Study RBC Processing and Storage ....................................................................27 
 
 
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Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AABB 
American Association of Blood Banks 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AS-5 
Additive Solution 5 
AUC 
Area Under the Curve 
BK080010 
510(k) Approval Number for Atreus 
CRF 
Case Report Form 
CDRH 
Center for Devices and Radiological Health 
CFR 
US Code of Federal Regulations 
CIP 
Clinical Investigation Plan 
CPD 
Citrate Phosphate Dextrose 
CPM 
Counts per Minute 
Cr-51 
Sodium Chromate 51 
CTA 
Clinical Trial Agreement 
CTS-5085 
Protocol Number 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
FDA 
US Food and Drug Administration  
G-6PD 
Glucose 6 Phosphate Dehydrogenase Deficiency 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
Hct 
Hematocrit 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
Helsinki, International Conference of Harmonization 
ICSH 
International Committee for Standardization in Hematology 
IDE 
IPU 
Investigational Device Exemption 
Interim Platelet Unit 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
LTFU 
Lost to Follow-up 
MDR 
mL 
EU Medical Device Regulation 
Milliliter 
MOP 
Manual of Procedures 
ng 
Nanogram(s) 
PE 
Procedure Emergent 
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Terumo Blood and Cell Technologies  
Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
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PEAE 
Treatment Emergent Adverse Event 
PI 
Principal Investigator 
PVC 
Polyvinyl Chloride 
RBC 
Red Blood Cell 
LR 
Leukoreduced Red Blood Cell 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
Tc-99m 
Technetium-99m pertechnetate 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
USID 
Unique Study Identification Number 
WB 
Whole Blood 
 
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Clinical Investigation Plan: CTS-5085 
Version 3.0: 11 March 2022 
Confidential  
Page 13 of 52 
1 
STATEMENT OF COMPLIANCE 
This study will be conducted according to this Clinical Investigation Plan (CIP), Good Clinical 
Practice (GCP) as described in the International Council for Harmonization Guidance for 
Industry E6(R2), and, as applicable, United States Code of Federal Regulations (CFR) 
concerning clinical studies (45 CFR Part 46; 21 CFR Parts 50, 56, 312 and 812), International 
Organization for Standardization (ISO) 14155:2020, European Union Medical Device 
Regulation (EU MDR) 2017/745, and other regulatory requirements of the region(s) where the 
study is conducted. The study will not begin until the required approvals or favorable opinions 
from the Ethics Committee (EC) and regulatory authority have been obtained, as applicable. As 
directed, any additional requirements imposed by the EC or regulatory authority will be 
followed. All individuals responsible for the design and conduct of this trial have completed 
Human Subjects Protection Training. Any applicable information required per above regulations 
that is not contained in this CIP may be submitted in separate documentation and will be attached 
to the CIP as an appendix. All essential documents will be archived together in the Trial Master 
File (TMF).  
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2 
INTRODUCTION 
Terumo Blood and Cell Technologies is a corporation that continuously develops medical 
devices for blood manufacturing and cell therapies. These devices include products for whole 
blood (WB) collection and processing, apheresis, therapeutic apheresis, pathogen reduction, and 
cell expansion. The focus in this study is whole blood processing with the Reveos® Automated 
Blood Processing System (Reveos System).  
Blood transfusions have been widely used in medical practice since the early 20th century.1 Blood 
transfusion is the most common procedure during hospital stays in the United States.2 In 2017 
over 12 million WB and apheresis red blood cell (RBC) units were collected in the US and 
approximately 85% of these units were WB collections.3 Patients may receive a unit of WB or 
individual blood components to treat any particular condition and the Global Database on Blood 
Safety reports that in high income countries 97% of WB donations are processed into blood 
components.4 
Whole blood consists of blood components with cellular elements, colloids, and crystalloids.   
Having different relative densities, sedimentation rate, and size, blood components can be 
separated when centrifugal force is applied. This separation is controlled in part by the specific 
gravities of these components including, in increasing order, plasma, platelets, leukocytes, and 
RBCs.5 WB units are currently separated into RBC, plasma, and platelet components through a 
labor intensive, largely manual processes, often including multiple steps. The first fully 
automated system for WB unit processing developed by Terumo Blood and Cell Technologies 
was Atreus (BK080010), which could process one unit of WB into blood components in one 
run.6 
The Reveos System can process up to four (4) WB units in one run. It combines balancing, 
centrifugation, component separation, and sealing into one platform.  
As an automated blood processor, the Reveos System is beneficial in reducing manual blood 
processing drawbacks including processing time, and variability in the procedures and end 
product leading to standardized blood component yield and quality.  
The aim of this study is to evaluate the in-vivo 24-hour recovery of autologous RBCs produced 
with the Reveos System and stored for 42 days, in order to meet the FDA’s criteria for 
manufactured RBCs. 
3 
DEVICE DESCRIPTION 
The Reveos® Automated Blood Processing System is an automated WB processing system.  
Within the protocol it will be referred as Reveos System. The Reveos System has been released 
for sale in certain regions accepting the CE mark since 2013, Terumo Blood and Cell 
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Technologies is seeking US Food and Drug Administration (FDA) 510(k) clearance of the 
Reveos System as an automated whole blood processor.  
The Reveos System consists of the Reveos device (processing equipment) that uses centrifugal 
force to separate WB into its components, a disposable Reveos blood bag set intended to collect 
and store separated components, and a software program to manage the operations.  
Reveos Device 
The Reveos System (Figure 3-1) is an easy-to-use platform that automates and integrates the 
manual steps involved in WB processing. The system processes up to 4 units of WB to produce 
RBCs, leukoreduced plasma, platelets, and residual leukocytes with a single centrifugation step. 
The Reveos System (Figure 3-2) consists of a computer-controlled centrifuge equipped with a 
rotor with 4 fixed buckets, in which the Reveos blood bag set can be placed. Each bucket 
contains a hydraulic-driven expressor to press the different fractions of the centrifuged blood 
from the top to the satellite bags.  
Figure 3-1  Reveos Equipment 
 
 
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Figure 3-2  Reveos Device Rotor Compartment 
 
 
The Reveos System produces three components from each unit of whole blood processed:  a 
plasma unit, an RBC unit, and an interim platelet unit (IPU)  Interim Platelet Unit (IPU). The 
IPU is pooled with other IPUs to create a therapeutic platelet dose. A residual leukocytes unit is 
also produced as a by-product. All buckets must contain a loaded blood bag set or 
counterbalance bag before beginning a procedure. 
Reveos System Manager  
Reveos System Manager is a software application that manages procedures and product data. 
This data is automatically transferred from the Reveos device to the Reveos System Manager. 
The Reveos System Manager lets users perform the following tasks:  
• Configure Reveos devices  
• Define users and assign permissions  
• Configure barcodes and procedures  
• Record and output process and product data  
• Track information entered into the Reveos System Manager  
• Standardization of workflows  
• Report generation 
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Reveos Blood Bag Set 
The Reveos blood bag set (Figure 3-3) consists of medical grade Polyvinyl Chloride (PVC) 
container closures (i.e. blood component bags and tubing). The blood bag set is steam sterilized, 
single use disposable set consisting of a needle connected to a sampling bag and a WB collection 
bag used to collect and process 500 mL ±10% WB. The WB bag has 70 ml of anticoagulant 
(CPD-citrate phosphate dextrose), and the RBC component bag has 111 mL of additive solution 
formula AS-5 (Optisol), and an integrated RBC leukoreduction filter.  
Figure 3-3  The Reveos blood bag set configuration 
 
A general overview of the investigational Reveos blood bag set with: 1) WB bag (processing 
bag) containing CPD anticoagulant, 2) Platelet bag, 3) Plasma bag, 4) RBC bag containing red 
cell additive solution (AS-5), 5) Residual leukocyte bag, 6) Cryoprecipitate bag 7) Blood 
collection assembly (needle, needle injury protector, sample/diversion bag) 8) RBC 
leukoreduction filter.  
The Reveos System primary equipment (processing device) does not come into contact with the 
study participants. After Reveos System processing, RBC units are diluted with AS-5 additive 
solution and transferred through an integrated leukoreduction filter to the RBC bag for storage.  
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CPD and AS-5 
(Optisol) solutions used in the disposable sets were approved for use with TERUFLEX (or 
IMUFLEX) blood bag Systems in 1988 (NDA: BN880217). 
Citrate Phosphate Dextrose (CPD) (Table 3-1) 
The WB bag has 70 ml of anticoagulant CPD. 
Table 3-1  The composition of CPD 
CPD Solution 
Description 
Concentration 
(1000ml) 
Reveos Blood 
Bag Set (70ml) 
Dextrose Anhydrous 
23.2 g 
1.624 g 
Sodium Citrate 
26.3 g 
1.841 g 
Citric Acid 
3.27 g 
0.229 g 
Sodium Dihydrogen Phosphate 
Dihydrate 
2.51 g 
0.176 g 
Water for Injection 
977 ml 
up to 70 ml 
 
Additive solution, AS-5 (Table 3-2) 
The RBC component bag has 111 mL of additive solution formula AS-5. 
Table 3-2  The composition of AS-5 
AS-5 Solution 
Description 
Concentration 
(1000ml) 
Reveos Blood 
Bag Set (111ml) 
Dextrose Anhydrous 
8.18 g 
0.908 g 
Sodium Chloride 
8.77 g 
0.973 g 
Mannitol 
5.25 g 
0.583 g 
Adenine 
0.315 g 
0.035 g 
Water for Injection 
984 ml 
up to 110 ml 
 
Relevant research personnel will be trained on the use of the Reveos System. Device 
accountability will be tracked throughout the study.  
The investigational products will be labeled per 812.5 (a) “Caution- Investigational Device. 
Limited by Federal (or United States) law to investigational use.”  
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4 
INTENDED USE STATEMENT 
Intended Use of the Reveos Device 
The Reveos device is intended to automatically separate units of whole blood into blood 
components.  
Intended Use and Description of the Reveos Blood Bag Set  
The Reveos Blood Bag Set is intended to collect a unit of whole blood and to process the unit on 
the Reveos device, producing blood components.  
Intended Use of the Reveos System Manager Software  
The Reveos System Manager is a software application that manages Reveos procedures and 
processing data. 
5 
NONCLINICAL STUDIES 
Nonclinical studies for verification and validation are ongoing for the Reveos System. 
To date a feasibility, in vitro study for Reveos System processed RBCs has been done. The study 
evaluated hemolysis on Reveos System processed and LR RBC units (n=52). The units were 
stored in CPD/AS-5 for 42 days. The mean hemolysis ± SD was 0.18% ± 0.09% with range of 
0.08% - 0.55%, meeting FDA defined criteria for hemolysis. 
6 
CLINICAL TRIAL EXPERIENCE 
The investigational Reveos System intended for US market does not have clinical trial 
experience. 
7 
RATIONALE FOR THE CURRENT STUDY  
Terumo Blood and Cell Technologies is seeking 510(k) clearance from FDA/CBER  for the 
Reveos® Automated Blood Processing System (Reveos System). 
The proposed study will provide validation on the in vivo performance of LR-RBC units derived 
from WB processed with the Reveos System.  The results will provide data as to whether the 
Reveos System produced LR-RBC can maintain required levels of 24-hour in vivo recovery that 
meet FDA criteria for RBC.7 
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8 
OBJECTIVES 
8.1 
Primary Objective 
The primary objective of this study is to evaluate whether the LR-RBC derived from WB 
processed with the Reveos System meet FDA criteria for in vivo 24-hour recovery.  
Based on FDA criteria for in vivo RBC quality, the following criteria will be assessed: 
LR-RBC mean 24-hour recovery ≥ 75% with SD ≤9 % and one-sided lower confidence limit for 
population proportion of RBC in vivo recovery 70%†. Success is >75%. 
†Allows for low recoveries (<75%) in 2/20 or 3/24 volunteers. 
If all three criteria are met, the Reveos System will be deemed to have met the FDA criteria for 
24-hour in vivo RBC recovery. 
Performance criteria will be evaluated in healthy adult participants, who receive radiolabeled, 
autologous infusions of LR-RBC components after being stored for 42 days at 1-6°C. 
9 
ENDPOINTS 
9.1 
Primary Endpoint 
The primary endpoint is the 24-hour in vivo RBC recovery. 
LR-RBC mean 24-hour recovery ≥ 75% with SD ≤9 % and one-sided lower confidence limit for 
population proportion of RBC in vivo recovery 70%†. Success is >75%. 
†Allows for low recoveries (<75%) in 2/20 or 3/24 volunteers. 
10 
INVESTIGATIONAL PLAN 
10.1 
Study Design 
Prospective:  
• Evaluation of LR- RBC recovery  
• Healthy adult volunteers  
• 24 total evaluable participants enrolled (i.e., approximately 12 participants at each site)  
• Single arm - autologus reinfusion of radiolabelled RBCs 
• Double radiolabel with 51Cr  (LR-RBCs for recovery) and 99mTc (Fresh RBCs for RBC 
volume/mass determination)  
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Multi- Center:  
• Hoxworth Blood Center  
• Bloodworks Northwest 
This study evaluates Day 42 RBC recovery.  After donation and processing of WB with the 
Reveos System, the RBCs are leukoreduced (LR) and stored for 42 days. An autologous aliquot 
of stored LR-RBCs and fresh RBCs will be radiolabeled with 51Cr and 99mTc, respectively, and 
reinfused to the donor. RBC recovery testing will be performed at 24-hour post-infusion. 
All procedures related to labeling, infusion, sampling and recovery/mass determination will 
follow site common standardized procedures and standard operating procedures (SOPs). 
The procedures for radiolabeling of RBCs to evaluate RBC recovery are based and adapted from 
methods recommended by International Committee of Standardization in Haematology (ICSH) 
Recommended Methods for Radioisotope Red-Cell Survival Studies 19808 and previously 
published literature by Moroff and colleagues Proposed Standardization of Methods for 
Determining the 24-Hour Survival of Stored Red Cells, 19849. The method of calculating the 
blood volume with 99mTc is based on the ICSH Recommended Methods for measurement of Red-
Cell And Plasma Volume 198010.  
10.2 
Study Duration 
The total study duration is expected to last 6 months from first participant enrollment.  Each 
study participant will have a total of 4 study visits (Figure 10-1) including screening within a 
time span of 57 days (1.9 months). Visit details are described in section 13.  
• Study visit 1(Screening 0-14 days)  
• Study visits 2 to 4 (over approximately 43 days) 
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Figure 10-1  Study Flow 
 
11 
STUDY POPULATION 
11.1 
Number of Participants and Selection 
It is estimated that up to 50 volunteers will be enrolled to allow targeted twenty-four (24) 
evaluable recovery endpoints. Healthy adult volunteer study participants will be enrolled at two 
(2) centers; approximately 12 at each study center. Study participants will come from the general 
population.  Eligible WB donors exhibiting normal health status and vital signs as determined by 
standard American Association of Blood Banks (AABB) blood donation criteria.   
Volunteers who cannot commit to completing all study requirements should not be considered 
for enrollment. No medical records are accessed during inclusion exclusion determination, all 
medical history is based on known or self-reported history of the prospective participants. A 
participant can screen multiple times but participate only once for the study. The Informed 
Consent process described below will be undertaken following determination of initial eligibility.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WB Donation of 500 mL ±10% into Reveos Blood Bag Set 
Store LR-RBC at 1-6° Celsius for 42 days 
RBC filtration 
Process into blood components with Reveos device 
DAY 0 
DAY 42 
Radiolabeling procedure with 51Cr and 99mTc per site SOPs 
DAY 43 
Blood sample for 24-hour recovery % 
Autologous Reinfusion of radiolabeled per site SOPs product 
DAY -14-0 
Screening 
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11.2 
Inclusion Criteria 
Inclusion criteria for participant selection: 
1. Healthy volunteers, of either gender 
2. Age 18 years or older. 
3. Normal health status as per AABB criteria for healthy donor. 
4. Able to commit to the study schedule. 
5. Meets the inclusion criteria defined by the Blood Center for whole blood donor. These 
criteria are based on FDA Regulations and AABB standards. Note: Participants who are 
deferred from volunteer community donations because of travel restrictions, piercings, 
tattoos or other reasons by PI approval may participate in the study, as products are re-
transfused to the autologous donor. 
6. Participants of childbearing potential (either male or female) must agree to use 
medically acceptable method of contraception throughout of the study. 
7. Females of childbearing potential must be willing to take a pregnancy test prior to 
WB donation and infusion of radiolabeled RBCs. 
8. Signed and dated informed consent form. 
11.3 
Exclusion Criteria 
Exclusion criteria for participant selection: 
1. Pregnant or nursing females.  
2. Serum ferritin <12 ng/mL 
3. Has previously completed this study with evaluable data points.  
4. Participation currently, or within the past 30 days, in another investigational trial that 
would potentially interfere with the analysis of this investigation (eg, pharmaceutical). 
5. As determined by the Investigator   
a. Has been diagnosed with a blood disorder(s) affecting RBC characteristics (eg, G-
6PD). 
b. Reported history of RBC autoantibodies/autoimmune hemolytic anemia, RBC 
alloantibodies.  
c. Clinically significant acute or chronic disease  
d. Reported history of known hypersensitivity to technetium or chromium. 
e. Treatment with any medication as specified in site deferral list (based on AABB 
medication deferral list for blood donors).  
6. Other unspecified reasons that, in the opinion of the investigator make the subject 
unsuitable for enrollment. 
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12 
ENROLLMENT 
12.1 
Recruitment and Pre-Screening 
Recruitment and pre-screening activities to identify appropriate candidates for study inclusion 
will be conducted prior to obtaining informed consent.  These pre-screening measures will be in 
accordance with Institutional Review Board (IRB) guidelines and approvals. Because this period 
precedes informed consent, study documentation (eg, AE reporting) will not be required during 
this period. 
Specific activities may include:  
1. Conducting pre-screening measures to identify appropriate candidates from blood 
center donor lists include: 
a. Reviewing for qualified donor status  
b. Reviewing donor demographics and phlebotomy history  
2. Introducing study and suggesting possibility of entry to potential participants. 
3. Providing information about the study to include informed consent process, required 
study schedule, specific study procedures, risks, benefits and compensation. 
4. Providing a copy of the informed consent forms (ICFs) to potential participants for 
review. 
12.2 
Informed Consent Process 
Prior to participant involvement in this study, the Investigator must obtain written IRB approval 
for the Clinical Investigation Plan (CIP) and ICF. A copy of the site-specific ICF must be 
provided to the Sponsor for review and approval prior to submission to the IRB for approval. 
The approved ICF will clearly reflect the IRB approval date. Once approved, the ICF must be 
provided to the Sponsor prior to implementation in this study. All study participants must provide 
written informed consent using the Sponsor and IRB approved ICF.  
Once the participants initial suitability for study participation has been determined per pre-
screening measures, the Investigator or person designated by the Investigator who has been 
trained on the CIP, will explain the nature and scope of the study, potential risks and benefits of 
participation, answer questions for the donor, and ask the donor to participate in the study. The 
study will be explained to the donor in lay terms, in English language in a quiet, non-disruptive 
setting. Potential participants will be given as much time and privacy as necessary to review the 
informed consent prior to agreeing to participate in the study. Additionally, if the donor requests, 
they can take a copy of the consent with them so that they can discuss potential participation 
with others outside the study team. If the donor agrees to participate, has read the ICF, and has 
had all of their questions answered, then the ICF must be signed and dated by the donor and the 
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person completing the consent process. A copy of the signed and dated ICF will be provided to 
the study participant and the original is placed in the study file.  
Failure to obtain a signed ICF prior to participant involvement in the study constitutes 
noncompliance with the Declaration of Helsinki, International Conference of Harmonization 
(ICH) Good Clinical Practice (GCP), US Code of Federal Regulations (21 CFR 812), and 
International Organization for Standardization (ISO) 14155. 
12.3 
Participant Enrollment 
A donor is considered an enrolled participant upon giving informed consent for study 
participation; this timepoint represents the beginning of a participant’s involvement in the study. 
After informed consent has been obtained, participants will receive a unique subject 
identification number (USID) to de-identify participants. The USID number will use the 
following convention: XX-YYY, where XX is the pre-assigned site number and YYY will be a 
sequential number starting with 001. The USID number will be recorded on the Case Report 
Form (CRF). Participant identifiers such as initials or names will not be used, for example: 
First participant enrolled at Site #01: John Doe = 01-001  
First participant enrolled at Site #02: Jane Doe = 02-001 
It is expected that some proportion of enrolled participants will not qualify for study inclusion 
per the screening and eligibility criteria, and some who are deemed eligible will not initiate the 
WB collection procedure. Participants will be considered study procedure discontinuations or 
study terminations if, following initiation of the WB collection, they do not complete the study 
procedures, as applicable and as described further in Section 13. 
13 
STUDY PROCEDURES 
The study procedures are to be performed following the WB collection day (Day 0), and are 
therefore referenced as days post WB collection (e.g. the reinfusion of autologous LR-RBC will  
take place 42 days after the WB collection day).  A study procedure schedule of events is 
provided in Table 13-1 Schedule of Procedures. 
13.1 
Visit 1 – (Day -14-0) 
SCREENING 
Visit 1 can take place within 14 days before WB Collection.  
Screening will consist of: 
1. Review and signing informed consent prior to initiating any protocol-required 
procedure that is not considered standard of care  
2. Assign USID number 
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3. Review of relevant health history and medications (relevant to RBC viability and 
study procedures)  
4. Record – Height, weight, and vital signs  
5. Demographics (date of birth, gender, race, ethnic origin,) 
6. Confirm subject eligibility. 
7. Blood draw for Serum ferritin (ABO/Rh, standard viral screen, CBC per site SOP) 
13.2 
Visit 2 – Day 0 
WB COLLECTION  
After enrolling the participant into the study, the following baseline activities will be done for the 
participant and will be recorded:    
1. Re-confirm eligibility  
2. Physical assessment  
a. Record vital signs (pulse rate, blood pressure, temperature) and skin integrity 
prior WB collection 
3. Female participant will have a serum or urine pregnancy test. No test is needed if 
participant has history of bilateral oophorectomy, hysterectomy, postmenopausal for 1 
year,  or PI confirmed justification  
4. Collect WB into the Reveos Blood Bag Set  
5. Laboratory(ies):  
a. Select complete blood count (Hgb, Hct) 
b. ABO/Rh of participant  
c. Donor laboratory tests (standard viral screen, if not done at screening)  
6. Record Adverse Events (AEs) 
The WB collection as well as sample testing will be performed in accordance with the study site 
SOPs. A target final volume of 500 mL +/- 10% of WB will be collected. Thereafter, at least 2 
hours after collection it will be maintained in an ambient temperature environment of 18 – 24° C 
until processing. Leukoreduced (LR) RBCs will be stored in < 8 hours. 
Reveos System Whole Blood Processing 
“Whole blood processing” in this study refers to the Reveos System separation of a WB product 
into its platelet, plasma and RBC components.  Study staff will be trained for the use of the 
Reveos System. Study staff will refer to Manual of Procedures, Reveos Blood Bag Set with RBC 
Leukoreduction Filter Instructions For Use (Package Insert) and the Reveos® Automated Blood 
Processing System Operator’s Manual on how to use the Reveos System.  
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In short summary, the Reveos Blood Bag Set with the collected WB will be placed into the 
Reveos System for WB processing. At the end of the separation procedure, the separated 
products are removed from the Reveos System device.  The residual leukocyte bag, the plasma 
bag and the platelet bag are discarded. Figure 13-1 below shows a schematic of WB processing 
and RBC processing and storage.  
Figure 13-1  Study RBC Processing and Storage 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RBC Product Sampling and Storage  
Additive Storage solution AS-5, enclosed in the bag set, will be used to prime the leukoreduction 
filter and RBCs will be then LR by gravitational filtration (Figure 13-1).  
RBC products from the collections will be sampled pre-and post-leukoreduction for yield 
assessment and leukoreduction for red cell quality assessments on Day 0 (beginning of storage). 
The LR-RBC product will then stored for 42 days at 1-6°C.  
Data recorded on Visit 2 (Day 0) from processes and products: 
1. WB collection date, start and end time  
2. WB weight or volume 
3. Reveos System processing start and end time  
4. RBC Filtration start and end time 
5. RBC bag weight pre-and post-filtration  
6. Select CBC pre- and post-filtration units (Hct)  
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7. LR-RBC Mass recovery %  
8. Residual WBC content per LR-RBC unit post-filtration  
9. Time of placement into refrigerated storage 
10. Reveos System device serial number 
11. Reveos System disposable serial/LOT number 
12. Device /procedure deficiencies 
Should LR-RBC Mass Recovery after filtration not meet recovery ≥ 85% or Leukoreduction not 
meet required FDA limit (< 5 x 106 WBC/per unit) LR-RBC unit will be discarded and the 
participant will be withdrawn from the study.  
Any participants with positive viral screens will be withdrawn from the study. 
Bacterial testing and/or visual inspection for RBC screening is done according to the site’s 
research SOPs.  
13.3 
Visit 3 (Day 42) 
REINFUSION 
Visit 3 is day 42 after WB collection and marks the end of storage of LR-RBCs. 
The procedures during this visit will follow site procedures for labeling, infusion, sampling and 
RBC recovery/mass determination (Study design 10.1). 
Ensure participants viral screening results are negative prior re-infusion. 
Bacterial testing and /or visual inspection for signs of unusual hemolysis or discoloration 
indicative of bacterial growth will be done per sites research SOP’s. Affected units will not to be 
further processed and will be discarded. 
Should LR-RBC not meet hemolysis requirement of ≤ 1 % after storage, the units will not to be 
further processed and will be discarded. The participant will be withdrawn from the study before 
reinfusion. 
Female participant will have a serum or urine pregnancy test per specific procedures. Pregnancy 
test results must be available before re-infusion and have to be negative for the subject to 
continue in the study. 
Measures to ensure the study donor receives his or her own (autologous) radiolabeled RBCs 
begin at donation when the study donor’s name, birth date and unique study identifying number 
will be recorded on the donor registration form.  Clinical sites must have a standard labeling and 
handling process intended to eliminate errors in linking packed RBC units with the correct study 
donor. 
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Qualified RBCs will be radiolabeled with 51Cr (LR-RBC) and 99mTc (fresh blood), and then 
reinfused back to the original participant. Radiolabeling will be done per site procedures and 
SOPs (Study Design 10.1). 
Procedures and data recorded from visit 3 (Day 42)  
Preinfusion 
1. Pregnancy test result, if applicable  
2. Vital signs: Blood Pressure (BP), Pulse Rate (PR), and temperature  
3. Draw blood for select CBC (Hct, Hgb), background radiation determination and for 
radiolabeling  
4. Confirm of continued eligibility prior to reinfusion of radiolabeled cells (record current 
health status, current medications, negative RBC bacterial test and/ or visual inspection, 
donor viral screen, hemolysis ≤1% of stored LR-RBC)  
Post infusion  
5. Record reinfusion start and end time 
6. Record vital signs: Blood Pressure (BP), Pulse Rate (PR), and temperature within 1 hour 
(±15 minutes) post-start reinfusion of the radiolabeled aliquots  
7. Draw blood for post-infusion samples per site SOP at approximately: 
• 5 min 
• 7.5 min 
• 10 min 
• 12.5 min 
• 15 min 
• 20 min  
• 30 min 
8. Complete post-infusion worksheet including, but not limited to (refer to Manual of 
Procedures for full detailed data collection): 
a. Exact time in minutes and seconds of post- infusion blood samples  
b. CPM for 51Cr and 99mTc for post-infusion blood samples in duplicate or as many 
samples as per site SOPs, background and empty counting tube CPM, weight of 
counting tubes and infusate, CPM at time 0 
c. Hematocrit of each post-infusion sample  
9. Record AEs 
10. Record device/product deficiencies  
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13.4 
Follow-Up Visits 
13.4.1 
Visit 4 (Day 43)  
Visit 4 is 43 days after WB donation. The visit follows site SOP for determining 24-hour 
recovery. 
A blood sample (6-10 mL) will be drawn 24 (± 2) hours post-infusion 
Data recorded from visit 4  
1. Complete worksheet including, but not limited to (refer to Manual of Procedures for 
detailed data collection): 
a. Exact time of the blood draw 
b. CPM readings from blood sample in duplicate or as many samples as per site 
SOPs, net CPM, corrected CPM 
c. Hematocrit(s) of the blood sample  
2. 24-hour RBC recovery (%) 
3. AEs 
Visit 4 will conclude the participants study participation. 
Primary endpoint, 24-hour RBC recovery, will be calculated from the data of this visit according 
to the sites’s standardized in vivo RBC recovery procedure.  
Data collection will be completed by both sites for RBC % recovery. Calculations for this will be 
conducted for enrolled participants by both sites.  
Table 13-1  Schedule of Procedures 
Study Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Days (-14-
0) 
Screening  
Day 0 
WB 
collection 
Day 42 
Infusion  
Day 43 
24-hr 
Post-
infusion  
Pre-
Infusion 
Post-Infusion 
Obtain informed consent 
X 
 
 
 
 
Confirm eligibility 
X 
X 
 
 
 
Collect demographics (date of birth, 
gender, race, ethnic origin), height, 
and weight  
X 
 
 
 
 
Record relevant medical history 
X 
 
 
 
 
Blood sample for Ferritin 
(approximately 3.5ml) 
X 
 
 
 
 
Confirm participant is healthy 
 
X 
X 
 
 
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Study Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Days (-14-
0) 
Screening  
Day 0 
WB 
collection 
Day 42 
Infusion  
Day 43 
24-hr 
Post-
infusion  
Pre-
Infusion 
Post-Infusion 
Pregnancy test for women of 
childbearing potentiala 
 
X 
X 
 
 
Blood sample for donor eligibility 
(approximately 35 ml) (Hgb or Hct, 
ABO, viral screenb) 
X 
(X) 
 
 
 
WB donation 500 ml ± 10% 
 
X 
 
 
 
Record serial numbersc, LOT#, and 
expiry dates of equipment and 
disposables  
 
X 
 
 
 
Label LR-RBC product with USID 
number  
 
X 
 
 
 
Confirm LR-RBC product meets 
mass recovery and leukoreduction 
requirements 
 
X 
 
 
 
Store LR-RBCs at 1°C ̶ 6°C  
 
X 
 
 
 
Bacterial testing and/or visual 
inspection on stored LR-RBCs per 
site SOP d 
 
 
X* 
 
 
Radiolabeling of blood e 
 
 
 X 
 
 
Infusion of radiolabeled sample (51Cr 
& 99mTC) f 
 
 
X 
 
Blood samples Pre-infusion and post- 
infusion 
 
 
Total of approximately 80 ml blood 
collected during visit 3 
X 
10 ml 
Pre-
infusion 
sample  
Post-infusion 
samples 
approximately at 5, 
7.5, 10, 12.5, 15, 20, 
30 minutes g 
Total blood volume drawn during the 
clinical investigation 
Approximately 678.5 ml 
Counts per minute h 
 
 
X 
X 
X 
Record vital signs (PR, BP, t°) 
X 
X 
X 
X 
 
Record AEs, SAEs, and UADEs 
X 
X 
X 
X 
Record current medications  
X 
X 
X 
X 
Record Device Deficiencies 
 
X 
X 
 
a Pregnancy test is done by serum or urine test per site SOP  
b Part of AABB criteria. If not determined within 14 days prior to planned blood collection date, then as part of 
standard blood bank donor screening process (all viral screen results have to be negative for infections). 
c Record Reveos machine serial number and lot number and expiration date of the disposable set used 
d, e, f, g, h Prescribed tasks will be done per site SOP 
*Timeframe per site SOP 
 
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Abbreviations: AE = adverse event; CBC = complete blood count; HCT = hematocrit; Hgb = hemoglobin; SAE = 
serious adverse event; UADE = unanticipated adverse device effect; USID = Unique Subject Identification number; 
PR = Pulse rate; BP = Blood pressure; t° = temperature; LOT# = control number for disposable products 
(combination of letters, numbers, or symbols) 
13.5 
Long-Term Follow-Up 
All Adverse Events(AEs) will be reported. AEs related to the study device or procedure will be 
followed until resolution, except the expected AE of mild hematoma (bruise) and/or mild infiltration, 
which are not followed to resolution as described in Section 16.7 otherwise there is no long term 
follow-up.  
13.6 
Participant Discontinuation/Termination 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified and unspecified, and without prejudice. Participants may be discontinued by the PI or 
study sponsor if it is in the best interest of the subject’s health, the study is placed on hold or 
other factors. Should this occur, the reason for discontinuation must be recorded in the source 
documentation, and the Study Exit CRF. Factors leading to participant discontinuation may 
include, but are not limited to the following:  
Screen failures: Participants will be considered screen failures if they fail to meet any of the 
eligibility criteria after signing informed consent.  
Participant withdrawal: Participant participation in a clinical trial is voluntary and the participant 
may discontinue participation (refuse all subsequent testing and follow-up) or withdraw their 
consent from the study at any time without affecting their future relationship with blood center.  
Participant withdrawn: Participants who test positive for infectious diseases will be notified of 
these results per the study site’s SOPs. Results of positive infectious disease testing will be 
reported to state and/or local health authorities as required in each site’s geography. Participant 
who do not return to visit 3 or 4. The collected blood fails quality checks, the blood will be 
considered non-evaluable for the primary endpoint analysis, the participant will not undergo 
reinfusion or recovery evaluations, and the participant will be discontinued from the study.   
Investigator /Sponsor Decision: The investigator /may terminate the participant’s participation 
without regard to the participant’s consent if, in the judgment of the investigator, the participant 
is unable to continue in the study for medical or other pertinent reasons.  
Lost to Follow-up (LTFU): A participant will be considered as LTFU only after three 
unsuccessful, documented attempts to contact the participant have been made. 
Death: Upon learning of the death of the participant, the study site will be responsible for 
notifying the sponsor, recording the information in the source documentation and in the 
appropriate study CRFs, and obtaining a copy of the autopsy report and death certificate, if 
available.  
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14 
LABORATORY TESTS 
Laboratory tests will be performed at each study site at the timepoints outlined in Table 14-1. 
Copies of the current laboratory certifications and/or calibrations and normal ranges will be 
provided to the Sponsor prior to start of the study and upon every renewal throughout the 
duration of the study. Some samples may be shipped to designated central laboratory facilities. 
Table 14-1  In vitro Tests  
Test type 
Visit 1 
(Screening) 
Visit 2  
(Day 0) 
Visit 2 (Day 0) RBC 
Unit:  
During 
storage 
LR-
RBC 
Unit or 
day 42  
Visit 3 
(Day 42): 
LR-RBC 
Pre-
infusion 
Visit 3 
(Day 42):  
Post-
infusion 
Visits 40  
(Day 43): 
 
RBC 
Unit 
pre-
filtration 
LR-RBC 
Unit 
post-
filtration 
Ferritin  
X 
 
 
 
 
 
 
 
Select CBC 
(Hct, Hgb) 
X 
(X)a 
X 
X 
 
X 
Xb 
X 
ABO/Rh 
X 
(X)a 
 
 
 
 
 
 
Viral screen 
X 
(X)a 
 
 
 
 
 
 
LR-RBC unit 
Residual 
WBC 
concentration  
 
 
 
X 
 
 
 
 
LR-RBC unit 
Mass 
recovery post 
filtration 
 
 
 
X 
 
 
 
 
LR-RBC unit 
Free 
hemoglobin 
 
 
 
 
 
X 
 
 
LR-RBC unit 
% Hemolysis  
 
 
 
 
 
X 
 
 
Bacterial 
testing and/or 
visual 
inspection on 
stored LR-
RBCs per site 
SOP 
 
 
 
 
Xc 
 
 
 
a Tests are done at screening and/or at visit 2, b Multiple blood samples will be drawn from participants during 
pre-and post-infusion, c Timeframe per site SOP. 
15 
CONCOMITANT MEDICATIONS, TREATMENTS, AND 
PROCEDURES 
Current medications and/or treatment administered to treat AEs will be recorded. 
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16 
ADVERSE EVENTS/EFFECTS 
16.1 
Potential Risks 
Risks of Venipuncture, Whole Blood Collection and Radiolabel Infusion 
The general common risks of venipuncture are apprehension, pain, discomfort, extravasation of 
blood into the tissue causing a bruising or hematoma and presyncope, including pallor, 
lightheadedness, dizziness, nausea, diaphoresis. Other, less common and rare side effects are 
fainting, nerve irritation, infection, arterial puncture, allergy(skin), neuropathic pain, phlebitis 
and deep vein thrombosis (DVT). Occurrence rates of venipuncture AEs are summarized in 
Table 16-1 below. 
Table 16-1  Venipuncture Adverse Event Frequency 
Location 
Very Common 
≥ 1/10 
Common 
≥ 1/100 to  
< 1/10 
Uncommon 
≥ 1/1,000 to  
< 1/100 
Rare 
≥ 1/10,000 
to < 1/1,000 
Very rare 
< 1/10,000 
Not known 
Sporadic case 
reports 
General11,12,13, 
14  
Apprehension 
 
Presyncopea 
 
Faintb 
 
 
 
At puncture 
site 11,12,14 ,15  
 
Hematoma 
 
Nerve 
irritation 
Arterial 
puncture 
 
Pain 
Infection 
Distant of 
puncture 
site11,14,16,17 
 
Discomfort 
 
 
Skin allergy 
Phlebitis 
 
 
 
 
 
Neuropathic 
pain 
DVT 
Abbreviations: DVT = deep venous thrombosis 
a Presyncope includes symptoms such as pallor, lightheadedness, dizziness, nausea, diaphoresis. 
b Faint defined as a brief loss of consciousness, usually less than 30 seconds. 
Since participants will be re-infused with small amount of their own, radiolabeled RBCs, the risk 
of a transfusion reaction is minimal, however, in very rare cases, a reaction may occur, causing 
severe illness or death.  
The amount of radiation exposure from radioisotopes, 51Cr and 99mTc, used in this study and 
received by the participant is low and is not considered to be harmful. However, women who are 
pregnant or who are nursing will be excluded from the study, as the risks of radiation exposure to 
a fetus or infant are unknown. All enrolled women of childbearing potential will have a 
pregnancy test performed during the screening process, and prior to her reinfusion as an added 
precaution. Any participant with a positive pregnancy test will not be given radiolabeled LR-
RBCs and will be withdrawn from the study.  
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There is a possibility of bacterial overgrowth if bacteria have inadvertently entered the blood bag 
collection system. The stored LR-RBCs will undergo bacterial testing and/or visual inspection, 
per site’s SOP. The results from this testing or inspection will be reviewed prior to the infusion of 
cells. Any participant with positive results will not be re-infused with their RBC. Total volume of 
blood drawn from subjects completing the study will be approximately 670 mL over 57 days. 
The standard blood center eligibility criteria for donating blood products includes tracking RBC 
loss. A standard single unit WB collection (211 ml of RBC loss) is between 450-550 mL. After a 
WB collection the body replaces the plasma in about 24 hours, RBCs are restored in two to four 
weeks, and platelets are replenished in about 72 hours.   
16.2 
Risk Mitigation 
The Reveos Blood Bag Sets are manufactured according to good manufacturing practices (GMP) 
and are sterile. The systems instructional labeling will be provided for the disposables blood bag 
sets and the hardware/software and the site will be trained for correct use of the system. Site 
SOPs will be used for technical aspects of blood collection. 
Risks for the subject can be minimized by:  
• Ensuring that all Investigators are properly qualified and meet pre-specified criteria for 
Investigator selection and that they and their study teams successfully complete the 
following training: site-specific training, Human Subject Protection, Good Clinical 
Practice (GCP), and CIP training to include device and procedure training.  
• Ensuring that participants who are enrolled meet all eligibility criteria  
• Ensuring universal precautions are used for handling all study blood products in 
accordance with each site’s SOPs. 
• With the collection of health data associated with this research study, there is a small risk 
of violation of privacy and loss of confidentiality. The source data and CRFs will only 
use de-identified subject USID number as participant identifiers, to ensure confidentiality. 
• Participants will be monitored for adverse experiences throughout the study. Suspected 
adverse events will be treated according to study sites’ SOPs and documented as 
described in Section 16.5. 
16.3 
Potential Benefits 
There is no direct benefit to the study subject. Real benefits are altruistic in nature: subjects 
participating in this study will assist in gathering important information for safety and 
performance, to assess The Reveos® Automated Blood Processing System (Reveos System) to 
obtain required regulatory clearance for future use in the USA. 
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16.4 
Adverse Event/Effect Definitions 
16.4.1 
Adverse Event 
An AE is defined (ISO 14155 Section 3.2) as any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs (including abnormal laboratory ﬁndings) in subjects, 
users or other persons, whether or not related to the investigational medical device and whether 
anticipated or unanticipated. This deﬁnition includes events related to the investigational medical 
device or the comparator and events related to the procedures involved. For users or other 
persons, this deﬁnition is restricted to events related to the use of investigational medical devices 
or comparators. 
16.4.2 
Procedure Related Adverse Event  
Procedure-emergent adverse events (PEAEs) are defined as any AE that occurs upon or after the 
exposure to Reveos Blood Bag set. As described in Section 16.5  AEs occurring after signing of 
the ICF and until participant study completion will be recorded and require follow-up; however, 
only PEAEs will be included in the safety analysis. Study timepoints (eg, start of study 
procedure, participant study completion) are defined in Section 13. 
16.4.3 
Serious Adverse Event 
A serious adverse event (SAE) is defined (21 CFR 312.32 and ISO 14155 Section 3.45) as an AE 
which meets any of the following criteria: 
1. Results in death 
2. Leads to serious deterioration in the health of the subject, users, or other persons that 
either results in:  
a. A life-threatening illness or injury, or 
b. A permanent impairment of a body structure or a body function including chronic 
diseases, or 
c. In-patient or prolonged hospitalization, or  
d. Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
3. Leads to fetal distress, fetal death or a congenital abnormality or birth defect 
including physical or mental impairment. 
NOTE: The following are not considered SAEs: 
Planned hospitalization for a pre-existing condition or a planned procedure required by 
the CIP, without serious deterioration in health. 
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Anticipated day-to-day fluctuations of pre-existing disease(s)/condition(s) present or 
detected at screening that do not worsen. 
16.4.4 
Adverse Device Effect 
An ADE (adverse device effect) is defined (ISO 14155 Section 3.1) as any AE related to the use 
of an investigational medical device. This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, implantation, installation, or 
operation, or any malfunction of the investigational medical device. This definition also includes 
any event resulting from use error or from intentional misuse of the investigational medical 
device. 
An AE is considered related to the use of the study medical device if the attribution is probably, 
possibly or definitely related, whereas the definition of “not related” is considered to be 
unrelated to the use of the study medical device. 
16.4.5 
Unanticipated Adverse Device Effect 
An unanticipated adverse device effect (UADE) is defined (21 CFR 812.3[s]) as any serious 
adverse effect on health or safety, any life-threatening problem or death caused by, or associated 
with a device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application; or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects.  
Whether an UADE is anticipated or not will be analyzed and determined by the Sponsor. 
16.5 
Adverse Event Recording 
Safety oversight and reporting during the course of this study will be per ICH GCP guidelines, 
US Code of Federal Regulations [CFR] part 812. The Investigator will monitor the occurrence of 
AEs for each subject during the course of the study.  All AEs reported by the subject, observed 
by the Investigator, or documented in medical records will be listed on the AE CRF, assessed by 
the Investigator to be  not related, possibly related, probably related or definitely related to the 
investigational product.  Only procedure emergent AEs (PEAEs) will be included to the safety 
evaluation. Collection of PEAEs will begin at the time of the first exposure to Reveos Blood Bag 
set per Section 13.2 and continue throughout the entire study until study exit or observed related 
AEs are resolved.  All AE’s will be classified by the site investigators for its relation to procedure 
per 16.6.2.  Starting with the first baseline procedure, any new event/experience that was not 
present at baseline, or worsening of an event present at baseline, will be considered an AE.  
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During reinfusion of RBC, the subject will be monitored for AEs; e.g., fever, chills, dyspnea, 
urticaria, or pain (infusion site, chest pain or other).  AEs will be recorded in the source and 
CRFs, and reported to the study investigator with the following conditions:  
• At each visit, AEs since the last visit will be actively assessed via subject interview, and if 
necessary, via physical exam, and will be documented.  
• Ongoing and/or recurrent conditions that were documented on Day 0 will be recorded as AEs 
only if their severity or frequency increases. 
16.6 
Adverse Event Classification 
16.6.1 
Severity 
The Principal Investigator (PI) at each site will review and document his/her opinion of the 
severity of the adverse events to the study and/or procedure(s) according to as follows: 
Grade 1 – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 – Moderate; minimal, local or noninvasive intervention indicated. 
Grade 3 – Severe; medically significant but not immediately life-threatening 
hospitalization or prolongation of hospitalization indicated. 
Grade 4 – Life-threatening consequences; urgent intervention indicated. 
Grade 5 – Death related to AE. 
16.6.2 
Relationship 
The PI at each site will document his/her opinion of the relationship of the event to the study 
procedure(s) as follows: 
Not Related: 
The event is clearly related to factors other than the study device and/or procedure(s), such as the 
participant’s clinical state or the relationship in time suggests that a causal relationship is 
impossible. 
Possibly Related:  
The event follows a reasonable temporal sequence from the time of study treatment 
administration/procedure, and/or follows a known response pattern to study device/procedure(s) 
but could have been produced by other factors, such as the participant’s clinical state or other 
therapeutic interventions. 
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Probably Related: 
The event follows a reasonable temporal sequence from the time of study device/procedure(s) 
and cannot be reasonable explained by other factors, such as the participant’s clinical state or 
therapeutic interventions. 
Definitely Related: 
The event follows a reasonable temporal sequence from the time of study device/procedure(s), 
and follows a known response pattern, and cannot be reasonably explained by other factors. In 
addition, the event occurs immediately following study procedure(s), and/or improves on 
stopping the study procedure, and/or reappears on resumption of study procedure(s). 
These criteria, in addition to good clinical judgment, should be used as a guide for determining 
the causal assessment. 
16.7 
Adverse Event Follow-up 
All study-related AEs must be followed at a minimum through to study completion and until return 
to baseline, resolution or until the Investigator deems the event to be chronic, the participant is 
stable, or the participant is lost to follow-up in accordance with the ICH GCP guidelines, and other 
applicable regulatory requirements (eg, 21 CFR 812). The Investigator should make a preliminary 
judgement regarding the relationship of each AE with the study device, the procedure, and the 
medical history.  
Targeted treatment to all AEs should be provided as needed. 
The Investigator should provide targeted treatment to AEs. All AEs must be followed at a minimum 
through to study completion and until return to baseline, resolution or until the Investigator deems 
the event to be chronic, the participant stable, or the participant is lost to follow-up in accordance 
with the ICH GCP guidelines. 
The expected AE of mild hematoma (bruise) and/or mild infiltration are not followed to resolution. 
16.8 
Serious Adverse Event Reporting Requirements 
In the interest of subject care and to allow the Sponsor to fulfill all regulatory requirements, any 
SAE, regardless of causal relationship to study treatment/procedure(s), and all UADEs must be 
reported to the Sponsor within 24 hours of knowledge of the event at the following email 
address: ClinicalAffairs@TerumoBCT.com. 
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Additionally, an SAE/UADE Form must be submitted to the Sponsor within 24 hours of 
knowledge of the event to: 
Terumo Blood and Cell Technologies  
Email: ClinicalAffairs@TerumoBCT.com 
Additionally, the SAE/UADE must be entered on the AE page(s) of the CRF. Follow-up 
SAE/UADE reports need to be submitted to the Sponsor as soon as additional information 
regarding the event becomes available. 
The Sponsor may request additional information from the Investigator to ensure the timely 
completion of accurate safety reports. 
The Sponsor is responsible for reporting SAE/UADEs to the regulatory authorities in accordance 
with applicable regulatory reporting guidelines. The Investigator is responsible for submitting 
SAE/UADEs to his/her IRB as required by local policy. 
16.9 
Medical Monitoring 
It is the responsibility of the PI to oversee the safety of the study at his/her site. The 
Sponsor/designee will review the patient data, SAEs, UADEs, and device deficiency reports to 
oversee the safety throughout the study. 
Terumo Blood and Cell Technologies will monitor the safety of the study on an ongoing basis.  
17 
DATA MONITORING COMMITTEE 
A Data Monitoring Committee will not be utilized for this study. 
18 
STUDY DEVICE DEFICIENCY 
18.1 
Device Deficiencies 
A Device Deficiency is defined (ISO 14155 Section 3.19) as an inadequacy of a medical device 
with respect to its identity, quality, durability, reliability, safety or performance, and includes 
malfunctions, use errors and inadequate labeling. All device deficiencies involving any device 
component must be reported and a Device Deficiency Form must be submitted to the Sponsor 
within 24 hours of knowledge of the event to: 
Terumo Blood and Cell Technologies  
Email: ClinicalAffairs@TerumoBCT.com 
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Every attempt should be made by the Site to save or collect the defective device, and if 
appropriate, the packaging, for return to the Sponsor. If the deficiency occurs with the device, a 
service technician from the Sponsor will evaluate and determine whether service or replacement 
is necessary. A qualified company representative will investigate and determine root cause and 
corrective actions as applicable, and directives will be provided to the site if warranted. If unable 
to retain the device, photographs should be taken to assist in the root cause investigation. 
If a device deficiency is associated with an AE, refer to Section 16 to assess severity criteria and 
for reporting requirements in the event of an SAE or UADE. 
18.2 
Device Accountability 
18.2.1 
Receipt of Study Device 
The contents should be examined upon receipt to ensure packaging and labeling is intact and the 
devices have not been damaged. Any damage should be immediately reported to the Sponsor. 
18.2.2 
Storage 
The Reveos System device, and the disposables should be stored in a dry place at room 
temperature. Proper care should be taken to ensure that the study inventory will not be damaged. 
18.2.3 
Accountability 
The investigator shall maintain adequate records of the receipt and disposition of the 
investigational devices.  This includes all investigational devices received, used, or returned, and 
includes those that malfunctioned and/or were discarded for any reason. Device accountability 
logs supplied by the sponsor must be completed for all investigational devices. The disposition 
of all devices must be documented, including those that have been discarded and those returned 
to the sponsor.  During the course of the study, device accountability logs will be monitored on a 
regular basis. When the enrollment phase of the study is complete, the investigator will return to 
the sponsor any unused devices and a copy of the completed device accountability logs. Any use 
of a device outside of this study protocol is strictly forbidden and will constitute immediate 
grounds for removal of the investigator and/or institution from the study. 
All investigational devices that are not used must be returned to the sponsor.  
These devices may include the following:  
• All unused investigational devices when enrollment is complete.  
• All expired study devices.  
• All investigational devices associated with a device malfunction or failure.  
• All opened but unused devices that may be contaminated, have a defect in the sterile 
barrier prior to use, or have some other potential defect identified.  
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Devices that were opened in error, prepared incorrectly, or contaminated in the lab (e.g., dropped 
on the floor), do not need to be returned to the sponsor. 
19 
STATISTICAL PLAN 
The following section summarizes the statistical methods that will be used in the analysis of the 
clinical data from this study.  Please see Statistical Analysis Plan for full details. 
General Considerations for Data Analysis 
Inferential statistical tests will be identified in the post-text tables as being either one or two 
sided, and the construct of the confidence limits will be defined (e.g. 90% or 95%). Asymptotic 
confidence limits will be presented based on the normal approximation to the binomial 
distribution for the proportion of subjects classified as a treatment success. Exact confidence 
intervals will be used for all other presentations. Continuous demographic parameters, such as 
the subject’s age at the time of enrollment, will be summarized using descriptive statistics (N, 
mean, median, standard deviation, minimum and maximum value, and 95% 2-sided confidence 
limits). 
In addition to examining the demographic and baseline parameters for establishing the pool-
ability of subject data across the 2 clinical sites participating in the study, adherence to the 
sampling preparation and reinfusion procedure will also be examined and presented as evidence 
of compliance. The examination for compliance to the study protocol will be performed both on 
a site-level and a subject-level within sites.  Failing to follow the sample handling and 
preparation procedures could have a demonstrative effect on the results. Including information 
from reinfusion where the sample was not properly prepared could dampen the results and 
significantly contribute to the variability and challenge the normality of the distribution of values 
used for calculating the average recovery values. 
The following general conventions will be applied to all data presentations and analyses. 
• 
Summary statistics will consist of the number and percentage of responses in each level 
for categorical variables, and the sample size (n), mean, median, standard deviation (SD), 
range, and 95% 2-sided confidence limits for continuous variables. 
• 
All mean and median values will be formatted to one more decimal place than the 
measured value.  Standard deviation values will be formatted to two more decimal places 
than the measured value.  Minimum and maximum values will be presented with the 
same number of decimal places as the measured value. 
• 
The number and percentage of responses will be presented in the form XX (XX %) where 
the percentage is in the parentheses.  
• 
All summary tables will include the analysis population sample size (i.e., number of 
subjects enrolled in the study). 
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19.1 
Sample Size Rationale 
The sample size in this study will be 24 evaluable subjects.7  In order to reach the total target 
number of evaluable subjects, additional subjects will be enrolled to replace subjects for whom 
the primary endpoints are not evaluable (i.e., those subjects who are lost-to-follow-up or 
withdrawn; those subjects whose health status has changed prior to their reinfusion, thereby 
potentially affecting their safety after receiving a reinfusion or potentially confounding study 
results; or those subjects for whom recovery calculations cannot be made due to missing value).  
It is anticipated that up to 50 donors may need to be enrolled to accrue 24 evaluable subjects to 
the primary endpoint analysis. All subjects, regardless of the availability of their endpoint data, 
will be included in evaluations of In vitro data (where samples are available) and in evaluations 
of AEs. 
Sample Size Estimates for LR-RBC Evaluation  
The 3 parts of FDA’s RBC recovery criteria that must be met are presented below.  The 
derivation of the sample size was based on the level of precision attained with 24 subjects 
relative to the 1st part of the criteria.  
1. The one-sided 95% lower confidence limit for the population proportion of success is greater 
than 70% where success of a unit is defined as the RBC in vivo 24-hour percentage recovery 
≥ 75%*,  
2. The sample mean of percent recovery ≥ 75%, and  
3. The sample standard deviation of in vivo 24-hour RBC recovery ≤ 9%.  
*Allows for low recoveries (<75%) in 2/20 or 3/24 volunteers. 
Estimates were prepared based on the 1st criterion (i) with 24 subjects, examining the one-sided 
lower 95% confidence limit relative to the a priori value of 70%. Results are presented in the 
table presented below. If the observed proportion of treatment successes is 21/24 (87.50%) or 
higher, the one-sided lower 95% binomial confidence interval will exceed 70% (lower 
confidence limit = 70.77%). 
Table 19-1  Statistical Scenarios 1-5 Estimation of LR-RBC Evaluation Sample Size. 
Scenario Number 
1 
2 
3 
4 
5 
6 
Number of Treatment 
Successes 
17/24 18/24 
19/24 
20/24 
21/24 
22/24 
Percentage of Treatment 
Success 
70.83 75.00 
79.17 
83.33 
87.50 
91.67 
One-Sided Lower 95% 
Confidence Limit 
52.13 56.53 
61.09 
65.82 
70.77 
76.02 
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19.2 
Endpoints 
19.2.1 
Primary Endpoint 
The analysis of the primary endpoint will be conducted using the evaluable population. 
Evaluable population is defined in section 19.3.3. 
In vivo RBC viability has been assessed for decades using radiolabeled autologous RBCs to 
assess the proportion of RBCs remaining in the circulation 24 hours after autologous infusion 
(24-hr RBC recovery). Radiolabeling methods and reporting of recovery have been standardized 
8,9,10 allowing comparison of data between studies. Calculation of the proportion of RBCs 
surviving at 24-hr post infusion requires that RBC mass be accurately measured. This can be 
performed by extrapolating the early disappearance of cells to the midpoint of the infusion.  
Additional exploratory analyses may be performed on estimates of RBC recovery using RBC 
mass derived from 99mTc radiolabeling. 
RBC recovery 24 hours after infusion will be reported using the single label method 
recommended by Moroff et al.9 The 51Cr value at time = 0 (T zero, T0) is obtained by doing a 
regression analysis of the values obtained for 51Cr labeled samples drawn at different time-points 
post-infusion. The T0 is used to calculate the percent recovery at 24 hours. The calculated T0 
may be falsely low if the labeled RBCs are removed by the reticulo-endothelial (RE) system in 
large numbers prior to the first blood being drawn at 5 minutes post injection. This would result 
in a falsely higher 24-hour recovery. Recovery at 24 hours will be calculated using the following 
equation:  
 % recovery = (Adjusted RBC CPM at 24 hours/ Adjusted RBC CPM at time 0) x 100  
Radiolabeled samples will be drawn at different time-points post-infusion. The counts will be 
adjusted for background counts and corrected for loss of label (elution) over time.8  
The primary endpoint of RBC recovery at 24 hours post-infusion will be used to assess each of 
the three criteria specified by FDA. The % recovery for analysis will be provided by the site(s), 
and not derived during analysis. To assess the criteria associated with the percent of samples with 
at least a 75% recovery, a success or failure for each observed value will be determined. RBC 
recovery of at least 75% will be deemed a success, and failure otherwise.  A one-sided 
confidence interval for the proportion of successes will be determined using an exact 95% 
confidence interval.  If the one-sided 95% lower confidence limit is greater than 70% the study 
will have met its primary endpoint, which will be met if no more than 3/24 data points have less 
than 75% recovery. 
Summary statistics and 2-sided confidence intervals will be presented to assess the actual RBC 
recovery values and to evaluate the remaining criteria specified by FDA. 
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19.3 
Analysis Populations 
19.3.1 
Full Analysis Population 
The Full Analysis Population will include all participants enrolled in the trial. 
19.3.2 
Safety Analysis Population 
The Safety Analysis Population will include all participants enrolled in the trial who are exposed 
to Reveos Blood Bag Set and experience adverse event that is related to the device or study 
procedure as determined per 16.6.2; accordingly, the safety analysis will be limited to PEAEs 
(defined in Section 16.5). The Safety Analysis Population will be utilized to assess safety of the 
device and procedure.  
19.3.3 
Evaluable Analysis Population 
The analysis of the primary endpoint in the evaluable population will be based on all recorded 
data. Subjects are considered evaluable for the primary endpoints if they have:  
• Met all of the inclusion and none of the exclusion criteria at enrollment,  
• Were not found, after being enrolled in good faith, to be in fact, non-compliant with one 
or more of the inclusion/exclusion criteria,  
• The subject has not had a change in health status which would cause them to fail the 
inclusion/exclusion criteria at the time of infusion of radiolabeled cells 
• Have not met any other protocol exclusion criteria as defined in Section 19.4. 
The Evaluable Analysis Population will be included in the analysis of the primary endpoint. 
Within the enrolled population, all attempts will be made to obtain complete recovery data from 
all subjects for the analysis of the primary endpoint.   
19.4 
Protocol Analysis Exclusions 
There may be situations wherein the data will be considered non-evaluable and will not be 
included in the Evaluable Analysis Population.  
Data will be excluded from the Evaluable Analysis Population in the following situations: 
1. Incomplete or incorrect  procedure  that affects the primary endpoint due to: 
a. Equipment failure or malfunction (e.g. filter plugs) 
b. Unanticipated processing failure 
c. Results of primary endpoint tests are not available 
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2. Protocol deviations that affect the primary endpoint due to: 
a. Failure to follow collection procedures outlined in the device Operator’s Manual, 
Instructions for Use (IFU) (Package Insert), Manual of Procedure(s), and site SOPs 
3. Product non-reinfusbale due to:  
a. Product does not pass quality check for reinfusion (residual WBC, LR-RBC mass 
recovery, visual inspection, hemolysis, bacterial growth) 
4. Subject issues 
a. Participant lost to follow-up or withdrawn from study 
b. Other participant issues (e.g. inadequate access, reaction, needle abort) 
19.5 
Missing, Unused, and/or Spurious Data 
Please see Statistical Analysis Plan (SAP) for the handling of Missing, Unused and/or Spurious 
Data. 
19.6 
Interim Analysis 
There will be no interim analysis for the study.  
20 
STUDY MANAGEMENT 
20.1 
Ethics 
This CIP will be submitted and reviewed by FDA(CBER) IDE committee and Institutional 
Review Board (IRB). The study will not begin until approvals for the study is received from the 
FDA and IRB. 
20.2 
Investigator Responsibilities 
20.2.1 
Investigator Agreement 
Each Investigator will provide the Sponsor a copy of his/her current curriculum vitae and a 
signed Investigator Agreement, prior to initiation of the study.  
20.2.2 
Institutional Review Board 
The Investigator/study staff is responsible for knowing and adhering to their IRB requirements. 
The institution’s IRB, or other committee functioning in a similar capacity, will review and 
approve the CIP, initial and revised ICFs, and CIP amendments. After approval by the IRB, 
documentation of approval and the approved ICF will be sent to Terumo Blood and Cell 
Technologies before any subject is enrolled into this study. 
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20.2.3 
Informed Consent 
The Investigator is responsible for preparing the written ICF for this study. Terumo Blood and 
Cell Technologies will provide the Investigator an ICF template. The Investigator may rearrange 
or reword the contents of this template, or may add other elements or language, provided the 
meaning and content are not changed or deleted. 
Prior to subject participation in this study, the Investigator must obtain written IRB approval for 
the CIP and the ICF. The approved ICF will clearly reflect the IRB approval date.  
All subjects are free to withdraw from participation in this study at any time, for any reasons, 
specified or unspecified, and without prejudice. The reason for the subject discontinuing or 
terminating from the study must be recorded on the CRF. 
20.2.4 
Study Files and Record Retention 
The Investigator must retain all study records until notified by the Sponsor that they are no 
longer needed. The Investigator will also notify the Sponsor in the event he/she relocates, or for 
any reason desires to dispose of the records. 
20.3 
Sponsor Responsibilities 
20.3.1 
General Responsibilities 
As per 21 CFR 812, Terumo Blood and Cell Technologies is responsible for selecting qualified 
investigators and providing them with the information they need to conduct the investigation 
properly, ensuring quality study conduct and proper monitoring of the investigation, ensuring 
required approvals are obtained and that significant new information about an investigation is 
promptly reported to reviewing IRB/EC and government authorities as well as annual reports as 
required.  
20.3.2 
Amendments to the Clinical Investigation Plan 
Any amendment to the CIP, as deemed appropriate by Terumo Blood and Cell Technologies, will 
be implemented as the study progresses. Amendments will be submitted to the IRB/EC and /or 
regulatory bodies as needed/FDA for written approval before implementation.  
20.4 
Joint Investigator-Sponsor Responsibilities 
20.4.1 
Access to Information for Monitoring and Auditing 
The Investigator and investigative sites will permit trial-related monitoring, audits, IRB/EC 
review, and regulatory inspections, providing direct access to source data/documents. 
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In accordance with ICH GCP guidelines, the Sponsor/auditor must have direct access to the 
subject’s source documentation to verify the data recorded in the CRF. The Sponsor is 
responsible for routine review of the CRFs at regular intervals throughout the study and to verify 
adherence to the CIP, as well as the completeness, consistency, and accuracy of the data being 
recorded. The Sponsor/auditor must have access to any subject records needed to verify the 
entries in the CRFs. The Investigator agrees to cooperate with the Sponsor/auditor to ensure that 
any problems detected in the course of these monitoring/auditing visits are resolved. This study 
will be source document verified by the Sponsor as per the criteria outlined in the study 
management and monitoring plan. 
20.4.2 
Training 
The Sponsor will train applicable study team members as to the device, protocol, and study 
procedures and will provide updated information as it becomes available during the course of the 
study, if applicable. The Investigator is responsible for ensuring that additional site personnel that 
were not trained by the Sponsor receive applicable documents and training.  
20.5 
Collecting and Recording Data 
The Investigator will maintain complete, accurate, legible, and easily retrievable data, and will 
allow personnel authorized by Terumo Blood and Cell Technologies access to all study data at 
any time. Such data will also be secured to prevent loss of data. All required data for this study 
will be recorded from the source documentation onto standardized CRFs.  
20.5.1 
Source Documents 
Source data is all information, original records of clinical observations, or other activities in a 
clinical study necessary for the reconstruction and evaluation of that trial. Examples of these 
original documents and data records include study site records, evaluation checklists, and 
laboratory results.  
20.5.2 
Case Report Forms 
Case report forms will be in electronic data capture (EDC) or paper format. 
All data must be recorded in English. Any missing data must be explained.  
Completed CRFs will be reviewed and signed by the Investigator. The Clinical Research 
Associate (CRA) will verify the CRF data with the participant’s source data, evaluate the data for 
accuracy, consistency, and completeness, and will ensure that all forms with missing data and/or 
errors are ultimately addressed. Accurate and complete CRFs for a participant must be completed 
in a timely manner. 
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20.5.3 
Data Queries 
Data Queries may be used by Terumo Blood and Cell Technologies staff or designee to attempt 
to correct or clarify missing, incomplete, or illogical data. Queries must be reviewed and signed 
off by the Investigator or his/her designee. 
20.6 
Clinical Investigation Plan Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this CIP. A protocol (CIP) deviation is defined as any 
event where the Investigator or site personnel deviate from the study CIP or study procedures for 
any reason.  
CIP deviations are prohibited during this study, except as described per ISO 14155 Section 
5.6.4(c) “Deviations from the CIP to protect the rights, safety and well-being of human subjects 
under emergency circumstances may proceed without prior approval of the sponsor and the EC – 
such deviations shall be documented and reported to the sponsor and the EC as soon as 
possible.” 
All deviations must be addressed in study source documents and reported to the Sponsor. 
Requests for deviations, and reports of deviations (if the deviation affects subject's rights, safety 
and wellbeing, or the scientific integrity of the clinical investigation), will be provided to the 
IRB/EC per their guidelines. Further details about the handling of CIP deviations will be 
included in the MOP. 
20.7 
Suspension or Termination of the Study 
For reasonable cause, either the Investigator or the Sponsor may terminate the Investigator’s 
participation in this study, provided a written notice is submitted within the time period provided 
for in the Clinical Trial Agreement (CTA). In addition, Terumo Blood and Cell Technologies may 
terminate the study at any time upon immediate notice for any reason, including but not limited 
to, Terumo Blood and Cell Technologies belief that termination is necessary for the safety of 
subjects. 
20.8 
Publication Policy 
Terumo Blood and Cell Technologies recognizes the importance of communication of medical 
study data and encourages the publication of such data in reputable scientific journals and the 
presentation of such data at scientific seminars and conferences. Any proposed publication or 
presentation of the data generated from the study must be provided to Terumo Blood and Cell 
Technologies for timely review in accordance with the terms of the CTA between the 
Investigator, the Institution, and Terumo Blood and Cell Technologies. Terumo Blood and Cell 
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Technologies will not, in its scientific publications or promotional material, quote from 
publications by Investigators without full acknowledgment of the source. For multi-site trials, all 
Investigators agree not to publish individual site data. All trial data will be published as one or 
more manuscripts based on the accumulated data from all trial sites. 
 
 
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21 
INVESTIGATOR SIGNATURE  
Study Title: 
An In Vivo 24-Hour Recovery Study of Leukoreduced RBCs 
After Automated Separation of Whole Blood by the Reveos 
System and Storage for 42 Days 
Study Number: 
CTS-5085 
Version/Date: 
Version 3.0: 01 MAR 2022 
I have read this Clinical Investigation Plan (CIP), including all appendices, and I agree that the 
CIP contains the necessary details for carrying out the clinical investigation as described. I will 
conduct this study in compliance with the CIP, Good Clinical Practices, and all applicable 
regulations. I will make every reasonable effort to complete the study within the time designated.  
I will provide copies of the CIP and access to appropriate information furnished by the Sponsor 
to study personnel under my supervision who are involved in carrying out the study. I will 
discuss this material with them to ensure they are fully informed about the investigational device 
and the study. 
I understand that under circumstances where an adverse event is likely to affect the safety of the 
subjects, appropriate urgent safety measures will be taken to protect the subjects against any 
immediate hazard. I understand that if it becomes necessary to protect the best interests of the 
subjects, they may be withdrawn from the clinical investigation, enrollment of the clinical 
investigation may be suspended, or the clinical investigation may be terminated as described in 
the CIP. I will give prompt notice to the Sponsor of any such event. The Sponsor may terminate 
the clinical investigation at any time, with or without cause. 
I have read the Confidentiality Statement of this CIP. The contents of this CIP may not be used in 
any other clinical investigation and may not be disclosed to any other person or entity without 
the prior written permission of the Sponsor. The foregoing shall not apply to disclosure required 
by law or regulation (eg, submission to an Ethics Committee); however, I will give prompt notice 
to the Sponsor of any such disclosure. 
Name: 
Principal Investigator Name, Credentials 
 
 
Title: 
Principal Investigator 
 
 
 
 
Signature: 
See Attached for Signature Pages 
Date: 
 
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22 
REFERENCES 
 
 
 
 
 
1 Yaddanapudi S, Yaddanapudi L. Indications for blood and blood product transfusion. Indian J Anaesth. 
2014;58(5):538-542.  
2 Pfuntner A, Wier LM, Stocks C. Most frequent procedures performed in U.S. hospitals, 2010. HCUP statistical 
brief #149. Rockville (MD): Agency for Healthcare Research and Quality; 2013 
3 Jones, J.M., Sapiano, M.R.P., Savinkina, A.A., Haass, K.A., Baker, M.L., Henry, R.A., Berger, J.J. and 
Basavaraju, S.V. (2020), Slowing decline in blood collection and transfusion in the United States – 2017. 
Transfusion, 60: S1-S9. doi:10.1111/trf.15604 
4 Global Status Report on Blood Safety and Availability. World Health Organization. 2016. 
5 Basu D, Kulkarni R. Overview of blood components and their preparation. Indian J Anaesth. 2014;58(5):529-537.  
6 El Ekiaby M. Automation in Blood Processing. ISBT Science Series. 2017:87-90.  
7 Vostal, Jaro: Presentation: FDA Evaluation of Red Cell Products, Laboratory of Cellular Hematology OBRR, 
CBER, FDA October 6, 2016. 
8 International Committee for standardization in Haematology. Recommended methods for radioisotope red cell 
survival studies. British Journal of Haematology 1980;45:659-666. 
9 Moroff et al.  Proposed Standardization of Methods for Determining the 24-Hour Survival of Stored Red Cells. 
Transfusion 1984;24(2):109-114. 
10 International Committee for standardization in Hematology. Recommended Methods for measurement of Red-
Cell And Plasma Volume. J. Nucl Med. 1980;21:793-800 
11 Eder AF, Dy BA, Kennedy JM, et al. The American Red Cross donor hemovigilance program: complications of 
blood donation reported in 2006. Transfusion. 2008;48(9):1809-1819. 
12 Danic B, Lefort C. [Serious adverse effects of blood collection]. Transfus Clin Biol. 2010;17(5-6):301-305. 
13 Deacon B, Abramowitz J. Fear of needles and vasovagal reactions among phlebotomy patients. J Anxiety Disord. 
2006;20(7):946-960. 
14 Sorensen BS, Johnsen SP, Jorgensen J. Complications related to blood donation: a population-based study. Vox 
Sang. 2008;94(2):132-137. 
15 McLeod BC, Price TH, Owen H, et al. Frequency of immediate adverse effects associated with apheresis 
donation. Transfusion. 1998;38(10):938-943 
16 Gavillet M, Tissot JD, Canellini G. Blood donation associated risks: data from a Swiss regional haemovigilance 
program. Transfus Med. 2013;23(4):269-271. 
17 Sorensen BS, Jorgensen J, Jensen TS, Finnerup NB. Pain following blood donation: a questionnaire study of long-
term morbidity (LTM) in blood donors. Vox Sang. 2015;109(1):18-24. 
 
 
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Where Used
Number
Version
Name
Context
Uses
Number
Version
Name
Context
References Documents
Number
Version
Name
Context
State
Last Modified
Referenced By Documents
Number
Version
Name
Context
State
Last Modified
Describes Parts
Number
Version
Name
Context
State
Last Modified
Referenced By Parts
Number
Version
Name
Context
State
Last Modified
Revision History Table
Revision
Date Approved
Change Notice / PR Number
Rev A
2022-03-15 20:41 GMT
TBCT Record Document Workflow
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