Evaluation of the AMICUS Red Blood Cell Exchange (RBCx) System in Sickle Cell Patients
Phase: NA
Conditions: Sickle Cell Anemia
Sponsor: Fenwal, Inc.

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AMIC-003-CMD 
Evaluation of the AMICUS Red Blood Cell Exchange (RBCx) System in Sickle Cell Patients  
 
 
 
 
Sponsor: 
Fresenius Kabi USA LLC 
Three Corporate Drive 
Lake Zurich, Illinois USA 60047 
 
 
 
 
 
Fenwal Inc. was acquired by Fresenius Kabi on December 1, 2012. Fenwal is a wholly owned 
subsidiary of Fresenius Kabi and is headquartered in Bad Homburg, Germany. 
 
 
Confidential Information 
 
The information contained in this protocol is confidential and is provided for the sole and 
exclusive use of investigators in this clinical study. The information in this document may not be 
disclosed unless such disclosure is required by Federal, or applicable State Law or Regulations, 
or unless there is prior written consent from Fresenius Kabi USA LLC.  Subject to the foregoing, 
this information may be disclosed only to those persons involved in the clinical investigation 
who need it, and who share the obligation not to disseminate this information further. This 
document and its associated attachments and appendices are subject to United States Freedom of 
Information Act Exemption 4. 

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I. 
SUMMARY OF CHANGES 
A. VERSION 09 10FEB2017 
Primary Sites and Primary Investigators 
Change 
Reason for Change 
a. Added Information 
Dr. Volker Witt 
St. Anna Kinderspital 
Kinderspitalgasse 6 
A 1090 Vienna 
 
Addition of clinical site. 
Throughout Entire Document 
a. Changed the total number of sites from 6 
to 7. 
The addition of St. Anna Kinderspital as a 
clinical site. 
Appendix B 
a. Addition of a label to be applied to FTX 
1707, FTX 1708 and FTX 1709 for Non-
US Clinical Sites. 
To meet the additional requirements for 
Austria.  
Appendix C 
a. Addition of Ethics Committee to ICF 
language. 
Addition of clinical site.  
 
B. VERSION 08 05MAY2016  
 
Throughout Entire Document 
Change 
Reason for Change 
a. Changed the total number of enrolled 
subjects meeting inclusion and no 
exclusion criteria from 100 to 130. 
To increase the total subject enrollment limit to 
ensure an adequate number of evaluable 
procedures.  
Primary Sites and Primary Investigators  
b. Deleted Nationwide Children’s Hospital 
and added Phoenix Children’s Hospital. 
Nationwide Children’s Hospital is not 
participating in the study; Phoenix Children’s 
Hospital is a new site. 
 
C. VERSION 07 08JAN2016 
 
Throughout Entire Document 
Change 
Reason for Change 

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a. Changed the initial enrollment limit from 
40 to 60. 
To increase the initial adult subject enrollment 
limit.  
Section 8.3. Waste Material Procedure 
a.  Replaced 10 mL sample requirement 
with representative sample.  
To allow flexibility in the waste sample testing 
procedure while maintaining a representative 
sample draw requirement.  
Appendix C SAMPLE INFORMED CONSENT AND ASSENT 
a. Changed first person narrative to second 
person narrative. 
To align with IRB procedures. 
D. VERSION 06 17AUG2015 
 
Throughout Entire Document 
Change 
Reason for Change 
a. Minor consistency/grammatical/spelling 
corrections 
To correct typographical errors. 
Participating Sites and Primary Investigators 
a. Added information: 
Washington University 
Brenda Grossman, MD, MPH 
660 S. Euclid Avenue, Box 8118 
Saint Louis, MO 63110 
Telephone: 314 362-6032 
Fax: 314 362-1461 
Addition of clinical site. 
Section 6 SCOPE 
a. Changed 5 to 6 sites 
Addition of clinical site. 
Section 8. STUDY PROCEDURES/METHODOLOGY 
a. Removal of automated footnote from Table 
5. SUMMARY OF REPLACEMENT RBC 
UNIT PARAMETERS  
To allow spun hematocrit method to be 
performed. 
Section 13.6. Evaluability Criteria 
a. Removal of the evaluability criterion If the 
procedure is terminated prior to delivering 
the target RF volume (±50 mL), then the 
FCR and End Hct are non-evaluable.  
To accommodate physician prescription. 
Appendix C. Sample Informed Consent and Assent 
a. Changed 5 to 6 sites 
Addition of clinical site. 
E. VERSION 05 08JAN2015 
 
Throughout Entire Document 

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Change 
Reason for Change 
a. Change of the statement The supplement 
must be approved by the FDA prior to 
enrolling subjects six years old or older to 
The supplement must be approved by the 
FDA prior to enrolling pediatric subjects 
six – 17 years old 
To clarify continued enrollment of adult 
subjects during the interim analysis if the 
initial maximum enrollment of 40 adult 
subjects has not been met 
Section 8. STUDY PROCEDURES/METHODOLOGY 
a. Change of type and cross match screening 
language to routine pre-procedure testing 
For clarity  
 
 

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F. VERSION 04 23DEC2014 
 
Throughout Entire Document 
Change 
Reason for Change 
a. Addition of an IDE supplement submission 
to the FDA following the DSMB review  
To allow the FDA to review and approve 
the initial study data prior to enrolling 
subjects six years old or older 
b. Minor grammatical/spelling corrections 
To correct errors 
c. Addition of an initial enrollment of up to 40 
adult subjects 
To limit enrollment to 40 adult subjects to 
assess safety prior to enrolling subjects six 
years old or older 
Section 7. STUDY DESIGN 
a. Removal of medically stable subjects 
prescribed RBC Exchange or RBC 
Depletion/Exchange procedure(s) prior to 
surgery inclusion criterion 
To not exclude subjects that do not require 
pre-surgery treatment 
b. Addition of prophylactic procedures that 
occur prior to surgery may be completed as 
part of the study to the study design 
narrative 
For clarity 
Section 8. STUDY PROCEDURES/METHODOLOGY 
a. Addition of a pregnancy test will be 
performed on women with childbearing 
ability prior to the start of the procedure to 
the subject evaluations narrative 
For clarity 
b. Addition of type and cross match screening 
information 
To clarify and document expected study 
methods 
c. Addition of Table 2. TYPE & CROSS 
MATCH SCREENING RESULTS  
To clarify and document expected study 
methods 
Section 13. STATISTICAL METHODS AND SAMPLE SIZE 
a. Addition of citation added to sample size 
calculation 
To cite source 
Section 15. REFERENCES 
a. Addition of reference number ten 
To cite source 

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G. VERSION 03 20NOV2014 
 
Throughout Entire Document 
Change 
Reason for Change 
a. Removal of all COBE Spectra information; 
all study procedures/design related to paired 
study removed; including change of primary 
objective and Section 13. STATISTICS 
Change to study design 
b. Change of N from 30 paired procedures to a 
minimum of 62 single-arm procedures 
Change to study design  
c. Removal of RBC from any reference to 
waste material 
For accuracy; waste material also includes 
WBC, platelets, and plasma 
d. Minor grammatical/spelling corrections 
To correct errors 
Section 4. BACKGROUND 
a. Modification to sub-section 4.2 Pre-Clinical 
Studies:  information was updated and 
moved to Appendix D; addition of 
statement that study results are summarized 
in Appendix D 
To present study results from the completed 
AMIC-002-CMD pre-clinical study 
Section 5. OBJECTIVES 
a. Change of secondary objective Monitor 
subject safety through adverse events 
during the procedure and approximately 
18-24 hours post-procedure, vital signs, 
laboratory parameters pre- and post-
procedure, and unexpected adverse device 
effects to Evaluate device related serious 
adverse events during the procedure and 
approximately 18-24 hours post-procedure  
For clarification; the secondary objective is 
to determine the safety of the device; 
however, all AE/SAEs will be evaluated in 
the safety analysis 
Section 6. SCOPE 
a. Removal of requirement that approximately 
half of the procedures should be RBC 
Exchange and half should be RBC 
Depletion/Exchange 
Procedures will follow standard of care at 
each site; therefore the contribution by each 
site for each procedure (RBC Exchange or 
RBC Depletion/Exchange) may vary. 
b. Modification to Table 1. SUBJECT 
ENROLLMENT 
To reflect updated enrollment plan 
Section 7. STUDY DESIGN 
a. Modification to Figure 2. Evaluation of the 
AMICUS RBCx System 
To reflect updated study design 
b. Addition of inclusion criterion Medically 
stable subjects prescribed RBC Exchange 
or RBC Depletion/Exchange procedure(s) 
prior to surgery 
To not exclude this patient population 

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c. Change of life expectancy fewer than 6 
months exclusion to fewer than 30 days 
To not exclude this patient population 
d. Addition of statement allowing subjects to 
contribute only one evaluable AMICUS 
procedure to the study 
To reduce bias 
H. VERSION 02 10NOV2014 
 
Throughout Entire Document 
Change 
Reason for Change 
a. Removal of Red Blood Cell (RBC) 
Depletion information; subsequent minor 
modifications to text to reflect the removal 
of the RBC Depletion procedure from study 
design 
RBC Depletion procedures will not be 
performed in the United States (US) 
b. Removal of French regulations, site, 
investigator, and study design information  
Investigation is limited to the US 
c. Modification to the primary objective 
To consistently define the comparator as 
being the mean difference of the target to 
actual fraction of cells remaining (FCR) in 
the Test device to the mean difference of the 
target to actual FCR in the Control device 
d. Addition of sickle cell disease/sickle cell  
To specify the intended treatment group 
e. Decrease of participating investigators from 
up to 6 to up to 5; decrease of participating 
sites from up to 6 to up to 5 
Investigation is limited to 5 US institutions 
f. Change of Gender to Sex 
Consistent with FDA guidance 
g. Addition of adverse event assessment 
approximately 18-24 hours post-procedure 
To require post-procedure adverse event 
assessment 
h. Modifications to the in-text citations 
To match updated 
Section 15. REFERENCES 
i. Minor spelling and grammatical changes; 
minor additions and rewording to the 
previous text to expand on the original 
thought being conveyed 
For clarification and to correct errors 
Title Page 
a. Addition of Sickle Cell Patients to the study 
title 
The investigation is limited to subjects with 
sickle cell disease 
b. Removal of European Community 
Representative 
Investigation is limited to the US 
Section 3. ABBREVIATIONS 
a. Addition of Hb C: Hemoglobin C to list of 
abbreviations 
To define the Hb C abbreviation 

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b. Addition of Hb F: Hemoglobin F to list of 
abbreviations 
To define the Hb F to list of abbreviations 
c. Addition of RID: Rapid Infusion Device to 
list of abbreviations 
To define the RID abbreviation 
d. Modification to SDV:  change of Source 
Document Verification to Source Data 
Verification 
To correct error 
Section 4. BACKGROUND 
a. Removal of abnormal, excess, and due to 
overproduction when the words pertain to 
blood removal 
Instructions For Use (IFU) has been 
modified to remove broad indications 
b. Removal of information about protozoan 
infections, carbon monoxide poisoning, 
thalassemia, and other pathologies of 
circulating RBCs 
To be specific to the indicated subject 
population 
c. Change of prevent secondary strokes to 
reduce secondary strokes. 
To eliminate the implication of treatment 
efficacy 
d. Addition of concurrent RBCs 510k number 
BK000039 
For clarification 
e. Modification to a prior non-clinical study 
objective; addition of obtained from patient 
procedures to evaluate the effects of 
abnormal RBCs when using the AMICUS 
RBCx System 
To expound and clarify  
f. Additions to the description of the in vivo 
study being completed in the Lake Zurich 
Donor Room in subsection 4.2. Pre-Clinical 
Studies 
To expound and clarify 
Section 6. SCOPE 
a. Inclusion of an enrollment plan that 
explains the intent to enroll and summarize 
safety data from adult subjects (N=~15) 
prior to enrolling all eligible subjects 
(N=~15); safety data will be reviewed by an 
independent Data Safety Monitoring Board 
(DSMB) 
To clarify the Sponsor’s enrollment 
procedure and rationale 
b. Modifications to  
Table 1. SUBJECT ENROLLMENT; 
addition of Age column and interim report 
row; updates to N column; modifications to 
the footnotes 
To depict the updated enrollment plan 
c. Modification to the statement Data 
collected from this study will be summarized 
and submitted to TÜV and the FDA; change 
to Data collected will be summarized and 
To clarify the Sponsor’s submission 
intentions  

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submitted to the Fresenius Kabi European 
notified body, Technischer Überwachungs-
Verein (TÜV) in Germany.  Data from the 
completed study will be submitted to the 
United States Food and Drug 
Administration (FDA) to support a 
premarket submission 
Section 7. STUDY DESIGN 
a. Modification to  
Figure 2. Evaluation of the AMICUS RBCx 
System; updates to the study population 
description 
To depict the updated study design 
b. Addition of subsection 7.1.1. Lead-In Phase 
To allow each site to perform approximately 
two, non-randomized, non-paired RBCx 
procedures on the AMICUS Separator for 
training purposes 
c. Modification to the inclusion criteria to 
specify subjects must have documented 
diagnosis of a type of sickle cell disorder 
Investigation is limited to patients with 
sickle cell disease 
d. Removal of weight requirement for study 
participation from subject inclusion criteria 
Subject inclusion will not be dependent 
upon the subject’s weight 
c. Addition of Subjects with sufficient vascular 
access to accommodate the RBCx 
procedure as determined by the medical 
staff responsible for obtaining venous 
access inclusion criterion 
To ensure subject has adequate vascular 
access to perform the RBCx procedure 
d. Addition of Subjects who are able and 
agree to report adverse events (AEs) during 
the required reporting period inclusion 
criterion 
To ensure subject is able and willing to 
convey all adverse events during the 
procedure and via telephone approximately 
18-24 hours post-procedure 
e. Modification to the adequate availability of 
leukoreduced compatible replacement RBC 
products inclusion criterion to include 
sickle trait negative, ABO blood group, 
Rhesus factor D (Rh (D) and non-expired 
standards 
To specify minimum replacement fluid 
critieria 
f. Modification to the inclusion criterion 
Medically stable subjects with a physician’s 
prescription for RBC Exchange or RBC 
Depletion/Exchange treatment; change to 
Medically stable subjects who have been 
previously treated for sickle cell disease 
with RBC Exchange or RBC 
Depletion/Exchange 
To establish that first study procedure is not 
the subject’s first exposure to RBCx 
treatment 
g. Addition of the exclusion criterion In the 
To ensure subjects will be able to complete 

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opinion of the investigator, subjects who 
have a life expectancy fewer than 6 months 
from time of first procedure 
paired procedures 
h. Addition of the exclusion criterion subjects 
who refuse blood products 
To exclude subjects who would not consent 
to receive replacement blood products 
i. Modification to the exclusion criterion 
Subjects who experience a serious adverse 
event with the first RBC Exchange or RBC 
Depletion/Exchange; change to Subjects 
who have experienced a serious adverse 
event associated with an RBCx procedure in 
the past 
To exclude subjects who have previously 
had an adverse event during an RBCx 
procedure 
j. Removal of exclusion criterion Subjects 
who have been treated with experimental 
anti-sickling medication/treatment (except 
hydroxyurea) within 30 days of Study Visit 1 
To allow this population to participate in the 
investigation 
k. Modification to the exclusion criterion 
History of drug abuse, alcohol, or other 
factors that in the opinion of the 
investigator could affect the ability of the 
subject to comply with the requirements of 
the protocol; removal of history 
To exclude only those subjects who 
currently have substance abuse problems 
that could interfere with study participation, 
not subjects who have had substance abuse 
problems in the past 
l. Addition of subsection 7.3. Subject 
Enrollment 
To define subject enrollment and 
requirements 
m. Addition of subsection 7.3.1. Procedure 
Deferral Criteria 
To define procedure deferral criteria and 
requirements 
n.  Addition of subsection 7.4. Screen Failures 
To define screen failures and requirements  
Section 8. STUDY PROCEDURES/METHODOLOGY 
a. Addition of language to define location of 
testing and when they will be performed; 
complete blood count and hemoglobin 
profile will be evaluated locally according 
to institutional SOPs; plasma hemoglobin 
will be evaluated centrally at one laboratory 
To clarify the standardization plan for study 
testing 
b. Addition of The blood warmer cannot be 
used as a rapid infusion device (RID) 
To explain that if a blood warmer is used, it 
cannot be used as a RID 
c. Addition of language defining the type(s) of 
anticoagulant used; to explain that in 
addition to anticoagulant citrate dextrose, 
Formula A (ACD-A), custom anticoagulant 
may be used and should be defined by the 
prescribing physician based on the subject’s 
medical need 
To clarify the Sponsor’s plan to standardize 
anticoagulant use across sites 

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d.  Modification to medication evaluation 
requirements; in addition to collecting 
medications that are taken on the day of 
procedure, site will collect concomitant 
medications taken up to 7 days prior to the 
procedure and during 
For safety assessment 
e. Addition of language a day-of-procedure 
CBC must be obtained 
To emphasize the requirement of a day-of-
procedure study CBC to be obtained; 
regardless of the standard clinical tests 
performed, a day-of-procedure study CBC 
must be obtained to assess procedure 
evaluability 
f. Addition of footnote to Post-procedure 
column in Table 2. SUMMARY OF 
SUBJECT EVALUATIONS to require 
post-procedure sample to be taken prior to 
reinfusion, if performed, and within 10-15 
minutes after the procedure if reinfusion is 
not performed 
To ensure consistency across sites and 
treatment data collection processes 
g. Addition of Age to the required subject 
evaluations; addition of age to Table 2. 
SUMMARY OF SUBJECT 
EVALUTIONS; age at signing of informed 
consent will be reported 
To ensure subject is eligible to participate; 
to ensure appropriate informed consent 
processes are performed 
h. Addition of pre-procedure samples should 
be drawn after kit installation 
To clarify study procedure process 
i. Addition of A sample for testing of each RF 
RBC unit should be taken prior to 
attachment of the unit to the kit 
To clarify study procedure process 
j. Addition of Post-procedure samples must 
be drawn from the inlet line 
To clarify study procedure process 
k. Removal of the requirement 10 milliliters of 
blood should be drawn and discarded as 
waste prior to taking the post-procedure 
sample 
For clarification; requirement no longer 
necessary since blood is being drawn from 
the inlet line (see Summary of Changes 
comment j in Section 8. STUDY 
PROCEDURES/METHODOLOGY) 
l. Addition of Automated footnote to Tables 2, 
4, and 5 
To clarify that the Hematocrit value 
obtained is from the automated CBC report 
m. Addition of End Time (Procedure 
Completed) to Table 3. SUMMARY OF 
PROCEDURE EVALUATIONS 
To document the end of procedure for AE 
assessment purposes 
n. Modification to waste material procedure 
description 
For clarification 
o. Removal of Primary Waste Container and 
Secondary Waste Container 
For clarification 

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p. Addition of Type of RBC Unit, ABO Type, 
Date Sample Drawn, Confirmation of Sickle 
Trait Negative, Confirmation of 
Leukoreduction, Confirmation of Rh (D) 
Compatibility, Expiration Date to Table 5. 
SUMMARY OF REPLACEMENT RBC 
UNIT PARAMETERS 
To ensure replacement RBC unit meets the 
criteria for use 
Section 9. DESCRIPTION OF DEVICE 
a. Modification to the intended use to a broad 
intended; statement that the protocol is 
limited to Red Blood Cell Exchange and 
Red Blood Cell Depletion/Exchange 
procedures 
To explain the recognized intended use of 
the AMICUS Separator; the investigation is 
limited to sickle cell disease 
b. Addition of subsection 9.4. Indications for 
Use 
To notify investigators of  the RBCx 
System’s indications for use 
c. Addition of subsection 9.5. 
Contraindications for Use 
To notify investigators of the RBCx 
System’s contraindications for use 
d. Addition of the AMICUS Operator’s 
Manual, Volume 5, RBCx (REC-009200) to 
subsection 9.6.1. Investigational Materials 
To document the investigational materials 
used 
e. Addition of the AMICUS Operator’s 
Manual, Volume 1, Operation Basics,  
(07-19-07-291) or equivalent to subsection 
9.6.2. FDA Cleared Materials 
To document the FDA cleared materials 
used 
f. Addition of custom anticoagulant may be 
used and should be defined by the 
prescribing physician based on the subject’s 
medical need to subsection 9.6.2. FDA 
Cleared Materials 
To clarify the Sponsor’s plan on how to 
standardize anticoagulant use across sites 
Section 10. RISK ANALYSIS 
a. Modification of the risk analysis to include 
and expound on information about the risks 
associated with apheresis, transfusion, 
hemolysis, air embolism, blood clotting, and 
fluid imbalance 
For clarification; to document the possible 
risks and how the risks are mitigated 
b. Addition of subsection 10.2. Risks to 
Pediatric Subjects 
To document the possible risks to children; 
to document the risks that are more common 
in children and how to risks are mitigated 
c. Change of hemoglobinopathies to sickle cell 
disease  
The investigation is limited to sickle cell 
disease 
Section 11. SAFETY EVALUATIONS 
a. Modification of the Adverse Event Grading 
Criteria 
To be consistent with the FDA’s New Draft 
Guidance on Safety Data Collection 

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b. Modification to Relationship to Study 
Article to Relationship to Study Device 
To grade an adverse event in relation to the 
device; to differentiate the adverse event 
related to the device from an event related to 
the procedure 
c. Addition of Relationship to Procedure 
section 
To grade an adverse event in relation to the 
event; to differentiate the adverse event 
related to the procedure from an event 
related to the device 
d. Modification to the definitions of the 
Adverse Event Relationship Criteria 
To be consistent with FDA’s New Draft 
Guidance on Safety Data Collection 
Section 12. Data Quality Assurance 
a. Addition of subsection 12.1. Data Reporting To define data reporting and requirements 
b. Clarification and description of the 
monitoring procedures that will be 
performed 
To ensure the protection of the rights, 
safety, and welfare of the subjects involved 
in the clinical investigation and the integrity 
of the resulting data 
Section 13. STATISTICAL METHODS AND SAMPLE SIZE 
a. Addition of the overall study success 
criteria 
To define the Sponsor’s plan for 
determining study success 
b. Additions to subsection 13.2. Determination 
of Sample Size to expound on sample size 
determination description 
For clarification 
c. Additions to subsection 13.3. Analysis Data 
Sets to expound on the analysis data sets 
and criteria plan description, including plan 
for intent to treat population 
For clarification 
d. Addition to subsection 13.3.1. Safety 
Analysis to expound on adverse event, 
safety, and system performance assessment 
description 
For clarification 
e. Addition of non-inferiority hypothesis for 
the mean of the paired effect formula; 
addition of non-inferiority description 
For clarification 
f. Addition of description of analysis of 
covariance (ANCOVA) use 
For clarification 
g. Addition of the evaluability criterion If the 
subject hematocrit input value and the 
actual day of treatment pre-procedure 
hematocrit differs by more than five (5) 
hematocrit points, then data for FCR and 
END Hct are non-evaluable 
To clarify evaluability criteria 

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h. Additions to the interim analysis report 
description 
To define the Sponsor’s plan of when the 
Interim Analysis will be completed, what 
information will be included, by whom it 
will be reviewed, and the purpose for 
completing the analysis 
Section 14. ADMINISTRATIVE RULES 
a. Addition of the requirement for age and 
time of consent to be documented on the 
informed consent form 
To ensure subject’s eligibility and 
appropriate informed consent processes are 
performed 
b. Addition of subsection 14.10. Publications 
To define Sponsor’s publication definitions 
and requirements 
Section 15. REFERENCES 
a. Modification to reference list 
To remove articles that are no longer 
applicable to the protocol; to cite literature 
used in the protocol 
Appendix 
a. Appendix B. LABELS:  Removal of 
Protocol ID and title from clinical inventory 
labels 
Not required by US to include Protocol ID 
and title on clinical inventory labels 
b. Appendix D. SAMPLE INFORMED 
CONSENT AND ASSENT: Addition of 
Assent to title 
Sample informed assent form was added to 
Appendix D 
c. Appendix D. SAMPLE INFORMED 
CONSENT AND ASSENT: Incorporation 
of all applicable changes made to the 
protocol into the Adult, Parent, and 
Adolescent Assent form 
To provide the investigator with an accurate 
sample informed consent/assent form that 
includes the required elements of the 
protocol 

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Person(s) authorized to sign the protocol 
and the protocol amendment(s) for the 
Sponsor: 
 
Carrie Pineda, Sr. Director  
Applied Product Testing 
 
Jason Friedmann, Senior Clinical Research Specialist 
Applied Product Testing 
 
Participating Sites and Primary Investigators 
Site 
Investigator 
BloodCenter of Wisconsin 
Milwaukee, WI 
 
Jerome Gottschall, MD 
638 N 18th Street 
Milwaukee, WI 53233 US 
Karmanos Cancer Institute  
Detroit, MI 
Paul Swerdlow, M.D. 
4100 John R St. 
Hudson Webber Bldg  #4HW-CRC 
Detroit, MI 48201 US 
Children’s Hospital of Philadelphia 
Philadelphia, PA 
David Friedman, MD 
34th Street and Civic Center 
Boulevard 
Philadelphia, PA 19104 US 
University of Texas Southwest 
Dallas, TX  
Karén Matevosyan, MD 
Charles Sprague Building 
3rd Floor, Suite 114 
5323 Harry Hines Blvd 
Dallas, TX 75235 US 
Washington University 
St Louis, MO 
Brenda Grossman, MD, MPH 
660 S. Euclid Avenue, Box 8118 
Saint Louis, MO 63110 
 
Phoenix Children’s Hospital 
Phoenix, AZ 85016 
Leon Su, MD 
Phoenix Children’s Hospital 
1919 E. Thomas Rd. 
Phoenix, AZ 85016 
St. Anna Kinderspital 
Vienna, Austria 
Dr. Volker Witt 
St. Anna Kinderspital 
Kinderspitalgasse 6 
A 1090 Vienna 
 

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1 
PROTOCOL SUMMARY 
Name of Sponsor: 
Fresenius Kabi USA LLC 
Name of Experimental Article: 
AMICUS Separator 4R4580 with 
SW Version 5.0 
IDE Number:  
G140172 
Study Number/Title: 
AMIC-003-CMD Evaluation of the AMICUS Red Blood Cell Exchange (RBCx) System in 
Sickle Cell Patients 
Estimated Duration: 2.5 Years 
Number of Subjects: Up to 130 enrolled  
Number of Procedures:   
RBC Exchange and RBC Depletion/Exchange Procedures:  A minimum of 62 evaluable 
procedures 
Background:   
The Sponsor has developed a new operating protocol on the AMICUS Separator that enables the 
device to perform Red Blood Cell Exchange (RBCx) procedures in accordance with the 
replacement fluid(s) (RF) prescribed by a physician for patients with sickle cell disease (SCD).  
The goal of these procedures is to remove a patient’s red blood cells (RBCs) and replace the 
blood volume removed with either healthy donor RBCs and/or colloid/crystalloid solutions.  
Depending on the RF used, the procedure can be considered an RBC Exchange or RBC 
Depletion/Exchange procedure.  The RBC Depletion/Exchange procedure is a modification of 
the RBC Exchange procedure.  The AMICUS RBCx protocol provides the ability to use various 
RFs including healthy donor RBCs or a combination of fluids, such as saline followed by RBCs.  
In RBC Exchange and the exchange portion of the RBC Depletion/Exchange procedures, RBC 
units are used as the RF, while colloid and/or crystalloid solutions are used as the RF in the 
depletion portion of the RBC Depletion/Exchange procedures. 
Objective:   
Primary Objective: 
To evaluate the accuracy of the subject’s original RBCs remaining (Actual FCR) as measured by 
subject’s post-procedure Hb S at the end of the procedure to the Target FCR 
Secondary Objectives: 
• To evaluate the accuracy of subject hematocrit post-procedure (End Hematocrit)* 
• To evaluate subject cellular loss (white blood cells, platelets) post-procedure 
• To evaluate device related serious adverse events during the procedure and 
approximately 18-24 hours post-procedure 
• To evaluate the cellular content of the waste material 
*For RBC Depletion/Exchange procedures, End Hematocrit will be measured at the end of the 
depletion phase and at end of the exchange phase. 

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Study Design:   
This study will be performed under the direction of up to seven investigators at up to seven sites 
in the United States (US) and Europe.  Data collected will be summarized and submitted to the 
Fresenius Kabi European notified body, Technischer Überwachungs-Verein (TÜV), in Germany.  
Data from the completed study will be submitted to the United States Food and Drug 
Administration (FDA) to support a premarket submission. 
This protocol will be a multi-center, single-arm, open label study to complete a minimum of 62 
evaluable RBCx procedures.  The type of procedure performed will be determined by the 
physician.  Up to a total of 130 subjects meeting all eligibility criteria will be enrolled.  Initially, 
up to 60 subjects 18 years old or older will be enrolled to complete approximately 31 evaluable 
procedures.  Aft Up to seven US investigational sites will participate in this study.  er the initial procedures 
are complete, an interim report including summary statistics and safety data will be reviewed 
independently by a Data Safety Monitoring Board (DSMB).  Following review by the DSMB, 
the interim report will be submitted to the FDA for review as an IDE supplement.  The 
supplement must be approved by the FDA prior to enrolling pediatric subjects six to 17 years 
old.   
The AMICUS RBC Exchange and RBC Depletion/Exchange procedures will be evaluated using 
a multi-center, single-arm, open label study design in subjects with SCD.  Each subject will 
complete one procedure during one Study Visit.  Dual venous access will be required using the 
method prescribed by the physician (e.g., peripheral venipuncture, catheter, Central Venous 
Access Device [CVAD], etc.).  The appropriate RF and procedure parameters as prescribed by a 
physician will be used.  Subject vital signs will be taken and laboratory samples will be drawn 
pre- and post-procedure.  Adverse events will be monitored during the procedure and via 
telephone approximately 18-24 hours post-procedure.  In addition to pre- and post-procedure 
vital signs and laboratory samples, subjects participating in the RBC Depletion/Exchange 
procedure evaluation will also have vital signs taken and laboratory samples drawn post-
depletion phase. 
Inclusion/Exclusion Criteria: 
Inclusion: 
• Subjects ≥6 years old.  
• Subjects with documented diagnosis of a type of sickle cell disorder who require RBC 
Exchange or RBC Depletion/Exchange treatment. 
• Medically stable subjects who have been previously treated for sickle cell disease with 
RBC Exchange or RBC Depletion/Exchange. 
• Subjects, or subject’s legal representative, who have provided signed informed consent, 
and assent when applicable, prior to participation. 
• Adequate availability of sickle trait negative, leukoreduced, ABO blood group, Rhesus 
factor D (Rh (D)) compatible, unexpired replacement RBC products.  
• Subjects with sufficient vascular access to accommodate the RBCx procedure as 
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• Subjects who are able and agree to report adverse events (AEs) during the required 
reporting period. 
Exclusion: 
• 
Procedures that occur during acute hospitalization. 
• 
Procedures prescribed within one week of discharge of a hospitalization. 
• 
Subjects with altered mental status that would prohibit the giving and understanding of 
informed consent, and assent when applicable, who do not have a legally authorized 
representative. 
• 
Drug abuse, alcohol abuse, or other factors that in the opinion of the investigator could 
affect the ability of the subject to comply with the requirements of the protocol. 
• 
Subjects who have experienced a serious adverse event associated with an RBCx 
procedure in the past. 
• 
In the opinion of the investigator, subjects who have a life expectancy fewer than 30 
days. 
• 
Subjects who refuse blood products. 
• 
Subjects who are pregnant. 
• 
Subjects who fail to comply with site requirements for cessation of medication that 
interfere or increase procedure risk. 
Statistical Methods:  
The RBC Exchange and RBC Depletion/Exchange procedures have the same therapeutic 
endpoint, FCR.  Hypothesis testing will be performed to evaluate the primary objective of the 
95% confidence interval around the mean ratio of actual to target FCR as measured by 
Hemoglobin S in the subjects pre- and post-procedure to a pre-defined FCR range of 0.75 to 
1.25. 
Hypothesis testing is not planned for secondary variables.  Summary statistics (mean, standard 
deviation, median, minimum, maximum and count) will be presented for continuous parameters 
with their 95% confidence limits as applicable.  Discrete parameters will be presented by total 
number and percentage.  A detailed statistical procedure will be outlined in the Statistical 
Analysis Plan. 
 

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2 
TABLE OF CONTENTS 
i. 
SUMMARY OF CHANGES................................................................................................... 2 
a. 
Version 08 05May2016 ........................................................................................................... 2 
b. 
Version 07 08Jan2016 ............................................................................................................. 2 
c. 
Version 06 17Aug2015 ............................................................................................................ 3 
d. 
Version 05 08Jan2015 ............................................................................................................. 3 
e. 
Version 04 23Dec2014 ............................................................................................................ 5 
f. 
Version 03 20Nov2014 ............................................................................................................ 6 
g. 
Version 02 10Nov2014 ............................................................................................................ 7 
1 
PROTOCOL SUMMARY .................................................................................................... 16 
2 
TABLE OF CONTENTS ...................................................................................................... 19 
3 
ABBREVIATIONS ............................................................................................................... 24 
4 
BACKGROUND ................................................................................................................... 26 
4.1 
Prior Non-Clinical Studies .......................................................................................................... 27 
4.2 
Pre-Clinical Studies .................................................................................................................... 28 
5 
OBJECTIVES ........................................................................................................................ 28 
5.1 
Primary Objective ....................................................................................................................... 28 
5.2 
Secondary Objectives .................................................................................................................. 28 
6 
SCOPE ................................................................................................................................... 28 
7 
STUDY DESIGN .................................................................................................................. 29 
7.1 
Overview of Study Design .......................................................................................................... 30 
7.1.1 
Lead-In Phase ...................................................................................................................... 31 
7.1.2 
AMICUS RBC Exchange Procedure .................................................................................. 31 
7.1.3 
AMICUS RBC Depletion/Exchange Procedure ................................................................. 32 
7.1.4 
Waste Material .................................................................................................................... 32 
7.2 
Subject Selection ......................................................................................................................... 32 
7.2.1 
Inclusion Criteria................................................................................................................. 32 
7.2.2 
Exclusion Criteria ............................................................................................................... 33 
7.3 
Subject Enrollment ...................................................................................................................... 33 
7.3.1 
Subject Re-enrollment ......................................................................................................... 33 

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7.4 
Screen Failures ............................................................................................................................ 33 
7.5 
Subject Drop-out ......................................................................................................................... 34 
8 
STUDY PROCEDURES/METHODOLOGY ....................................................................... 34 
8.1 
Subject Evaluations ..................................................................................................................... 35 
8.2 
AMICUS RBCx Procedures ....................................................................................................... 37 
8.2.1 
RBC Exchange Procedure ................................................................................................... 37 
8.2.2 
RBC Depletion/Exchange Procedure .................................................................................. 37 
8.3 
Waste Material Procedure ........................................................................................................... 41 
8.4 
Appropriateness of Measures ...................................................................................................... 41 
8.5 
Study Completion ....................................................................................................................... 41 
8.6 
Site Closure ................................................................................................................................. 41 
8.7 
Discontinuation ........................................................................................................................... 42 
8.8 
Study Termination ...................................................................................................................... 42 
9 
DESCRIPTION OF DEVICE ............................................................................................... 42 
9.1 
AMICUS RBCx System ............................................................................................................. 42 
9.2 
Intended Use ............................................................................................................................... 43 
9.3 
Indications for Use ...................................................................................................................... 43 
9.4 
Contraindications for Use ........................................................................................................... 43 
9.5 
Materials and Supplies ................................................................................................................ 44 
9.5.1 
Investigational Materials ..................................................................................................... 44 
9.5.2 
FDA Cleared Materials ....................................................................................................... 44 
9.6 
Labeling ...................................................................................................................................... 45 
9.7 
Method of Assignment to Experimental Article ......................................................................... 45 
9.8 
Blinding/Randomization ............................................................................................................. 45 
10 RISK ANALYSIS ................................................................................................................. 45 
10.1 
Risks Associated with an Apheresis Procedure .......................................................................... 46 
10.2 
Risks to Pediatric Subjects .......................................................................................................... 48 
10.2.1 
Risks Associated with Use of the RBCx Investigational Device ........................................ 49 
10.3 
Demographic Risks ..................................................................................................................... 50 
11 SAFETY EVALUATIONS ................................................................................................... 50 
11.1 
Adverse Events ........................................................................................................................... 50 

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11.2 
Event Severity ............................................................................................................................. 51 
11.3 
Episode Pattern ........................................................................................................................... 51 
11.4 
Action Taken (Procedure) ........................................................................................................... 51 
11.5 
Action Taken (Subject) ............................................................................................................... 52 
11.6 
Relationship to Device ................................................................................................................ 52 
11.7 
Relationship to Procedure ........................................................................................................... 53 
11.8 
Outcome ...................................................................................................................................... 54 
11.9 
Serious Adverse Events .............................................................................................................. 54 
12 DATA QUALITY ASSURANCE......................................................................................... 55 
12.1 
Data Reporting ............................................................................................................................ 55 
12.2 
Data Capture System ................................................................................................................... 55 
12.3 
Data Recording ........................................................................................................................... 55 
12.4 
Electronic Case Report Forms (eCRF) ....................................................................................... 55 
12.5 
Monitoring Procedures ................................................................................................................ 56 
12.6 
Maintenance of Records.............................................................................................................. 56 
12.7 
Record Retention ........................................................................................................................ 57 
13 STATISTICAL METHODS AND SAMPLE SIZE .............................................................. 57 
13.1 
General Overview ....................................................................................................................... 57 
13.2 
Determination of Sample Size .................................................................................................... 58 
13.2.1 
Analysis Data Sets .............................................................................................................. 58 
13.2.2 
Safety Analysis ................................................................................................................... 59 
13.3 
Study Endpoints and Methodology ............................................................................................. 59 
13.4 
Criteria for End of Study or Stopping Rules ............................................................................... 61 
13.5 
Evaluability Criteria .................................................................................................................... 61 
13.6 
Subject Disposition ..................................................................................................................... 62 
13.7 
Subject Demographics and Baseline Characteristics .................................................................. 62 
13.8 
Interim Analysis .......................................................................................................................... 62 
14 ADMINISTRATIVE RULES ............................................................................................... 63 
14.1 
Investigator’s Responsibilities .................................................................................................... 63 
14.2 
Confidentiality ............................................................................................................................ 64 
14.3 
Protocol Modifications ................................................................................................................ 64 

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14.4 
Protocol Deviations ..................................................................................................................... 65 
14.5 
On-Site Audits ............................................................................................................................ 65 
14.6 
Ethics........................................................................................................................................... 65 
14.6.1 
Institutional Review Board ................................................................................................. 65 
14.7 
Informed Consent ........................................................................................................................ 66 
14.8 
Experimental Article(s) ............................................................................................................... 66 
14.9 
Documentation of Laboratory Methods and Test Results ........................................................... 67 
14.10 
Publications ............................................................................................................................. 67 
15 REFERENCES ...................................................................................................................... 68 
 

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LIST OF TABLES 
Table 1. SUBJECT ENROLLMENT ........................................................................................... 28 
Table 2. ROUTINE PRE-PROCEDURE TESTING DATA ........................................................ 35 
Table 3. SUMMARY OF SUBJECT EVALUATIONS............................................................... 35 
Table 4. SUMMARY OF PROCEDURE EVALUATIONS ........................................................ 38 
Table 5. SUMMARY OF REPLACEMENT RBC UNIT PARAMETERS................................. 40 
Table 6. WASTE MATERIAL EVALUATIONS ........................................................................ 41 
Table 7. REQUIRED REPORTS FROM INVESTIGATOR ....................................................... 63 
 
LIST OF FIGURES 
Figure 1. RBCx PROCEDURES .................................................................................................. 27 
Figure 2. EVALUATION OF THE AMICUS RBCx SYSTEM .................................................. 31 
 
TABLE OF APPENDICES 
Appendix A. INVESTIGATOR APPROVAL ............................................................................. 70 
Appendix B. LABELS .................................................................................................................. 72 
Appendix C. SAMPLE INFORMED CONSENT AND ASSENT .............................................. 75 
Appendix D. SUMMARY OF PRIOR NON-CLINICAL STUDIES ........................................ 109 
Appendix E. SUMMARY OF PRIOR PRE-CLINICAL STUDIES .......................................... 125 
 
 
 

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3 
ABBREVIATIONS 
AABB 
Formerly American Association of Blood Banks 
ACD-A 
Anticoagulant Citrate Dextrose-Formula A 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
APT DM 
Applied Product Testing Data Management  
APT SM 
Applied Product Testing Site Management  
APT Stats 
Applied Product Testing Statistics 
°C 
Degrees Centigrade 
CAP 
College of American Pathologists 
CE 
European Conformity 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Act 
CRF 
Case Report Form 
CRA 
Clinical Research Associate 
CV 
Curriculum Vitae 
CVA 
Central Venous Access 
CVAD 
Central Venous Access Device 
DVD 
Digital Video Disc 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 
g 
Grams 
g/dL 
Grams per Deciliter 
GCP 
Good Clinical Practice 
Hb 
Hemoglobin 
Hb A 
Hemoglobin A 
Hb C 
Hemoglobin C 
Hb F 
Hemoglobin F 
Hb S 
Hemoglobin S 
HBs Ag 
Hepatitis B Antigen 
Hct 
Hematocrit 
HIPAA 
Health Information Portability and Accountability Act 

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ICH 
International Conference on Harmonisation 
IEC 
International Electrotechnical Commission 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IVH 
Isovolemic Hemodilution 
kg 
Kilogram 
L 
Liter 
min 
Minute 
mL 
Milliliter 
MNC 
Mononuclear Cell 
µL 
Microliter 
PN 
Part Number 
RBC 
Red Blood Cell 
RBCx 
Red Blood Cell Exchange 
RF 
Replacement Fluid 
RID 
Rapid Infusion Device 
SAE 
Serious Adverse Event 
SCD 
Sickle Cell Disease 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure 
SW 
Software 
TPE 
Therapeutic Plasma Exchange 
TÜV 
Technischer Überwachungs-Verein (Technical Inspection 
Association) 
UADE 
Unanticipated Adverse Device Effect  
US 
United States 
WB 
Whole Blood 
WBC 
White Blood Cell 
 
 

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4 
BACKGROUND 
Red Blood Cell Exchange (RBCx) is a type of therapeutic procedure used to remove red blood 
cells (RBCs) from sickle cell patients, exchanging them for healthy donor RBCs and/or 
crystalloid or colloid solutions to maintain fluid balance.  Depending upon the replacement 
fluid(s) (RF) used, the procedure can be considered an RBC Exchange or an 
RBC Depletion/Exchange procedure.  The RBC Depletion/Exchange procedure is a modification 
of the RBC Exchange procedure.  Removal of RBCs may be performed manually or using an 
apheresis device. The removal of RBCs and replacement with healthy donor RBCs is most 
frequently used in the treatment of patients with complications of sickle cell disease (SCD).  
Depending upon institutional practices, RBC Exchange may also be employed after an RBC 
depletion pre-step (also known as isovolemic hemodilution), in which the initial replacement 
fluid used is a crystalloid or colloid solution instead of RBCs (refer to Figure 1). 
In SCD and its variants, patients have an abnormal hemoglobin gene(s).  In the predominant 
homozygous form, sickle cell anemia, the hemoglobin S (Hb S) has a single amino acid mutation 
in the beta globin chain compared to normal hemoglobin A (Hb A).  The deoxygenation of Hb S 
results in the formation of rod-like structures that stiffen the RBC into a crescent or sickle shape.  
The deformed RBCs have decreased flexibility and cause microvascular occlusions.  This results 
in a cycle of cell sickling, blood flow stasis, and progressive hypoxia that leads to severe pain 
crises, stroke, ischemia, or infarction causing tissue damage.  Reduction of the Hb S 
concentration to approximately 30% allows persistence of adequate levels of normal Hb A for 
several weeks and decreases the potential for clinical signs and symptoms.1  
In some centers, an RBC Depletion/Exchange procedure is used to reduce secondary strokes in 
SCD patients.  The RBC Depletion/Exchange treatment is a two-step process – an RBC 
depletion step is performed prior to the start of the RBC exchange portion of the treatment.1  This 
additional pre-step has demonstrated several advantages including increased efficiency of Hb S 
removal, increased treatment intervals by two weeks, decreased the total number of procedures 
per patient over time, reduced RBC utilization by 33%, and lowered donor exposure and the risk 
for alloimmunization, as well as significantly decreased costs.2   
The AMICUS Separator System is an automated blood cell separator indicated for the collection 
of blood components and mononuclear cells (MNCs).  It has been marketed since 1997 for the 
collection of platelets and concurrent plasma using ACD-A anticoagulant (BK960005, 
BK990009).  In 2002, cleared collection protocols were expanded to include concurrent RBCs 
and MNCs (BK000039, BK000047).  Additionally, in 2012, AMICUS was cleared to perform 
therapeutic plasma exchange (TPE) (K111702).  
The Sponsor has developed a new operating protocol on the AMICUS Separator that enables the 
machine to perform RBCx procedures in accordance with the RF prescribed by a physician.  The 

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Sponsor’s documented product development process (including risk management) has been 
followed to evaluate the safety, effectiveness, and functionality of the AMICUS RBCx System.   
 
Figure 1. RBCx PROCEDURES  
4.1 
Prior Non-Clinical Studies 
To ensure adequate subject protection, the development of the RBCx System included in vitro 
evaluations to assess performance, safety and efficacy, and completion of a Human Use 
Approval.  A summary of the in vitro studies using bagged blood are found in Appendix D.  The 
following objectives were evaluated: 
• Confirm that RBC Exchange, RBC Depletion/Exchange and RBC Depletion procedures 
meet established internal requirements for key endpoints (e.g., FCR, End Hct and Fluid 
Balance accuracy). 
• Evaluate the generation of hemolysis during procedures under worst case scenarios (high 
hematocrit, high hematocrit replacement fluid, high and low flow rates and small gauge 
needles).   
• Perform RBC Exchange procedures using sickle cell waste blood obtained from patient 
procedures to evaluate effects of abnormal RBCs when using the AMICUS RBCx 
System.  Also, the flow and pressure characteristics and hemolysis generation using high 
and low flow rates and small gauge needles was examined with these cells. 
• Replacement fluid = RBCs 
• Used to exchange patient RBCs with healthy 
donor RBCs to achieve a target FCR, target End 
Hct, and target fluid balance. 
RBC Exchange 
• Replacement fluid = crystalloid or colloid 
solution followed by RBCs 
• Used to:  
• reduce patient RBCs to a target Hct while 
maintaining isovolemia, quickly followed by 
• exchange of patient RBCs with healthy donor 
RBCs to achieve target FCR, target End Hct, 
and target fluid balance. 
RBC 
Depletion/Exchange 

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4.2 
Pre-Clinical Studies 
An in vivo study, AMIC-002-CMD, was completed in the Lake Zurich Donor Room.  The results 
of the study are summarized in Appendix E.  
5 
OBJECTIVES 
5.1 
Primary Objective 
To evaluate the accuracy of the subject’s original RBCs remaining (Actual FCR) as measured by 
subject’s post-procedure Hb S at the end of the procedure to the Target FCR.   
5.2 
Secondary Objectives 
The following secondary objectives will be assessed: 
• Evaluate the accuracy of subject hematocrit post-procedure (End Hematocrit)* 
• Evaluate subject cellular loss (white blood cells, platelets) post-procedure 
• Evaluate device related serious adverse events during the procedure and approximately 
18-24 hours post-procedure 
• Evaluate the cellular content of the waste material  
*For RBC Depletion/Exchange procedures, End Hematocrit will be measured at the end of the 
depletion phase and at the end of the exchange phase. 
6 
SCOPE 
It is estimated that a minimum of 62 evaluable RBC Exchange and RBC Depletion/Exchange 
procedures will be completed.  Up to a total of 130 subjects meeting inclusion and no exclusion 
criteria will be enrolled.  Initially, up to 60 subjects 18 years old or older will be enrolled to 
complete approximately 31 evaluable procedures.  After the initial procedures are complete, an 
interim report including summary statistics and safety data will be reviewed independently by a 
Data Safety Monitoring Board (DSMB).  Following review by the DSMB, the interim report will 
be submitted to the FDA for review as an IDE supplement.  The supplement must be approved 
by the FDA prior to enrolling pediatric subjects six to 17 years old.  The interim analysis will not 
evaluate the primary objective.   
The scope is depicted in Table 1. 
Table 1. SUBJECT ENROLLMENT 

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Age 
RBCx System Procedure 
N1 
≥18 yrs 
RBC Exchange 
31 
RBC Depletion/Exchange 
Interim Report Including Summary 
Statistics and Safety Data 
≥6 yrs 
RBC Exchange 
31 
RBC Depletion/Exchange 
1N = Approximate minimum number of subjects completing evaluable 
procedures  
 
The evaluations of the RBC Exchange and RBC Depletion/Exchange procedures will be a multi-
center, single-arm, open label study.  The AMICUS RBCx procedures will evaluate the accuracy 
of the subject’s original RBCs remaining (Actual FCR) as measured by subject’s post-procedure 
Hb S at the end of the procedure to the Target FCR.  Secondary objectives will be evaluated.  
Subjects will be required to complete one study visit.   
Up to seven investigational sites will participate in this study.  All sites may enroll subjects for 
treatment with RBC Exchange or RBC Depletion/Exchange based on the physician’s 
prescription. 
Data collected will be summarized and submitted to the Fresenius Kabi European notified body, 
Technischer Überwachungs-Verein (TÜV), in Germany.  Data from the completed study will be 
submitted to the United States Food and Drug Administration (FDA) to support a premarket 
submission.    
7 
STUDY DESIGN 
The sites will perform this study in accordance with, but not limited to, the following applicable 
guidelines: 
• The study protocol  
• The World Medical Association Declaration of Helsinki (2013 Version) 
• ICH E6 (R1) Consolidated Guideline for Good Clinical Practice (GCP) 
• ISO 14155:2011 (E) Clinical investigation of medical devices for human subjects - Good 
Clinical Practice 

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• The privacy regulation of the Health Insurance Portability and Accountability Act of 
1996 
• 21 CFR 50 Protection of Human Subjects 
• 21 CFR 54 Financial Disclosure by Clinical Investigators 
• 21 CFR 56 Institutional Review Boards 
• 21 CRF 640 Additional Standards for Human Blood and Blood Products 
• 21 CFR 812 Investigational Device Exemptions 
7.1 
Overview of Study Design 
This study will evaluate the AMICUS RBCx System in adult and pediatric subjects diagnosed 
with SCD.  Subjects will complete one RBC Exchange or RBC Depletion/Exchange procedure 
on the AMICUS Separator at one study visit.  The type of procedure performed (RBC Exchange 
or RBC Depletion/Exchange) will be as prescribed by the physician.  Initially, up to 60 subjects 
18 years old or older will be enrolled to complete approximately 31 procedures.  After the initial 
procedures are complete, an interim report including summary statistics and safety data will be 
independently reviewed by a DSMB.  Following review by the DSMB, the interim report will be 
submitted to the FDA for review as an IDE supplement.  The supplement must be approved by 
the FDA prior to enrolling pediatric subjects six to 17 years old.  The interim analysis will not 
evaluate the primary objective.  
Procedures that occur during acute hospitalization will not be completed as part of the study.  
Procedures that are prescribed within a week of discharge from a hospitalization will not be 
completed as part of the study.  Prophylactic procedures that occur prior to surgery may be 
completed as part of the study, provided the subject meets all eligibility requirements. 
Target subject and procedure parameters will be entered at the beginning of the procedure and 
procedure summary data will be recorded.  Adverse events, alarms, and device malfunctions that 
occur during the procedure will be recorded.  Adverse events will be assessed approximately 18-
24 hours post-procedure.  

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Figure 2. EVALUATION OF THE AMICUS RBCx SYSTEM 
7.1.1 Lead-In Phase 
Each site will be able to perform approximately two RBC Exchange or 
RBC Depletion/Exchange procedures on the AMICUS Separator for training purposes.  
Representatives of the Sponsor will be present for the lead-in procedures to provide training and 
support to the site regarding device set up, system performance, and procedure management.  
The lead-in phase subject population will include subjects 18 years old or older who provide 
informed consent and meet all eligibility criteria.  The type of procedure performed, parameters, 
and RF will be as prescribed by the physician.  Lead-in subjects will not be included in the 
evaluable population but will be included in the safety analysis.     
Subjects participating in the lead-in phase may return to re-enroll into the full study if they meet 
eligibility criteria, provide new informed consent, and will be assigned a new Subject 
Identification number (Subject ID). 
7.1.2 AMICUS RBC Exchange Procedure 
The AMICUS RBC Exchange procedure will be evaluated using a multi-center, single-arm, open 
label study design in subjects with SCD.  Dual venous access will be required using the method 
prescribed by the physician (e.g., peripheral venipuncture, catheter, Central Venous Access 
Device [CVAD]).  The appropriate RF and procedure parameters as prescribed by a physician 
will be used.  The subject’s sickle cell diagnosis and demographics will be documented.  Subject 
vital signs will be documented and laboratory samples will be drawn pre- and post-procedure.  
Adverse events will be monitored during the procedure and assessed approximately 18-24 hours 
post-procedure. 

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7.1.3 AMICUS RBC Depletion/Exchange Procedure 
The AMICUS RBC Depletion/Exchange procedure will be evaluated using a multi-center, 
single-arm, open label study design in subjects with SCD.  Dual venous access will be required 
using the method prescribed by the physician (e.g., peripheral venipuncture, catheter, CVAD).  
The appropriate RF and procedure parameters as prescribed by a physician will be used.  The 
subject’s sickle cell diagnosis and demographics will be documented.  Subject vital signs will be 
documented and laboratory samples will be drawn pre-, post-depletion phase, and post-
procedure.  Adverse events will be monitored during the procedure and assessed approximately 
18-24 hours post-procedure. 
7.1.4 Waste Material 
The waste material removed will be pooled, weighed, and assessed for cellular content. Refer to 
Section 8.3 for additional details. 
7.2 
Subject Selection 
Subjects will be identified by the site investigator(s) who will discuss details of study 
participation.  Each subject will provide written informed consent, and assent when applicable, 
as approved by the EC/IRB before participating in the study.  If a subject is unable to provide 
written informed consent or assent, his/her legally authorized representative may sign on his or 
her behalf.  All subject information will be kept confidential in compliance with all state and 
federal laws and regulations, including the HIPAA Privacy Rule.  After choosing to participate, 
the subject can withdraw from the study at any time without prejudice, penalty or loss of benefits 
or care that he or she would otherwise be entitled.  All subjects will be assessed for eligibility 
into the study using the inclusion and exclusion criteria. 
7.2.1 Inclusion Criteria 
• Subjects ≥6 years old. 
• Subjects with documented diagnosis of a type of sickle cell disorder who require 
RBC Exchange or RBC Depletion/Exchange treatment.  
• Medically stable subjects who have been previously treated for sickle cell disease with 
RBC Exchange or RBC Depletion/Exchange. 
• Subjects, or subject’s legal representative, who have provided signed informed consent, 
and assent when applicable, prior to participation. 
• Adequate availability of sickle trait negative, leukoreduced, ABO blood group, Rhesus 
factor D (Rh (D)) compatible, unexpired replacement RBC products. 
• Subjects with sufficient vascular access to accommodate the RBCx procedure as 
determined by the medical staff responsible for obtaining intravenous access.    

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• Subjects who are able and agree to report adverse events (AEs) during the required 
reporting period. 
7.2.2 Exclusion Criteria 
• Procedures that occur during acute hospitalization. 
• Procedures prescribed within one week of discharge of a hospitalization. 
• Subjects with altered mental status that would prohibit the giving and understanding of 
informed consent, and assent when applicable, who do not have a legally authorized 
representative. 
• Drug abuse, alcohol abuse, or other factors that in the opinion of the investigator could 
affect the ability of the subject to comply with the requirements of the protocol.  
• Subjects who have experienced a serious adverse event associated with an RBCx 
procedure in the past. 
• In the opinion of the investigator, subjects who have a life expectancy fewer than 30 
days.  
• Subjects who refuse blood products.  
• Subjects who are pregnant.  
• Subjects who fail to comply with site requirements for cessation of medication that 
interfere or increase procedure risk. 
7.3 
Subject Enrollment 
Enrollment will occur at the time of informed consent, and assent when applicable.  After 
enrollment, the subject will be assigned a unique Subject ID.  The procedure type will be as 
prescribed by the physician. Each subject may provide only one evaluable AMICUS procedure 
for the study. 
7.3.1 Subject Re-enrollment 
If a subject is able to establish vascular access and begin the procedure but does not complete the 
procedure, the procedure will not be evaluable (see Section 13.6 Evaluability Criteria).  
However, subjects not successfully completing the procedure may re-enroll into the study if they 
meet eligibility criteria, provide new informed consent, and assent when applicable, and will be 
assigned a new Subject ID.  Subjects may re-enroll only one time into the study following an 
incomplete procedure.  
7.4 
Screen Failures 
Enrolled subjects who do not meet all eligibility criteria will be considered a screen failure.  The 
subject may then re-enroll into the study if they meet eligibility criteria, provide new informed 

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consent, and assent when applicable, and will be assigned a new Subject ID.  Subjects may re-
enroll only one time into the study following a screen failure. 
7.5 
Subject Drop-out 
If the subject signs an informed consent form (ICF) but does not return to complete the study 
visit prior to the end of the study, the subject will be considered a drop-out. 
8 
STUDY PROCEDURES/METHODOLOGY  
The AMICUS Separator will be operated by qualified healthcare professionals who are trained in 
the operation of the system.  The Operator’s Manual should be followed for RBCx procedures, 
kit installation, and instructions for general operation of the instrument.  
Procedure parameters will be entered into the AMICUS Separator in compliance with the 
physician’s prescription.  Summary of routine pre-procedure testing data used for input 
calculations, subject evaluations, procedure evaluations, replacement RBC unit parameters, and 
waste material evaluations are listed in Tables 2, 3, 4, 5, and 6.  The subject’s complete blood 
count (white blood cell count (WBC), RBC, platelet count, and hematocrit; also known as CBC) 
and hemoglobin profile (Hb A, Hb S, Hb C, and Hb F) will be evaluated locally according to 
institutional SOPs.  Plasma hemoglobin will be evaluated centrally at one laboratory. 
If necessary, a blood/fluid warmer can be used according to the manufacturer’s directions and 
following institutional SOPs.  The return line should be connected to the blood warmer and 
primed prior to use.  The blood warmer cannot be used as a rapid infusion device (RID). 
Typically, anticoagulant citrate dextrose, Formula A (ACD-A) is used for therapeutic apheresis.  
Custom anticoagulant may be used and should be defined by the prescribing physician based on 
the subject’s medical need. 
A commercially available 10 L Waste Bag and Plasma Transfer Set will be provided and used to 
pool procedure waste material into one container to alleviate manual combining of multiple 
waste containers at the end of the procedure.    
A sample of the hematocrit and plasma hemoglobin of each replacement RBC unit will be taken 
prior to transfusion and recorded.  The replacement RBC unit parameters listed in Table 5 will be 
recorded.  All units should be sickle cell trait negative, leukoreduced, ABO type and Rh (D) 
compatible, and meet institutional requirements for transfusion. 

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8.1 
Subject Evaluations 
For each subject enrolled, the date of birth, age, sex, height, weight, ethnicity, race, primary 
sickle cell diagnosis requiring RBCx, and concomitant medications taken up to seven (7) days 
prior to the procedure and during the procedure will be documented.  A pregnancy test will be 
performed on women with childbearing ability prior to the start of the procedure.  In addition, the 
following study evaluations will be assessed in each subject pre- and post-procedure:  vital signs 
(blood pressure, temperature, pulse, and respirations), CBC, plasma hemoglobin, and a 
hemoglobin profile.  Subjects requiring RBC Depletion/Exchange will have post-depletion phase 
vital signs taken and CBC and plasma hemoglobin samples drawn as well.  Post-procedure and 
post-depletion phase sampling must be taken from the inlet line.  Blood samples shall be 
collected in appropriate laboratory tubes per institutional SOPs.  As needed, a three-way 
stopcock may be utilized to facilitate subject sampling.   
Routine pre-procedure testing (e.g., type and cross-match, Hb S, and Hct) may be performed per 
institutional SOPs; however, a day-of-pre-procedure study CBC and Hb profile must be 
obtained.  The Hb S and Hct values from the routine pre-procedure visit sample(s) may be used 
to calculate pre-procedure input values; once the day-of-procedure results are available, the 
Sponsor will compare the Hb S and Hct input values to the day-of-procedure Hb S and Hct 
values to establish procedure evaluability.  Routine pre-procedure testing data used for pre-
procedure input values are listed in Table 2; subject evaluations are listed in Table 3. 
Pre- and post-procedure samples and waste material should utilize the same local 
methodology/equipment (e.g., cell counter, scale) for the samples.  Plasma hemoglobin samples 
will be prepared, frozen, and shipped to a central laboratory following Sponsor requirements.  
Adverse events will be monitored during the procedure and assessed approximately 18-24 hours 
post-procedure.  
Table 2. ROUTINE PRE-PROCEDURE TESTING DATA 
Parameter 
Pre-procedure 
Actual Hemoglobin S value used for FCR calculation  
X 
Target Hemoglobin S value used for FCR calculation  
X 
Hematocrit value 
X 
Sample Date 
X 
Sample Time 
X 
 
Table 3. SUMMARY OF SUBJECT EVALUATIONS  

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Parameter 
Pre-procedure 
End of Depletion 
Phase1 
Post-procedure2 
Subject  
Primary Diagnosis 
X 
-- 
-- 
Date of Birth 
X 
-- 
-- 
Age5 
X 
-- 
-- 
Sex 
X 
-- 
-- 
Ethnicity 
X 
-- 
-- 
Race 
X 
-- 
-- 
Weight 
X 
-- 
-- 
Height 
X 
-- 
-- 
Medications taken day of 
procedure and up to 7 days 
prior  
X 
-- 
-- 
Vital Signs 
Blood Pressure 
X 
X 
X 
Temperature 
X 
X 
X 
Pulse 
X 
X 
X 
Respiration Rate 
X 
X 
X 
Laboratory 
White Blood Cell Count3 
X 
X 
X 
Red Blood Cell Count3 
X 
X 
X 
Platelet Count3 
X 
X 
X 
Hematocrit3,7 
X 
X 
X 
Plasma Hemoglobin4  
X 
X 
X 
Hemoglobin A3 
X 
-- 
X 
Hemoglobin S3 
X 
-- 
X 
Hemoglobin C3 
X 
-- 
X 
Hemoglobin F3 
X 
-- 
X 
Pregnancy Test3 
X 
-- 
-- 
Adverse Events 
During the procedure and approximately 18-24 hours post-
procedure6 
1Applicable for RBC Depletion/Exchange procedure 
2If performing reinfusion, the operator must draw the post-procedure sample before reinfusion is 
performed.  If reinfusion is not performed, the sample must be taken within approximately 10-15 minutes 
after the end of the procedure. 
3 Study Test performed locally according to institutional SOPs. 

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Parameter 
Pre-procedure 
End of Depletion 
Phase1 
Post-procedure2 
4Test performed at central  laboratory. 
5Age at signing of informed consent will be reported. 
6Post-procedure assessment will be performed via telephone.  
7 Automated. 
8.2 
AMICUS RBCx Procedures 
8.2.1 RBC Exchange Procedure 
The operator will select RBC Exchange on the AMICUS display.  A sample for testing each RF 
RBC unit should be taken prior to attaching to the kit (refer to Table 5).  After the kit is installed, 
and primed, the subject and the RF units will be connected to the kit following institutional 
SOPs; the pre-procedure samples should be drawn and the procedure will start.  Anticoagulated 
whole blood will be drawn through the inlet line and separated in the separation chamber of the 
centrifuge pack.  RBCs, some plasma, WBCs, and platelets will be removed and transferred to 
the kit’s waste container.  The waste blood should be pooled in the 10 L Waste Bag.  The plasma 
exiting the centrifuge will be combined with healthy donor RBCs and will be returned to the 
subject.  The procedure will continue until the prescribed procedure targets are reached and the 
AMICUS will automatically stop.   
The procedure may be ended with or without reinfusion.  If reinfusion is desired, the operator 
must draw the post-procedure blood sample before reinfusion is performed or the procedure will 
be non-evaluable.  If reinfusion is not performed, the blood sample must be taken from the 
subject within approximately 10-15 minutes after the end of the procedure.  Post-procedure 
samples must be drawn from the inlet line.  
After the procedure is complete, the subject will be disconnected and appropriate hemostasis care 
will be provided according to institutional SOPs. 
The 10 L Waste Bag should be disconnected and aseptically sealed using the attached cap. 
8.2.2 RBC Depletion/Exchange Procedure 
The operator will select the RBC Depletion/Exchange procedure on the AMICUS display.  A 
sample for testing each RF RBC unit should be taken prior to attaching to the kit (refer to 
Table 5).  After the kit is installed and primed, the RF (i.e., crystalloid/colloid solutions) may be 
attached.  The subject will be connected to the kit following institutional SOPs, the pre-
procedure samples should be drawn, and the depletion phase will start.  Anticoagulated whole 
blood will be drawn through the inlet line and separated in the separation chamber of the 
centrifuge pack.  RBCs, some plasma, WBCs, and platelets will be removed and transferred to 
the kit’s waste container.  The waste blood should be pooled in the 10 L Waste Bag.  The 
depletion phase will continue until the Target Depletion Hematocrit limit is reached.  A post-

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depletion blood sample from the subject must be taken prior to the start of the exchange phase.  
The post-depletion sample must be drawn from the inlet line.  Once the Depletion phase is 
completed, the replacement fluid should be changed to the physician prescribed RF for the 
exchange phase.  The procedure will continue with the exchange phase and will end once the 
procedure targets have been reached.   
The procedure may be ended with or without reinfusion.  If reinfusion is desired, the operator 
must draw the post-procedure blood sample before reinfusion is performed or the procedure will 
be non-evaluable.  If reinfusion is not performed, the blood sample must be taken from the 
subject within approximately10-15 minutes after the end of the procedure.  Post-procedure 
samples must be drawn from the inlet line.  
After the procedure is complete, the subject will be disconnected and appropriate hemostasis care 
will be provided according to institutional SOPs. 
The 10 L Waste Bag should be disconnected and aseptically sealed using the attached cap. 
Table 4. SUMMARY OF PROCEDURE EVALUATIONS 

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Parameter Description 
Pre-procedure 
Input/ 
Estimator 
Values 
End of 
Depletion 
Phase Values2 
End of 
Exchange 
Procedure 
Values 
Procedure Performed 
(RBC Exchange, RBC Depletion/Exchange) 
X 
-- 
-- 
Venous Access Used 
X 
-- 
-- 
Replacement Fluid Used2 
X 
-- 
-- 
Total Blood Volume 
X 
-- 
-- 
Fraction Cells Remaining  
X 
-- 
X 
Subject Hematocrit1 
X 
-- 
-- 
End Hematocrit1 
X 
-- 
X 
Depletion Hematocrit2 
X 
X 
-- 
Average Replacement Fluid Hematocrit 
X 
-- 
-- 
Replacement Volume to Subject 
X 
-- 
X 
Fluid Balance 
X 
X 
X 
Maximum Whole Blood Flow Rate 
X 
-- 
X 
AC Ratio 
X 
-- 
-- 
Whole Blood Flow Rate 
X 
-- 
X 
Procedure Time 
X 
X 
X 
Anticoagulant to Subject 
X 
X 
X 
Anticoagulant Used 
X 
X 
X 
Other Replacement Fluid 
X 
-- 
-- 
Depletion Red Cell Volume2 
X 
-- 
-- 
Anticoagulant Type 
X 
-- 
-- 
Citrate Infusion Rate  
X 
-- 
X 
Reinfusion  
X 
 
 
Was prime diverted? 
X 
-- 
-- 
Custom Prime 
X 
-- 
-- 
Start Prime Hematocrit 
X 
-- 
-- 
End Prime Hematocrit 
X 
-- 
-- 
Whole Blood Processed  
-- 
X 
X 
Plasma Returned3 
-- 
X 
-- 

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Saline to Subject  
-- 
X 
X 
Replacement Fluid Albumin Returned 
-- 
X 
X 
Replacement Fluid RBC Returned 
-- 
-- 
X 
Replacement Fluid Saline Returned 
-- 
X 
X 
Custom Replacement Fluid Returned 
-- 
X 
X 
Was reinfusion performed? 
-- 
-- 
X 
End Time (Procedure Completed) 
-- 
-- 
X 
Device Alarms 
During the Procedure 
Device Malfunctions 
During the Procedure 
1For RBC Depletion/Exchange, the RBC Depletion subject  hematocrits pre-procedure 
and at the completion of the depletion phase  (Depletion Hematocrit) will be measured.  
The RBC Depletion Hematocrit may be used as the starting hematocrit for the RBC 
Exchange phase. 
2Applicable for the RBC Depletion/Exchange Procedure. 
3Plasma with anticoagulant.  Applicable for RBC Depletion/Exchange Procedure. 
 
Table 5. SUMMARY OF REPLACEMENT RBC UNIT PARAMETERS 
Parameter 
Pre-procedure 
Type of RBC Unit1 
X 
ABO Type  
X 
Unit Identification Number 
X 
Date/ Time Sample Drawn 
X 
Hematocrit 
X 
Volume 
X 
Plasma Hemoglobin 
X 
Confirmation of Sickle Trait Negative 
X 
Confirmation of Leukoreduction 
X 
Confirmation of Rh (D) Compatibility 
X 
RBC Unit Expiration Date 
X 
1Additive Solution (AS) RBCs, CPD RBCs, CP2D RBCs, CPDA-1 
RBCs, Washed RBCs, Other 

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8.3 
Waste Material Procedure 
Waste material should be in a single container prior to sampling.  Pooling into a 10 L Waste Bag 
may be necessary.  The bag containing the waste material should be weighed to calculate the 
volume removed.  Care should be taken to ensure that the waste bag is folded and placed 
appropriately on the top loading scale to avoid inaccurate readings.     
The waste material should be manually mixed well, taking care not to induce hemolysis. The 
sampling port on the 10 L Waste Bag should be flushed carefully prior to removing the sample to 
ensure a representative sample.  A representative sample from the waste material should be 
drawn and used for testing.  The remaining waste material and waste bag(s) should be discarded 
as biohazardous material according to institutional SOPs.  
For RBC Depletion/Exchange procedures, the waste material from the depletion phase of the 
procedure should be collected separately from the waste material collected from the exchange 
phase of the procedure.  A new container and a transfer set or comparable tubing set should be 
used.   
Table 6. WASTE MATERIAL EVALUATIONS 
Parameter 
End of Depletion Phase1 
Post-Exchange Phase 
Gross Weight 
X 
X 
Container Tare Weight 
X 
X 
Hematocrit2 
X 
X 
Platelet Count 
X 
X 
White Blood Cell Count 
X 
X 
1Applicable for RBC Depletion/Exchange procedure only. 
2Automated 
8.4 
Appropriateness of Measures 
Test measurements employed are standard in the industry or validated research methods. 
8.5 
Study Completion 
The Sponsor considers the study complete after the last observation (last test completed). 
8.6 
Site Closure 
The Sponsor considers the site closed after the collection of the final data/data clarification and 
closure of all queries, EC/IRB has been notified, and the Sponsor has completed the Site 
Closeout Visit. 

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8.7 
Discontinuation 
Details of discontinuation of subjects or the site may include, but are not limited to:  
• Failure of the investigator to comply with the study protocol, regulatory requirements, 
Good Clinical Practices (GCP) guidelines or other study provisions. 
• Safety concerns. 
• Inadequate study subject enrollment by the investigator. 
8.8 
Study Termination 
Site closure or study termination may be decided at any time by the Sponsor or site investigator, 
provided there is reasonable cause and/or sufficient notice is given in advance of the intended 
withdrawal, e.g., safety concerns. 
9 
DESCRIPTION OF DEVICE 
9.1 
AMICUS RBCx System 
The AMICUS Separator is an FDA cleared (and CE marked) centrifuge-based apheresis system 
that will contain investigational software capable of performing a new RBCx operating protocol 
comprised of similar types of procedures based on the prescribed RF:  RBC  Exchange and 
RBC Depletion/Exchange.  The AMICUS Separator is able to collect blood components of 
interest and return RF and the remaining blood components with saline and anticoagulant back to 
a patient.  The new RBCx operating protocol is an extension of the intended use for the 
AMICUS Separator System.  RBCx builds on processes that are already cleared for the 
AMICUS device system including RBC separation and collection, fluid return while maintaining 
fluid balance, and control and delivery of anticoagulant solution.  The system already has proven 
capability in separating and collecting RBCs (in conjunction with a platelet collection, 
BK000039) with appropriate control and delivery of anticoagulant solution.  The RBCx System 
is a continuous-flow process that utilizes the same hardware, technological characteristics and 
disposable kit (AMICUS Exchange Kit) as the cleared AMICUS TPE procedure (K111702).  A 
new disposable waste transfer set has been developed to allow the transfer of removed RBCs 
from the smaller waste container on the front right scale hook to the two larger waste containers 
located on the side hook of the AMICUS Separator.  An additional volume of the AMICUS 
Operator’s Manual, Volume 5, RBCx (REC-009200) is available.   
In general, whole blood is drawn from the patient, anticoagulated, and centrifuged in the 
AMICUS Separator.  Separation occurs in the separation chamber of the centrifuge pack, while 
the collection chamber is filled with saline during prime and serves as balance for the separation 
chamber.  The WBCs, RBCs, platelets, and plasma are separated in the kit’s separation chamber.  

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The RBCs, some plasma, WBCs, and platelets are transferred to the waste containers.  
Anticoagulated plasma is mixed with the RF (healthy RBCs or albumin/saline) and pumped back 
to the patient.  
During the procedure, the instrument uses weight scales and pumps to accurately track the RBC 
volume that has been removed from the patient and monitor the volume of RF or RBCs that have 
been returned.  The AMICUS Separator uses algorithms to maintain appropriate hematocrit and 
fluid balance and achieve the desired volume exchange.   
The RBCx software version is investigational; the AMICUS Separator containing the 
investigational software will be labeled in accordance with 21CFR 812.5.  The AMICUS 
Exchange Kit and waste transfer set will also be labeled investigational. 
A plastic overlay found on the top panel traces the replacement fluids, solutions, and blood paths 
and provides a visual aid during kit installation. 
9.2 
Intended Use 
The AMICUS Separator, a blood component separator, is intended for use in therapeutic 
apheresis applications, and may be used to perform Red Blood Cell Exchange, Depletion, and 
Depletion/Exchange (RBCX) procedures. 
This protocol is limited to the use of the RBC Exchange and RBC Depletion/Exchange 
procedures. 
9.3 
Indications for Use 
The AMICUS Separator, a blood component separator, can be used to perform Red Blood Cell 
Exchange (RBCx) procedures for the transfusion management of Sickle Cell Disease in adults 
and children.   
9.4 
Contraindications for Use 
There are no known contraindications for use of the AMICUS Separator except those associated 
with the infusion of solutions and replacement fluids as required by the apheresis procedure, and 
those associated with all types of automated apheresis systems.   
Use of the AMICUS Separator is contraindicated in those cases where adequate anticoagulation 
cannot be achieved.  

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9.5 
Materials and Supplies 
An AMICUS Operators Manual, Volume 5, RBCx (REC-009200) will be provided.  Also, the 
cleared AMICUS Operator’s Manual, Volume 1, Operation Basics (07-19-07-291) will be 
provided.  This volume provides information for the general care and use of the AMICUS 
Separator System. All information on traceability of materials (i.e., lot numbers) will be 
documented. 
9.5.1 Investigational Materials 
The following investigational materials are intended for use in this study: 
• FDA cleared AMICUS Separator, Codes 4R4580 or 4R4580R with investigational 
Software Version 5.0.  FTX1708.   
 The AMICUS Separator includes spool (PN# 0112682396) and spool 
holder (PN# A10418001 C) cleared for use in TPE procedures.  
• AMICUS Exchange Kits, Code R4R2339 cleared for use in TPE procedures will be 
labeled as clinical inventory with FTX1709.  The cleared kit is labeled, “For Therapeutic 
Plasma Exchange (TPE) Procedure,” and as such, use of the kit in the evaluation of the 
RBCx System is a new indication for use.  
• AMICUS Waste Transfer Set FTX 1707, Lot #XXXX, Qty XX 
• AMICUS Separator Operator’s Manual, Volume 5, RBCx (REC-009200) 
9.5.2 FDA Cleared Materials  
The following FDA cleared materials intended for use in this study may include, but are not 
limited to: 
• Blood Component Filter Set with Vented Spike and Luer Adapter, R4C2170 or 
equivalent 
• Plasma Transfer Set, Code 4C2240 or equivalent 
• Apheresis needle with Masterguard Protector, Code 4R2441 or equivalent 
• Replacement RBC Units: Additive Solution (AS) RBCs, CPD RBCs, CP2D RBCs, 
CPDA-1 RBCs, Washed RBCs, other, or comparable as defined by the prescribing 
physician based on the subject’s medical need. 
• 0.9% Sodium Chloride for Injection USP 1L, Code 2B1324X or equivalent 
• Anticoagulant Citrate Dextrose Solution (ACD) USP Formula A, 1L, Code 4B7891X or 
comparable; custom anticoagulant may be used and should be defined by the prescribing 
physician based on the subject’s medical need. 
• Transfer Pack, any size or code as needed 
• Product Sample Packs, Code 4R2335H or equivalent 

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• Sampling devices or equivalent 
• Terumo Sterile Connection Device SCD 312 or equivalent 
• Sebra Tube Sealer or equivalent 
• Sample Sites, Code 1C8333 or equivalent 
• Fresenius Kabi 10 L Waste Bag, Code 9006281 or equivalent 
• AMICUS Separator Operator’s Manual, Volume 1, Operation Basics, Product Number 
07-19-07-291 or equivalent 
 
9.6 
Labeling 
Appropriate labels for the following materials are included in Appendix B. 
• AMICUS Separator, FTX1708 
• AMICUS Exchange Kits, FTX1709 
• AMICUS Waste Transfer Set, FTX 1707 
• Exchange waste red blood cell material containers 
• Depletion waste red blood cell material containers 
9.7 
Method of Assignment to Experimental Article 
This study is non-randomized.  Each subject will complete one RBC Exchange or 
RBC Depletion/Exchange procedure using the AMICUS Separator. 
9.8 
Blinding/Randomization 
This study is non-blinded and non-randomized. 
10  RISK ANALYSIS 
The new RBCx operating protocol is an extension of the indications for use of the AMICUS 
Separator System.  RBCx builds on processes that are already cleared for the AMICUS Separator 
system including RBC separation and collection, fluid return while maintaining fluid balance, 
and control and delivery of anticoagulant solution.  The system already has proven capability in 
separating and collecting RBCs (in conjunction with a platelet collection, BK000039) with 
appropriate control and delivery of anticoagulant solution.  The RBCx System is a continuous-
flow process that utilizes the same hardware, technological characteristics, and disposable kit as 
the cleared AMICUS TPE procedure (K111702).  Although testing of the investigational 

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software has been performed in pre-clinical studies and target procedure parameters have been 
achieved, there is a possibility that the procedure may not achieve the desired results. 
10.1 Risks Associated with an Apheresis Procedure 
Risks and discomforts that are unique to apheresis procedures may occur.  Mild symptoms of 
hypocalcemia, such as finger or perioral discomfort (e.g., tingling), unusual smell or taste 
sensation, vibrations, muscle discomfort and/or headache, or paresthesia (abnormal sensation of 
the skin) may occur temporarily and are caused by citrate in the anticoagulant that is returned to 
the subject more rapidly than the subject can metabolize it.4  Study subjects will be monitored for 
signs and symptoms of hypocalcemia.  The return rate may be lowered, the procedure may be 
paused, or other medical interventions may be indicated by the physician if any of these 
symptoms occur.  Continued rapid administration of citrate anticoagulant may result in more 
severe evidence of citrate toxicity, including tetany, convulsions or in extremely rare occasions, 
cardiac arrest and death.  Other symptoms, although unlikely, may include skin redness, itching, 
hives, bronchospasm (difficulty breathing), and abdominal cramps. 
On rare occasions, there is a risk of hemolysis, air embolus, blood loss, or blood clotting.  In the 
rare occurrence of hemolysis during a one-time procedure, the subject may experience back pain, 
nausea, low blood pressure, excess of hemoglobin in the blood plasma, abnormal urine color, and 
impaired renal function.  With chronic therapy, it is possible that chronic hyper-hemolysis in 
sickle cell subjects may increase the potential for increased blood pressure, higher prevalence of 
leg ulcers, priapism, and increased pressure in the pulmonary arteries.7  Air infusion (infusion of 
>30 mL bolus of air) may interfere with the heart’s ability to pump blood from the right 
ventricle, may disrupt pulmonary blood flow with impaired blood oxygenation, reduce oxygen 
delivery to the tissues, low blood pressure, chest pain, shortness of breath, lack of oxygen to 
body tissue, or death (Sponsor’s Therapeutics Hazardous Situations and Harms Analysis, 123-
RSK-022188).  In the rare occurrence of the procedure causing blood clotting during the 
procedure, the subject may experience severe effects such as stroke, heart attack, kidney 
problems, or deep vein thrombosis (causing pain, swelling in the affected limb, or redness).  In 
the case of deep vein thrombosis, it is possible for the clot to break off, travel to the lungs, and 
cause pulmonary embolism.  It is important to note that sickle cell subjects are genetically 
predisposed to the risk of blood clotting.  Investigators treating sickle cell subjects should be 
aware that such patients are at increased risk for blood clots, especially pulmonary embolism.8  
Apheresis technology is designed to monitor for the presence of air, hemolysis, leaks or blockage 
in the disposable kit during the procedure.  The redundant monitoring systems and all the safety 
features of the AMICUS are the same as in the previously FDA cleared platelet, with concurrent 
plasma, and/or red blood cell collection, MNC, and TPE procedures. 

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There are known potential side effects associated with transfusion of blood components that are 
similar when these components are employed during RBCx procedures.  Blood components can 
result in transmission of infectious agents, even though donated blood is extensively tested.3  
Subjects will be closely monitored throughout the procedure for any discomfort that may result 
in more serious reactions such as muscle twitching, convulsions, or in extremely rare occasions, 
cardiac arrest and death.  Subjects will be asked to report any adverse events that they are 
experiencing during the procedure and approximately 18-24 hours post-procedure. 
Although the kit, needles, catheters, and CVAD lines that are used are sterile and proper aseptic 
technique is employed, in rare cases infection or inflammation may occur. CVADs and lines may 
also have access complications due to clotting.  A transient decrease in cell counts may occur.  
Decreased coagulation factor concentrations in subjects may occur depending on the RF(s) used 
and the frequency of therapeutic procedures.  
Although testing of the investigational software has been performed during in vitro and in vivo 
preclinical studies in healthy subjects and target fluid balance has been achieved, there is a 
possibility that during the procedure inadequate or excess fluid may be given resulting in 
hypovolemia or hypervolemia.  When blood loss is greater than 15% of the total blood volume, 
symptoms of hypovolemia may develop resulting in changes to cardiac output, vascular tone, 
arteriolar contraction leading to reduced blood flow to skin and muscles, and other compensatory 
metabolic and endocrine responses.  When blood loss is greater than 30% of the total blood 
volume, the majority of subjects will experience circulatory shock due primarily to hypovolemia.  
Hypovolemia can also occur as a result of too little fluid in the body and may cause the subject to 
experience rapid heart rate, dizziness upon standing, narrow pulse pressure, apprehension, 
weakness, nausea, lightheadedness, pallor, thirst, cool skin, and even loss of consciousness.6  
Hypervolemia may occur as a result of too much fluid in the body.  Most subjects will pass the 
excess fluid through their urine; however, subjects with compromised cardiac, pulmonary, and/or 
renal function may not be able to efficiently complete this process.  If they are unable to excrete 
the excess fluid, it is possible that the fluid may enter the subject’s lungs, making it difficult to 
breathe.  These risks may be greater in subjects with SCD since the disease affects the blood’s 
ability to carry oxygen throughout the body; this is especially notable in subjects of lower weight 
(< 40 kg).  To mitigate the risks of fluid imbalance, investigators will ensure subjects are 
medically stable and should not enroll subjects with compromised cardiovascular or multiple 
organ diseases who may not tolerate the apheresis procedure.  Furthermore, the subject’s fluid 
balance is shown in real-time on the AMICUS procedure display and the operator will monitor 
the subject’s fluid balance during the procedure.  The physician will prescribe the appropriate 
volume of RF as clinically indicated.   

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Concomitant medication seven days prior to and during the procedure will be documented.  
Adverse events during the procedure and approximately 18-24 hours post-procedure will be 
recorded and standard institutional SOPs will be followed to treat subjects who may develop 
adverse events.  
An alternate option for the subject would be not to participate in this study and continue RBCx 
therapeutic treatments using a commercially available device. 
10.2 Risks to Pediatric Subjects 
In addition to the apheresis and investigational procedure risks, there may be risks that affect 
pediatric subjects greater than adult subjects.  Maintaining constant fluid balance is important for 
safe apheresis procedures in pediatric subjects.9  When the volume of blood loss is fixed, the 
degree of blood loss is greater in a child than an adult and the effects of fluid and blood loss 
(listed in Section 10.1 Risk Associated with an Apheresis Procedure) on the circulatory system 
are greater in a child than an adult.  
The Sponsor’s Therapeutics Hazardous Situations and Harms Analysis (123-RSK-022188) 
includes analyses of the AMICUS Separator that evaluated potential harms of fluid imbalance 
resulting from blood loss and the inappropriate or inadequate infusion of electrolyte or colloid 
solution replacement fluids (e.g., 0.9% sodium chloride or Ringer’s lactate, or colloids, such as 
albumin solution or fresh frozen plasma).  Adjustment of values specific for pediatric patients 
were made based on weight comparisons between patients (45 kg) and pediatric patients (10 kg).  
The analysis shows that blood loss at different volumes for pediatric patients will vary from 
experiences of transient hypovolemia, hypotension, occasional lightheadedness, and occasional 
temporary loss of consciousness to more serious effects as decreased cardiac output, significant 
circulatory impairment with possible organ damage, hypovolemic shock, shortness of breath, 
severe shock, tissue hypoxia, brain damage, cardiac arrest, and death with greater blood loss 
(>25% loss of blood volume for a pediatric patient).  Infusion of excess (>220 mL of 
electrolyte/colloid solution in addition to the normal replacement volume) or inadequate 
replacement fluid can lead to hypervolemia and transient hypovolemia, respectively, with the 
degree depending on the volume and type(s) of fluid infused.  However, the significant effect of 
hypervolemia is unlikely unless cardiovascular status is compromised.  
To mitigate the risks of fluid imbalance, investigators will ensure pediatric subjects are medically 
stable and should not enroll subjects with compromised cardiovascular or multiple organ 
diseases who may not tolerate the apheresis procedure.  Furthermore, the subject’s fluid balance 
is shown in real-time on the AMICUS procedure display and the operator will monitor the 
subject’s fluid balance during the procedure.  The physician will prescribe the appropriate 
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The pediatric subject’s peripheral veins may not be able to accommodate the size of needles 
necessary for RBCx and therefore may require CVAD lines for adequate flow.  Although proper 
aseptic technique is employed, this may cause infection, thrombosis, or other serious 
complications.  In this study, vascular access will be established as clinically indicated by the 
physician. 
The Sponsor’s Hazards and Harms Analysis (123-RSK-022188) includes all risks associated 
with the RBCx Investigational Device in adult and pediatric subjects.   
10.2.1 Risks Associated with Use of the RBCx Investigational Device 
The Sponsor has completed a Hazards and Harms Analysis (123-RSK-022188) of all risks 
associated with the AMICUS RBCx intended use.  The analysis includes:5   
• Potential loss of blood due to leaks 
• Thrombosis due to activation of factors by foreign surfaces 
• Moderate to severe toxic reaction to citrate anticoagulant (e.g., tetany, seizures, cardiac 
arrhythmias) 
• Damage to RBCs, activation of complement, and denaturation of proteins. 
• Potential for sepsis and fever due to bacterial contamination of the subject’s returned 
blood. 
• Infectious disease risk to the subject or to the operator due to leaks. 
• Electrical shock hazard. 
• Subject stress reaction due to removal or loss of blood. 
• Air embolism 
• Hemolysis 
Safety levels for all apheresis-related hazardous situations have been established in alignment 
with currently accepted industry practice and regulations; these levels have been approved 
through a cross-functional review including a physician.  The Sponsor’s documented design and 
development processes include risk management activities that assess the probability of these 
hazardous situations, and risk controls are established to maintain device safety.  The device is 
verified to maintain performance within these established safety limits, with results of the 
verification and risk management activities reviewed through a formal cross-functional design 
review prior to first human use release.  All changes to the device go through the same process of 
analysis, risk management, verification, and review prior to human use. This process ensures that 
the original device and all subsequent modifications to the device, do not present unacceptable 
risks to the subject.  

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These special controls when combined with general controls (e.g., Good Manufacturing Practice) 
should mitigate risks associated with the use of the AMICUS Separator with the RBCx software. 
The AMICUS instrument hardware including exchange spool and spool holder, disposable 
AMICUS Exchange Kit, and Blood Component Filter Set with Vented Spike and Luer Adapter 
to be used in the study were previously cleared by the FDA for AMICUS TPE procedures.   
10.3 Demographic Risks 
The Sponsor acknowledges the importance of heterogeneity across sex groups in study design 
and interpretation of primary endpoints.  Because beta and alpha globin mutations are located on 
chromosomes 11 and 16 respectively, and follow the Mendelian laws of genetics for a recessive 
mutation, the use of the RBC Exchange and RBC Depletion/Exchange in treatment of SCD is not 
sex associated.  Non-sex limited diagnoses prompting RBC Exchange and 
RBC Depletion/Exchange are found to occur in equal frequency.  Additionally, based on the 
subject evaluation parameters, the AMICUS Separator utilizes programmed algorithms for age 
and sex-related blood volumes.  Therefore, sex enrollment will not be pre-specified.  Even 
though no substantial sex difference is expected, the variability in data across sex groups and its 
interpretation will be considered.  Demographic information, including sex, will be collected and 
included in the summary statistics.  
11 SAFETY EVALUATIONS 
11.1 Adverse Events 
Each subject will be monitored for signs of adverse events (AEs) and will be asked to provide 
input as to his/her condition.  AEs occurring during the procedure and approximately 18-24 
hours post-procedure will be recorded and standard procedures will be followed to treat subjects 
who may develop adverse events.  Up to two attempts to contact the subject by phone will be 
made approximately 18-24 hours post-procedure.  If the site is unable to contact the subject, a 
certified letter will be sent and the subject will be lost to follow up; however, they will remain 
evaluable if all other evaluability criteria are met. 
AEs will be recorded per Adverse Event Reporting, SOP CLA02011, current issue.  All serious 
adverse events (SAEs) will be recorded per Serious Adverse Event Reporting, SOP CLA02012, 
current issue.  
SAEs and unanticipated device effects (UADEs) related to the device or to study participation 
will be reported to the EC/IRB and the Sponsor within FDA-specified guidelines. 
An AE is defined as any undesirable experience occurring to a subject during a clinical trial 
whether or not it is considered related to the experimental article.  

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An adverse device effect (ADE) is an AE related to the use of an investigational medical device.  
11.2 Event Severity 
The AE will be graded as mild, moderate, or severe.  For purposes of consistency, these intensity 
grades are defined as follows: 
ADVERSE EVENT GRADING CRITERIA 
Grade 
Definition 
MILD 
Causing no limitation of usual activities.  Asymptomatic or mild 
symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
MODERATE 
Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). Causing 
some limitation of usual activities. 
SEVERE 
Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL.  Causing inability to carry out usual activities. 
 
11.3 Episode Pattern 
The episode pattern of the AE shall be classified as: 
EPISODE PATTERN CRITERIA 
Pattern 
Definition 
SINGLE 
The AE occurred one time during use of the investigational device. 
INTERMITTENT 
The AE occurred two or more times with or without intervention. 
CONSTANT 
The AE continued consistently during use of the investigational 
device. 
11.4 Action Taken (Procedure) 
During the use of the investigational device, an AE may require that some action regarding the 
procedure be taken.  The action taken may be: 
1. No change 
2. Interrupted 
3. Permanently Discontinued 
4. Change in procedure parameter(s) 

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11.5 Action Taken (Subject) 
Any treatment or intervention performed for the subject in response to an AE should be 
documented and an explanation of the intervention provided in the Comment Section. 
11.6 Relationship to Device  
Any AE will be graded to its relationship to the device.  For purposes of consistency these grades 
are as follows: 
ADVERSE EVENT RELATIONSHIP CRITERIA 
Relationship 
Definition 
NOT RELATED 
The adverse event can be reasonably attributed to another cause and 
can be considered unrelated to the study device. 
UNLIKELY 
RELATED 
The relationship may or can exist, but other factors may make 
interpretation difficult.  If the relationship cannot be ruled out, it 
must be considered possible. 
1. It may or may not show a reasonable temporal sequence 
from use of the device. 
2. It is likely produced by the subject’s clinical condition, 
environmental or toxic factors, or other modes of therapy 
administered to the subject, however use of the device 
cannot be ruled out. 
3. It may follow a known or anticipated response pattern to the 
suspected device. 
POSSIBLY 
RELATED 
There is a suggestion of the relationship between use of study 
device and the adverse event, supported generally, but not 
conclusively, by the evidence. 
1. It follows a reasonable temporal sequence from use of the 
device. 
2. It could not be reasonably explained by the subject’s 
clinical condition, environmental or toxic factors, or other 
modes of therapy administered to the subject. 
3. It follows a known or anticipated response pattern to the 
suspected device. 
RELATED 
There is a strong relationship to the use of the study device, which 
may or may not stop upon discontinuation of the study device use 
and may reoccur if the subject is re-exposed to the device. 

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11.7 Relationship to Procedure  
Any AE will be graded to its relationship to the procedure.  For purposes of consistency these 
grades are as follows: 
ADVERSE EVENT RELATIONSHIP CRITERIA 
Relationship 
Definition 
NOT RELATED 
The adverse event can be reasonably attributed to another cause and 
can be considered unrelated to the procedure. 
UNLIKELY 
RELATED 
The relationship may or can exist, but other factors may make 
interpretation difficult.  If the relationship cannot be ruled out, it 
must be considered possible. 
1. It may or may not show a reasonable temporal sequence 
from the procedure. 
2. It is likely produced by the subject’s clinical condition, 
environmental or toxic factors, or other modes of therapy 
administered to the subject, however the procedure cannot 
be ruled out. 
3. It may follow a known or anticipated response pattern to the 
suspected procedure. 
POSSIBLY 
RELATED 
There is a suggestion of the relationship between use of study 
procedure and the adverse event, supported generally, but not 
conclusively, by the evidence. 
1. It follows a reasonable temporal sequence from use of the 
procedure. 
2. It could not be reasonably explained by the subject’s 
clinical condition, environmental or toxic factors, or other 
modes of therapy administered to the subject. 
3. It follows a known or anticipated response pattern to the 
suspected procedure. 
RELATED 
There is a strong relationship to the use of the procedure which may 
or may not stop upon discontinuation of the procedure and may 
reoccur if the subject is re-exposed to the procedure. 
 

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11.8 Outcome 
The outcome of the AE shall be documented using the following key: 
OUTCOME CRITERIA 
Outcome 
Definition 
RECOVERED 
The subject fully recovered from the AE without after-effect(s). 
RECOVERED WITH 
SEQUELA(E) 
The subject recovered from the AE with after-effect(s) subsequent to 
the AE. 
CONTINUING 
The adverse event continued after the procedure was completed. 
DEATH 
Death due to this AE or other causes. 
11.9 Serious Adverse Events 
A serious adverse event (SAE) is any adverse event that results in any of the following 
outcomes: 
• Death 
• Life-threatening 
• Disability or permanent damage 
• Hospitalization (initial or prolonged) 
• Congenital anomaly/birth defect 
• Other serious (important medical event) 
• Required intervention to prevent permanent impairment or damage (Devices) 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed.   
Unanticipated adverse device effect (UADEs) is any serious ADE on health, safety or 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 study 
protocol, or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 

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All SAEs and UADEs must be reported to the Applied Product Testing Site Management (APT 
SM) within 24 hours after onset or identification of an event. 
12 DATA QUALITY ASSURANCE 
12.1 Data Reporting 
Sites must fax Screening and Enrollment Logs and redacted copies of source documents labeled 
with the subject’s Subject ID as soon as they become available and at least weekly to (847) 550-
2956 to allow the Sponsor to assess study enrollment and procedure evaluability.  
12.2 Data Capture System 
An electronic data capture (EDC) system will be used for data collection. 
12.3 Data Recording 
All data provided to the study Sponsor will be encoded to maintain study subject confidentiality.  
Subject related procedure and AE data will be entered onto worksheets that will serve as source 
data.   
All original laboratory data (such as laboratory test results, instrument print-outs, laboratory 
results, notebook entries, etc.) must be retained by the investigator or designee for a minimum of 
two years or as deemed by the Sponsor and be accessible by cross-reference to laboratory 
notebooks, hospital medical records, subject history summary, etc. 
12.4 Electronic Case Report Forms (eCRF) 
All entry of study data into the Electronic Data Capture (EDC) system will be performed by 
authorized and trained personnel from the study site, who will receive a secure login and 
password from the Sponsor.  Data will be entered from source documentation into the EDC 
system.  The EDC system will generate automatic queries defined in the Data Checks 
Specification document, as data are entered and saved in the EDC database.  Applied Product 
Testing Data Management (APT DM) may perform additional manual review of the data to 
ensure that data are within the pre-defined criteria and may generate manual queries as 
necessary. Applied Product Testing Statistician (APT Stats) and APT SM may also identify 
additional manual queries during the review of the data.  Authorized personnel from the site will 
need to address each query in a timely matter. 
After data are entered by the study site personnel, source data verification (SDV) will be 
performed by the Sponsor or Sponsor designee. APT SM will review responses to automated 

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electronic data checks.  Data that are changed after verification will be re-verified by APT SM 
until all pages are completely verified.  
At the completion of the study, the electronic data will be archived using a digital video disc 
(DVD). 
12.5 Monitoring Procedures 
The Sponsor will perform periodic centralized and remote monitoring, at least once prior to the 
interim report and at least once prior to the final report, in addition to the initiation and close out 
visits.  Additional site/monitoring visits may be performed as necessary.  The monitor's on-site 
visit will be recorded by the monitor on the Site Visit Log kept at each study site.  A site 
monitoring plan is available from the Sponsor upon the site's request. 
The monitor will compare data entered into the eCRFs with source documents (i.e., laboratory, 
hospital, or clinical records).  At a minimum, source documents must be available to substantiate 
subject identification, eligibility, proper informed consent procedure, visit dates, adherence to the 
protocol, adequate reporting, and follow up of all adverse events. Specific items required as 
source documents will be reviewed with the study staff prior to the study.  Discrepancies 
following the review of the eCRFs and source documents will be discussed with investigational 
personnel. 
The monitor will review study documents including, but not limited to, EC/IRB approvals and 
correspondence, ICF for completeness, compliance with 21 CFR 52, and to ensure the correct 
ICF version is being used.  The monitor will also ensure PI compliance and accountability of 
investigational inventory.  
The Sponsor expects that relevant study personnel, source documents and a suitable environment 
for review of study-related documents will be available to the monitor at the time of monitoring 
visits.  The monitor will communicate with the investigator periodically during the study to 
provide feedback on the study conduct. 
12.6 Maintenance of Records 
Documents that must be provided to the Sponsor prior to any site initiating the study include but 
may not be limited to: 
• Medical Device Agreement 
• Financial Disclosure and Arrangements of Clinical Investigator  
• Investigators Signed Protocol Signature Sheet  
• Study Site Personnel Curriculum Vitae (CVs) and Medical Licenses 

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• A copy of the EC/IRB-approved ICF and other adjunctive material (e.g., marketing 
flyers) to be used in the study, including written documentation of EC/IRB approval for 
these materials. 
• Name and address of the EC/IRB, a statement that it is organized and operates according 
to GCP and applicable laws and regulations or the Federal Wide Assurance (FWA) 
number and list of the EC/IRB's current members. 
12.7 Record Retention 
During or after the study, the appropriate regulatory agency may inspect study records at the 
investigational site.  Since inspection may arise at any time, records should be kept current at all 
times.  The Sponsor must be advised of any request by a regulatory agency to visit or inspect the 
site.  Records must be maintained for: 
a. A period of at least two years after the last approval of a marketing application in an ICH 
region when there are no pending or contemplated marketing applications in an ICH 
region. 
b. A period of at least two years after the formal discontinuation of development of the 
experimental article. 
These documents should be retained for a longer period of time if required by the applicable 
regulatory requirement(s) or if required by the Sponsor. 
13 STATISTICAL METHODS AND SAMPLE SIZE 
13.1 General Overview 
The RBC Exchange and RBC Depletion/Exchange procedures have the same therapeutic 
endpoint, FCR.  The RBC Depletion/Exchange procedure is a modification of the 
RBC Exchange procedure that automates the transition between the depletion phase and the 
exchange phase of the procedure. 
This is a multicenter, single-arm, open label study. Hypothesis testing will be performed to 
evaluate the primary objective of the 95% confidence interval around the mean ratio of actual to 
target FCR as measured by Hemoglobin S in the subjects pre- and post-procedure to a pre-
defined FCR range of 0.75 to 1.25. 
Hypothesis testing is not planned for secondary variables.  Summary statistics (mean, standard 
deviation, median, minimum, maximum and count) will be presented for continuous parameters 
with their 95% confidence limits as applicable.  Discrete parameters will be presented by total 
number and percentage.  A detailed statistical procedure will be outlined in the Statistical 
Analysis Plan. 

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Any change to the data analysis methods described in this protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the final study report. 
The overall study success for testing the hypothesis of equivalence is that the 95% confidence 
interval around the AMICUS mean ratio of the FCR actual to target is within the pre-defined 
range of 0.75 and 1.25.  
13.2 Determination of Sample Size 
Sample size determination is based on historical in vitro data from evaluable RBC Exchange and 
evaluable RBC Depletion/Exchange AMICUS procedures for the therapeutic endpoint of the 
mean ratio of FCR. The margin of 25% was chosen to allow for the known intrinsic variability of 
the RBCx procedure, principally in actual Hct of replacement RBCs, total blood volume of 
patients, Hb S assay and intraprocedure mobilization of RBCs.9  The sample size needed for the 
study design is given as:10 
N= 2(Z1-α + Z1-β)2 σ2  ÷ δ2 
Where Z1-α and Z1-β are the standard normal deviates corresponding to 1 minus significance 
level (α) and 1 minus the type II error (β) respectively, σ2 is the variance or squared standard 
deviation of the outcome and δ is the margin. 
Since we planned to have a 90% power at the 0.025 significance level to detect equivalence to a 
ratio of 1, then the sample size with the margin of 0.25 and observed standard deviation of the 
difference of 0.43 with β =0.10 will yield:10   
N= 2(1.96 +1.28)2 0.432 ÷ .252 = 2(10.4976) 0.185 ÷ 0.0625 = 62. 
Therefore, a sample size of 62 evaluable procedures will be used to demonstrate that AMICUS is 
within a margin of 25% with at least 95% (two sided) confidence and at least 90% power. 
13.2.1 Analysis Data Sets 
Formal hypothesis testing per the sample size statement will be performed for the primary 
endpoint across investigational sites including the all evaluable population.  This population is 
defined as those subjects who successfully complete the AMICUS Separator RBCx procedures 
and have all values for the primary endpoint calculation reported by the site.  The primary 
endpoint is calculated based on actual FCR as measured by Hb S in subjects pre- and post-
procedure as well as the target FCR.  Subjects will be analyzed as treated and missing values will 
not be imputed.   

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The primary analysis of the all evaluable population will establish that the analysis for the 
accuracy of the AMICUS Separator as measured by 95% confidence interval around the mean 
ratio of the FCR actual to target range is within the pre-defined range of 0.75 and 1.25.   
In addition, a second analysis of an Intent-to Treat (ITT) will be performed that will consist of all 
enrolled subjects.  Every effort will be made to obtain missing data.  The pre- and post-procedure 
Hb S values used to calculate the primary endpoint, Fraction of Cells Remaining, are laboratory 
measurements.  Several potential reasons for missing laboratory data include lost, broken, and 
mislabeled samples or technical issues.  Missing values in the primary endpoint are assumed to 
be a random event, since the fact that they are missing is unrelated to the measured parameter, 
Hb S.  The ITT analysis, will be analyzed imputing the missing value with the observed mean. 
A sensitivity analysis will also be conducted to evaluate the impact of the imputed missing data.  
Secondary objectives will be evaluated using RBC Exchange and RBC Depletion/Exchange 
summary statistics (mean, standard deviation, median, minimum, maximum, and count).   
13.2.2 Safety Analysis 
Safety measures that will be summarized in this study include subject and device related SAEs.  
Subject AEs will be recorded during each procedure and approximately 18-24 hours post-
procedure.  AEs will be presented using the Description of Event key on the Case Report Form 
(CRF).  Events classified as Other will be presented as verbatim terms.  AEs occurring multiple 
times per subject will be counted once for subject-reported frequencies, where the highest severity 
or least favorable relationship will be assumed.  The following adverse event analyses will be 
performed: 
• The frequency of subjects who reported AEs and the frequency of AEs reported by and 
across severity, seriousness, and relationship to study test article will be presented across 
and by investigational sites overall  
• The frequency of subjects who reported AEs and the frequency of AEs reported will be 
presented for each adverse event type across and by investigational sites overall.  
AEs will be presented for All Subjects Enrolled and Evaluable Subject populations.  The action 
taken with respect to the procedure, any action taken to treat the subject, and outcome will be 
recorded.  The adequacy of the performance of the AMICUS system during the RBCx procedure 
will be assessed through documentation of alarms or UADEs.  
13.3 Study Endpoints and Methodology 
The study endpoints include the primary and secondary objectives.  This is a multicenter, single-
arm, open label study.  Hypothesis testing will be performed to evaluate the primary objective of 

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the 95% confidence interval around the mean ratio of actual to target FCR as measured by Hb S 
in the subjects pre- and post-procedure to a pre-defined FCR.  
Hypothesis testing is not planned for secondary variables.  
The calculation for the primary endpoint ratio is given by the formula for the AMICUS Separator 
RBC Exchange and RBC Depletion/Exchange procedures in the efficacy evaluable subject 
population as  
𝑇𝑇𝑇𝑇𝑇𝑇 𝐹𝐹𝐹=
𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐸𝐸𝐸 𝐻𝐻𝑆 𝑉𝑉𝑉𝑉𝑉 (%)
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐻𝐻𝐻 𝑉𝑉𝑉𝑉𝑉 (%)  𝑥 100% 
 
𝐴𝐴𝐴𝐴𝐴𝐴 𝐹𝐹𝐹= 𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐻𝐻𝐻 𝑉𝑉𝑉𝑉𝑉 (%)
𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐻𝐻𝐻 𝑉𝑉𝑉𝑉𝑉 (%)  𝑥 100% 
 
The resultant ratio would be FCRa ÷ FCRt. 
A two-sided hypothesis test is given as:  
H0:  PT LL<0.75   and/or  PT UL>1.25 
Versus 
H1: 0.75 ≤ LL PT UL ≤ 1.25 
Where PT = the 95% CI for AMICUS mean ratio and LL = Lower limit and UL = Upper limit 
We will reject Ho at the alpha level of significance if the entire 95% confidence interval around 
the mean ratio is within the predefined range.  Stated explicitly, if the lower limit of the 95% 
confidence interval around the mean ratio is greater than or equal to the lower predefined range 
boundary (0.75) and simultaneously the upper limit of the 95% confidence interval around the 
mean ratio is less than or equal to the upper predefined range boundary (1.25). 
Summary statistics (mean, standard deviation, minimum, median, maximum, and count) of the 
RBC Exchange and RBC Depletion/Exchange procedure data will be used to evaluate the 
secondary objectives:  evaluation of the accuracy of subject End Hematocrit, accuracy of Fluid 
Balance, subject cellular loss post-procedure, and serious device related adverse events.    

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For the primary and secondary analyses, there are circumstances during an RBC Exchange or 
RBC Depletion/Exchange procedure that may cause one of the parameters to be non-evaluable.  
Procedures with these irregularities will not be evaluable for the affected procedure parameter. 
The overall study success for testing the hypothesis of equivalence is that the 95% confidence 
interval around the AMICUS mean ratio of the FCR actual to target is within the pre-defined 
range of 0.75 and 1.25.  Data from all sites will be pooled for the hypothesis test. Descriptive 
statistics will be presented for the primary endpoint ratio by site.   
A detailed statistical procedure will be outlined in the Statistical Analysis Plan.  All data analyses 
will be performed using SAS, Cary, NC version 9.4.  
13.4 Criteria for End of Study or Stopping Rules 
Upon completion of approximately 62 evaluable subjects the sites will be notified to stop 
enrollment. 
13.5 Evaluability Criteria 
• If the procedure is terminated prior to completion, the procedure is non-evaluable. 
• If reinfusion is performed, the post-procedure blood sample must be drawn prior to 
reinfusion during any study procedure. 
• The operator should not change the following parameters after the procedure start, 
Subject Hct, Avg RF Hct, or Total Blood Volume. 
• If a saline bolus is given during the procedure, END Hct is not evaluable.  
• The procedure is dependent on accurate input data.  
− If the mean of the measured hematocrit of the RF units transfused and the entered 
Avg RF Hct used differs by more than five (5) hematocrit points, then data for 
FCR and END Hct are non-evaluable.  
− If the subject hematocrit input value and the actual day of treatment pre-procedure 
hematocrit differs by more than five (5) hematocrit points, then data for FCR and 
END Hct are non-evaluable.  
− If the subject day of treatment pre-procedure Hb S value results in a calculated 
Target FCR that differs by more than six (6) FCR points from the entered Target 
FCR, then data for FCR is non-evaluable. 
All procedures performed during this study will be assessed for evaluability using the current 
criteria.  Parameter non-evaluability will not result in the procedure being non-evaluable for 
other analyses.  A detailed statistical procedure will be outlined in the Statistical Analysis Plan.  
All data analyses will be performed using SAS 9.4 Procedure Guide, Second Edition, Volumes 
1-4 (2013). 

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The primary endpoint will be assessed for the evaluable subject population in this study.  This 
population is defined as those subjects who successfully complete the AMICUS Separator 
procedures and values for all parameters of the RBC Exchange formula are reported (e.g. day of 
procedure pre- and post-procedure Hb S results are obtained) and all evaluability criteria are met.   
All other parameters will be analyzed with summary statistics (mean, standard deviation, 
median, minimum, maximum and count) presented for continuous parameters with their 95% 
confidence limits as applicable.  Discrete parameters will be presented by total number and 
percentage. 
13.6 Subject Disposition 
Subject disposition and reasons for study or study procedure discontinuation will be listed and 
summarized in the final report. 
13.7 Subject Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be collected and summarized in the final 
report.  
13.8 Interim Analysis 
An interim analysis is planned when approximately half the subjects are enrolled and will 
include summary statistics only, without Hypothesis Testing of the primary objective.  The 
interim report will summarize the details of the subjects enrolled, laboratory data, safety data, 
device related serious adverse events and results of the evaluable procedures. 
The investigational study will initially enroll up to 60 subjects who are 18 years of age and older 
to obtain approximately 31 evaluable procedures.  After approximately 31 evaluable subjects 
have completed the study, pre- and post-procedure safety data including vital signs (blood 
pressure, temperature, pulse, and respiration rate), hematology results, AEs including SAEs, and 
UADEs will be summarized for all subjects enrolled.  An independent DSMB composed of 
transfusion medical experts, including physicians familiar with RBCx treatment of patients will 
be established by the Sponsor for this study.  The DSMB will review summary statistics and 
reported subject safety data to determine if it is safe to begin enrollment in a pediatric 
population.  Following review by the DSMB, the interim report will be submitted to the FDA for 
review as an IDE supplement.  The supplement must be approved by the FDA prior to enrolling 
pediatric subjects six to 17 years old.  In addition to FDA approval, the results of the DSMB will 
be sent to the EC/IRBs to obtain approval to start with pediatric subjects.  
The interim report will be submitted to TÜV for the purpose of CE marking. 

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14 ADMINISTRATIVE RULES 
14.1 Investigator’s Responsibilities 
The study will be conducted in a manner designed to assure the acceptability of the data by 
regulatory authorities.  All investigators and sub-investigators, as defined in 21 CFR 54.2(d), are 
required to complete a Disclosure of Financial Interest supplied by the Sponsor.  This section 
contains a summary of investigator responsibilities that will help ensure the study is performed in 
compliance with regulations.  Specific mechanisms and procedures are described to maintain the 
compliance of both the investigator and the Sponsor. 
Certain events in the performance of the study require particular reports from the investigator 
within prescribed time frames.  Refer to Table 7 for a summary of the required investigators' 
reports. 
Table 7. REQUIRED REPORTS FROM INVESTIGATOR 

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Report 
Submit To 
Time 
Withdrawal of EC/IRB approval Sponsor 
Within 5 working days 
Progress Report(s) 
Sponsor  
EC/IRB 
Regular intervals (at least yearly) 
Deviation from protocol 
Sponsor  
EC/IRB 
As soon as it becomes apparent 
but no later than 5 working days 
Failure to obtain informed 
consent 
Sponsor  
EC/IRB 
As soon as it becomes apparent 
but no later than 5 working days  
Final Report 
(Completed Case Report Forms 
constitute a Final Report from 
Investigator) 
Sponsor 
EC/IRB 
Within 3 months after 
termination 
 
Both Serious and Unexpected 
Adverse Events 
21CFR 312.64 
 
Sponsor 
As soon as it becomes apparent 
but no later than 24 hours by 
telephone, facsimile or email 
EC/IRB 
As soon as it becomes apparent 
but no later than 10 working 
days 
Both Serious and Unexpected 
Adverse Device Events 
21CFR 812.150 
 
Sponsor 
As soon as it becomes apparent 
but no more than 24 hours by 
telephone, facsimile or email 
EC/IRB 
As soon as it becomes apparent 
but no later than 10 working 
days 
14.2 Confidentiality 
The investigator and his/her staff will agree to treat all aspects of the study in a confidential 
manner.  All documents and data pertaining to the study can only be released with the consent of 
the Sponsor or as required by federal or state law or authorized regulatory agencies.  Each 
investigator agrees to permit review of all pertinent data by the Sponsor or its agents as well as 
representatives of the FDA, or other appropriate regulatory agencies during and/or following 
performance of the study. 
14.3 Protocol Modifications  
All protocol amendments must be issued by the Sponsor, signed and dated by the investigator 
and should not be implemented prior to EC/IRB approval except where necessary to eliminate 

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hazards to subjects or when the change(s) involve only logistical or administrative details (e.g., 
address or telephone changes). 
14.4 Protocol Deviations 
In situations regarding a departure from the protocol, the investigator will contact the appropriate 
Sponsor representative by fax or telephone.  Notification to the Sponsor should be made prior to 
implementing a departure from the protocol, if at all feasible.  In all cases, contact with the 
Sponsor should be made as soon as possible in order to discuss the situation and agree on an 
appropriate course of action.  The protocol deviation log will describe any departure from the 
protocol and the circumstances that necessitated the departure. Protocol deviations will be 
entered into the database. 
14.5 On-Site Audits 
Representatives of the Sponsor may visit the investigational site to carry out an audit of the study 
in compliance with regulatory guidelines and company policy.  Such audits will require access to 
all study records, including source documents, for inspection and comparison with eCRFs. In 
accordance with HIPAA, as applicable, subject privacy will be respected at all times.  Sufficient 
prior notice will be provided by the Sponsor to allow the investigator time to prepare for the 
audit. 
The governing EC/IRB may conduct an on-site audit during the course of the study.  The 
investigator should notify the Sponsor, if they have been contacted by the EC/IRB regarding an 
audit. 
Similar auditing procedures may be conducted by agents of any regulatory body reviewing the 
results or procedures of this study.  The investigator should immediately notify the Sponsor if 
they are contacted by a regulatory agency concerning an inspection.  
14.6 Ethics 
14.6.1 Institutional Review Board 
The investigator will be responsible for obtaining Ethics Committee (EC)/Institutional Review 
Board (IRB) approval for the study as appropriate and for either completing the EC/IRB 
Certification form (provided to the investigator) or providing the Federal Wide Assurance 
(FWA) number.  After approval of the protocol, ICF, and any other adjunctive material (e.g. 
marketing flyers) by the EC/IRB, the investigator must provide a copy of the EC/IRB approval 
document and the completed EC/IRB Certification form or assurance number to the Sponsor.  
Copies of these documents are to be maintained at the study site.  The completed EC/IRB 

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Certification form verifies that the review board complies with federal regulations as described 
in 21 CFR Part 56. 
The written notification must be signed by the Chairman of the EC/IRB, or his/her designee and 
must identify the specific protocol.  In cases where an EC/IRB member has a specific conflict of 
interest, abstention of the individual from the vote should be documented.  An investigator or 
sub-investigator may be a member of the EC/IRB, but may not participate in the deliberation or 
vote on any research in which he/she is involved. 
14.7 Informed Consent 
The ICF, or assent when applicable, will be in accordance with the Declaration of Helsinki, 
principles of GCP, applicable regulatory requirements, subject privacy requirements and the 
Sponsor's policies.  The ICF, and assent when applicable, will include the subject’s age and the 
time consent was signed by the subject.  The subject will provide a current working phone 
number on the ICF so that the site can assess adverse events approximately 18-24 hours post-
procedure.  The ICF that is used must be approved by both the Sponsor and the reviewing 
EC/IRB. Each subject, or legally authorized representative, must provide written informed 
consent, or assent when applicable, according to local requirements after the nature of the study 
has been fully explained in order to participate in the study.  The ICF must be signed prior to 
performance of any study-related activity.  
The investigator, or designee, must explain to potential subjects, or their legal representatives, 
the aims, methods, reasonably anticipated benefits, potential hazards and risks of the study, right 
to refuse participation and right to withdraw without affecting the subject's medical care.  The 
other elements of the informed consent will be explained and subjects will be given the 
opportunity to ask questions.  After this explanation, but before entry into the study, consent 
should be appropriately documented by the subject, or his/her legally authorized representative's 
dated signature. If a subject, or his/her legal representative, is unable to read or requires a 
translator, an impartial witness must be present during the entire informed consent discussion 
and process. The signature of the impartial witness will certify the subject's consent. The subject, 
or his/her legal representative, will be given a signed and dated copy of the ICF. 
14.8 Experimental Article(s) 
Any experimental article under evaluation must be kept under strict control and used only as 
described in the protocol.  The investigator will be asked to ensure that the experimental 
article(s) is stored and returned/destroyed appropriately and to provide documentation in support 
of this. 

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All experimental article(s) will be labeled according to regulatory requirements.  Experimental 
article(s) must be stored under conditions set forth by the Sponsor in this protocol, on the product 
label, or communicated in writing.  The experimental article must be stored in a secure area 
segregated from non-experimental articles. 
If an experimental article(s) fails to perform in the expected manner, the investigator will notify 
the Sponsor immediately. 
14.9 Documentation of Laboratory Methods and Test Results 
Prior to the start of a study, the Clinical Research Associate (CRA) may visit the investigator’s 
laboratory to evaluate the facility, personnel and the subject population available for study. 
The investigator is required to have SOPs in place for routine tests performed in the 
investigator’s laboratory.  Quality control measures should be in place for routine tests 
performed in the investigator’s research laboratory to ensure the acceptability of test results.  If a 
routine test method must be modified during the study, the nature and reasons for the 
modifications and a statement of scientific soundness must be provided by the investigator. 
When ancillary laboratory facilities are used by the investigator (e.g., hospital clinical 
laboratory) to perform particular tests, that laboratory should be licensed or accredited for the 
tests being performed in the study under the current Clinical Laboratories Improvement Act 
(CLIA), the College of American Pathologists (CAP), state licensure, or other acceptable 
certifying body. 
If a new test procedure is being used in the study, literature and documentation of the test method 
development and a validation of suitable scientific rigor performed in the investigator’s 
laboratory must be documented.  The new test method development should include a suitable 
quality control procedure to ensure the acceptability of test results from each run.  If the new test 
method must be modified during the study, the nature and reasons for the modifications must be 
documented by the investigator. 
14.10 Publications 
The protocol, procedures, and data pertaining to this study will be treated as confidential 
information.  Publication of data and/or information derived from these studies must be done 
with the prior review and approval of the Sponsor.  Sponsor personnel may share authorship with 
investigators on abstracts, oral presentations, and manuscripts.  The principal author will be the 
person assuming primary responsibility for the abstract or manual.  

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15 REFERENCES 
 
1. Matevosyan K, Anderson C, and Sarode R.  Isovolemic Hemodilution- Red Cell 
Exchange for Prevention of Cerebrovascular Accident in Sickle Cell Anemia: The 
Standard Operating Procedure. J Clin Aph 27(2): 88-92, 2012. 
 
2. Sarode R, Matevosyan K, Rodgers Z, Burner J, and Rutherford C.  Advantages of 
Isovolemic Hemodilution-Red Cell Exchange Therapy to Prevent Recurrent Stroke in 
Sickle Cell Anemia Patients.  J Clin Aph 26(4):200-207, 2011. 
 
3. United States Department of Health and Human Services, United States Food and Drug 
Administration (FDA), Center for Biologics Evaluation and Research (CBER) Guidance 
for Industry, An Acceptable Circular of Information for the Use of Human Blood and 
Blood Components. 2014.   
 
4. McLeod B.C., et al. Frequency of Immediate Adverse Effects Associated with Apheresis 
Donation. Transfusion 38:938-943, 1998. 
 
5. United States Food and Drug Administration (FDA) Guidance for Industry and FDA 
Staff: Class II Special Controls Guidance Document: Automated Blood Cell Separator 
Device Operating by Centrifugal or Filtration Separation Principle. 2011. 
 
6.  Kim HC. Therapeutic Pediatric Apheresis. J Clin Aph 15:129-157, 2000. 
 
7. Taylor JG, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT, Steinberg MH. Chronic 
Hyper-Hemolysis in Sickle Cell Anemia:  Association of Vascular Complications and 
Mortality with Less Frequent Vasoocclusive Pain. PLoS ONE 3(5): e2095, 2008. 
  
8.  Austin H, Key NS, Benson JM, Lally C, Dowling NF, Whitsett C, Hooper WC. Sickle 
Cell Trait and the Risk of Venous Thromboembolism Among Blacks. Blood 110 (3) 
August, 2007. 
 
9. Quirolo K, Bertolone S., Hassell K., Howard T., King KE, Rhodes DK, Bill J. The 
Evaluation of a New Apheresis Device for Automated Red Blood Cell Exchange 

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Procedures in Patients with Sickle Cell Disease. Transfusion 21 OCT 2014 | DOI: 
10.1111/trf.12891 
 
10. Kadam P, Bhalerao S. Sample size calculation. Int J Ayurveda Res 1(1): 55-57, Jan-Mar, 
2010. 
 

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Cell Patients V.09 10 Feb 2017 
Adult ICF V.XX, dd/Mmm/yyyy 
 
 
 
Appendix A. INVESTIGATOR APPROVAL 
 
 

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Cell Patients V.09 10 Feb 2017 
Adult ICF V.XX, dd/Mmm/yyyy 
 
 
 
Investigator’s Approval  
 
I have reviewed the Fresenius Kabi USA LLC Protocol AMIC-003-CMD Evaluation of the 
AMICUS Red Cell Exchange System in Sickle Cell Patients.  I have fully discussed the objective 
of this study and the contents of this protocol with the Sponsor's representatives. 
I confirm that I have read and understand this protocol. I agree to conduct this study in 
accordance to this protocol, the applicable FDA Code of Federal Regulations (21 CFR Parts 50, 
54, 56, and 812), ISO 14155:2011 (E) and World Medical Association Declaration of Helsinki 
(2013 Version), the ICH Tripartite Guideline for Good Clinical Practice (GCP), the privacy 
regulation of the Health Insurance Portability and Accountability Act of 1996 (21 CFR Parts 160 
and 164), any local regulations and with the terms outlined in the Study Agreement. 
I will accept the Sponsor's oversight of the study. I have read and understand all related 
information and guides provided by Fresenius Kabi USA LLC, as applicable. I will abide by the 
publication plan set forth in my agreement with Fresenius Kabi USA LLC, and will promptly 
submit the protocol to the EC/IRB. 
 
 
___________________________  
_______________________   
______ 
Principal Investigator (Print Name)  Signature  
 
 
 
Date 
 
___________________________ 
Institution 
 
 

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Appendix B. LABELS 

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AMIC-003-CMD Evaluation of AMICUS Red Blood Cell Exchange (RBCx) System in Sickle 
Cell Patients V.09 10 Feb 2017 
Adult ICF V.XX, dd/Mmm/yyyy 
 
 
 
Labeling 
 
The AMICUS  Separator will display a label with the following text:  
 
 
 
 
 
 
 
 
 
 
 
The AMICUS Exchange Kits will contain a label with the following text for US sites only: 
 
 
 
 
 
 
 
 
The AMICUS Waste Transfer Set will contain a label with the following text for US sites only: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caution:  Investigational device limited by United States 
law to investigational use. 
 
FTX 1708  AMICUS Separator 
This AMICUS Separator contains Investigational Software 
Version 5.0. 
Caution:  Investigational device limited by United States 
law to investigational use. 
 
FTX 1709  AMICUS Exchange Kits 
 
Caution:  Investigational device limited by United States 
law to investigational use. 
 
FTX 1707  AMICUS Waste Transfer Set 
Lot#: XXXX, Exp: XXXX, Qty: XX 
 
Store at Controlled Room Temperature.  
Protect from Freezing. Avoid Excessive Heat. 

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AMIC-003-CMD Evaluation of AMICUS Red Blood Cell Exchange (RBCx) System in Sickle 
Cell Patients V.09 10 Feb 2017 
Adult ICF V.XX, dd/Mmm/yyyy 
 
 
 
An additional label will be applied for the AMICUS Exchange Kits, AMICUS Waste Transfer 
Sets, and AMICUS Separator for Non-US Sites: 
Caution:  Investigational device limited by United States 
law to investigational use. 
 
AMIC-003-CMD: Evaluation of the AMICUS Red Blood Cell 
Exchange (RBCx) System in Sickle Cell Patients 
 
 
 
The waste container(s) will be labeled with the following text for all sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Laboratory Use Only – Human blood collected into these 
containers or blood components prepared from this blood must not 
be transfused into humans. Not for transfusion.  
 
EXCHANGE WASTE RED BLOOD CELL MATERIAL 
 
Subject Study ID#:___________________Date: ______________ 
For Laboratory Use Only – Human blood collected into these 
containers or blood components prepared from this blood must not 
be transfused into humans. Not for transfusion.  
 
DEPLETION WASTE RED BLOOD CELL MATERIAL 
 
Subject Study ID#:___________________Date: ______________ 

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Appendix C. SAMPLE INFORMED CONSENT AND ASSENT 
 
 

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SAMPLE INFORMED CONSENT FORM 
Italicized writing is for guidance only and should not be included in the final document. 
Adult Consent to Participate in a Research Study 
Investigators at (institution’s name) invite you to consider taking part in a research study 
called: 
AMIC-003-CMD 
Evaluation of the AMICUS Red Blood Cell Exchange (RBCx) System  
in Sickle Cell Patients 
Sponsored by Fresenius Kabi USA, LLC and carried out by (investigator’s name). 
You are being asked to be in a research study of a medical device known as the 
AMICUS Separator. 
The purpose of this form is to help you decide if you want to be in this study.  Please 
read this form carefully.  It may contain words that you do not understand.  Please ask 
the study doctor or nurse to explain any words or information that you do not clearly 
understand.  You may take home an unsigned copy of this form to think about or 
discuss with family or friends before making your decision.  
If you sign this form, you are giving your permission (or consent) to be a part of this 
study.  You can agree to take part in this study and change your mind later without any 
negative effects. 
You should not sign this form if you have any questions that have not been answered.  
I. 
INTRODUCTION  
Blood is made up of four parts:  plasma, platelets, white blood cells, and red blood cells.  
Hemoglobin is a protein found in the red blood cells.  It carries oxygen from the lungs to 
other parts of the body.     
You are being asked to take part in this study because you have a hemoglobin disorder 
called sickle cell disease.  Hemoglobin disorders are passed down through families.  
They are known for abnormal production and shape of hemoglobin proteins.  Abnormal 
hemoglobin production and shape interfere with the body’s ability to circulate blood and 

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carry oxygen throughout the body.  This causes a variety of problems and symptoms 
that you may have.  
Removing red blood cells (which contain abnormal hemoglobin) and replacing them with 
healthy red blood cells or another fluid is a procedure called red blood cell exchange 
(also called RBCx).  RBCx is used to treat people with some hemoglobin disorders. 
II. 
WHY IS THIS STUDY BEING DONE? 
This study is being done because a new procedure, red blood cell exchange (also 
called RBCx) has been added to the AMICUS Separator.   
The AMICUS Separator is a blood collection machine called an apheresis device.  It 
collects blood from the patient.  As the blood is collected, the device separates it into its 
four different parts:  plasma, platelets, white blood cells, and red blood cells.  The 
device removes the unwanted blood parts and returns some of the other parts back to 
the patient along with healthy donor blood and/or another fluid, like salt water solution 
(also called saline), to replace what was removed.  This is called the replacement fluid.  
Replacement fluid is needed to keep the patient’s blood level normal.   
In RBCx, the red blood cells that are removed from you are replaced with a new fluid 
that your doctor will prescribe.  The doctor may use healthy red blood cells or a mixture 
of other fluids that do not contain blood (like saline) and blood to replace the red blood 
cells that were removed.     
The parts of the blood that are removed (also called waste blood material) and any 
samples taken are tested and then discarded after the testing is finished.   
The AMICUS Separator can perform similar types of exchange procedures based on 
the type of replacement fluid the doctor prescribes.  This study will look at two types of 
RBCx procedures:  RBC Exchange and RBC Depletion/Exchange. 
The doctor will prescribe the type of RBCx procedure you need based on your medical 
condition. 
The AMICUS Separator is approved for other treatment procedures.  It is also approved 
for several blood collection procedures in healthy donors. The AMICUS Separator is not 
approved to perform RBCx procedures.  Any RBCx procedures performed on the 
AMICUS Separator are for research purposes only.   

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III. 
SUBJECT SELECTION 
You can take part in this study if: 
• You are 6 years old or older. 
• You have sickle cell disease and require RBC Exchange or RBC 
Depletion/Exchange treatment. 
• You are medically stable and have been previously treated with an RBC 
Exchange or Depletion/Exchange procedure. 
• You give informed consent by signing this form before you begin any activities 
related to this study.  If you cannot give your informed consent, your legal 
representative can give it for you.  
• Your doctor has enough RBC replacement products that are right for your blood 
type. 
• The doctor or nurse can access your veins well enough to run the RBCx 
procedure. 
• You are able to tell the doctor or nurse how you are feeling. 
• You agree to tell the operator, doctor, and/or nurse any bad side effects you feel 
during the procedure and by telephone about 18-24 hours after the procedure. 
 
You cannot take part in this study if: 
• The RBCx treatment is done during a hospital emergency visit.  
• You were released from the hospital less than a week ago.   
• You are not able to fully understand the rules of the study and give informed 
consent and do not have a legal representative who can provide it for you.   
• Your doctor feels there are factors (such as drug or alcohol abuse, etc) that could 
interfere with your ability to follow his or her instruction or the rules of the study. 
• You have experienced a bad side effect with an RBCx procedure in the past.  
• If your doctor feels you have a life expectancy fewer than 30 days. 
• You refuse blood products. 
• You are pregnant. 
• You do not follow the doctor’s instructions to stop any medicine that he or she 
tells you to while taking part in this study. 
 

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IV. 
WHAT IS INVOLVED IN THE STUDY AND HOW LONG WILL I BE IN THE 
STUDY? 
You will be 1 of up to 130 subjects taking part in this study at up to 7 study sites.   
Your doctor will prescribe the type of RBCx procedure that will be used:   
• RBC Exchange 
• RBC Depletion/Exchange 
 
You will be required to complete 1 RBCx procedure at the Study Visit.   
The following figure shows how this study is designed: 
 
 
RBCx Study Design 
 
 
During the Study Visit, your doctor or nurse will collect information from you. Your date 
of birth, age at the time of signing this form, sex, ethnicity, race, and sickle cell 
diagnosis will be documented.  Your height and weight will be collected.   
A. Informed Consent Form is 
understood and signed. 
B. Study Visit 
1 RBCx procedure is done on the 
AMICUS Separator 

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Medicines you have taken up to 7 days before the Study Visit and during the procedure 
will be recorded.  These will include medicines that have been prescribed to you by a 
doctor and medicines that do not need a prescription. 
Before the start of the procedure, your doctor or nurse will measure your blood 
pressure, temperature, pulse, and breathing rate.  About 20 milliliters of blood (about 
1 ½ tablespoons) will be taken from you to measure your blood cell counts, test your 
hemoglobin, hematocrit, and plasma hemoglobin (to determine if red cells have broken).  
If you are female with child bearing ability, you will also be required to take a pregnancy 
test at the beginning of the Study Visit.  If you find out you are pregnant during the study 
and up to 30 days after the procedure is completed, you have to tell the study doctor.  
Two (2) of your veins will be accessed using the method your doctor or nurse 
prescribes.  In an RBCx procedure, your blood will remain within a sterile, single use kit 
during the procedure.  Blood will be taken from one vein and the device will separate it 
into its 4 parts.  Your red blood cells will be collected in a plastic bag (waste blood 
material).  Healthy donor red blood cells will be returned to you along with some of your 
plasma and blood cells in the other vein.  Depending on your sex, height, weight, and 
doctor’s orders, about 3-5 liters of your blood will be processed and returned to you 
during the RBCx procedure.  Only a portion of your blood will be removed at one time 
during the RBCx procedure. 
After the procedure is finished, the doctor or nurse will measure your blood pressure, 
temperature, pulse, and breathing rate again.  They will also take about 20 milliliters of 
blood (about 1 ½ tablespoons) to measure your blood cell counts, test your hemoglobin, 
hematocrit, and plasma hemoglobin.   
The waste blood material will be tested after the procedure is finished.  All samples and 
waste blood cells removed will be discarded after testing is finished.    
For the RBC Depletion/Exchange procedure, about half way through the procedure, the 
doctor or nurse will measure your blood pressure, temperature, pulse, and breathing 
rate again.  They will also take about 15 milliliters of blood (about 1 tablespoon) to 
measure your blood cell counts, test your hemoglobin, hematocrit, and plasma 
hemoglobin. 

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If your doctor or nurse cannot start the procedure for certain reasons, you may come 
back one more time to try again.  This may happen if your doctor or nurse cannot 
access your veins or if there isn’t enough blood that is right for you.   If you have an 
emergency RBCx procedure after you have agreed to participate in the study, it will not 
be counted as part of the study.  You will be able to come back another time to 
complete the study procedure. 
Your current working telephone number is: 
____________________________________(enter current working phone number 
and area code).  A member of the study team will call you about 18-24 hours after the 
procedure is done to see how you are feeling.  The study team will try to call you up to 2 
times.  They will ask you how you are feeling.  You will tell them how you are feeling.  If 
the study team is not able to reach you, they will send you a letter in the mail. 
An electronic database will be used.  Your name will not be entered into the database.  
You will be given a unique subject identification number that will be used in place of 
your name.   Your date of birth will be entered into the electronic database.  The 
database will be password protected and only approved people will have access to the 
database. 
V. 
ARE THERE BENEFITS (GOOD THINGS) TO TAKING PART IN THE 
STUDY? 
You may or may not receive any benefit from being in this study.  It is possible that you 
may get better, stay the same, or get worse.  The risks and benefits of the AMICUS 
RBCx procedure are believed to be similar to any RBCx procedure.  If you take part in 
this study, other people with sickle cell disease may be helped in the future.   
VI. 
WHAT ARE THE POSSIBLE RISKS OR SIDE EFFECTS (BAD THINGS) OF 
THE STUDY? 
You might have some side effects and discomfort while taking part in this study.  The 
risks to you in this study are similar to the risks related with any RBCx procedure.  
These risks include a risk of damaged red blood cells, air pocket in the blood system, 
blood loss, or blood clotting.  Although very rare, these risks can cause serious and 
even life-threatening problems for you like back pain, low blood pressure, different urine 
color, and lowered kidney function.  If your red blood cells are damaged from many 
procedures, it is possible for you to have increased blood pressure, greater increase in 

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leg sores, and pressure in your lungs.  If you are a man, and your penis is hard for 
several hours it could harm you (priapism).  If air enters your body, it may affect your 
heart, making it harder for it to pump blood throughout your body.  This may make it 
difficult for your lungs and other organs to receive the right amount of blood flow.  If this 
happens it could damage those organs, or cause pain in your chest.  It may also make 
you have shortness of breath and low blood pressure.  In the rare case of that the 
procedure caused a blood clot, the blood clot may cause pain, swelling, and redness.  It 
can also cause a stroke or be life-threatening.  These risks are rare and your doctors 
and nurses will be watching your vital signs and lab work to reduce the risks if they do 
occur.  Other risks and discomforts that may happen are low blood pressure or blood 
volume, cooling by the saline or replacement fluids may cause you to feel cold, bruising, 
allergic reactions, skin redness, itching, hives, trouble breathing rate, stomach cramps, 
sweating, fainting, tiredness, fast pulse, feeling dizzy, feeling sick to your stomach, and 
throwing up.  Your blood count may go up or down. 
During the procedure, you will receive some saline and anticoagulant (also called ACD) 
that is used to keep your blood from clotting.  This is a common anticoagulant solution 
and is often used other RBCx procedures.  An increased risk of bleeding with ACD is 
very low since your body quickly processes the ACD and the ACD keeps your blood 
from clotting in the machine.   
You may have symptoms of low calcium, such as a tingling feeling, around your mouth, 
fingers, or toes.  You may also have feelings of vibrations, unusual taste, or brief muscle 
discomfort.  You will be closely monitored during the procedure.  If these symptoms 
happen, it is important for you to tell the operator.  The operator can then slow the 
return rate of the blood to reduce the symptoms.  If you do not tell the operator the 
symptoms you have, more serious reactions like muscle twitching or convulsions can 
happen. 
Although donors are tested for numerous diseases, transfusion of blood can spread 
harmful diseases. 
If you are using a medicine called an ACE inhibitor and do not follow the doctor’s 
instruction to stop taking the medicine before your procedure, you may experience a 
reddened face, low blood pressure, or increased anxiety during your RBCx procedure.   

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Although the kit, needles, and central lines (if appropriate) that are used are sterile and 
proper technique under sterile conditions will be used to prevent infections, in rare 
cases, infections or inflammation may happen.  Sometimes the central lines become 
clogged.   
The system has been designed to lower the possibility that air will enter the kit.  A 
special air detector and bubble trap are present.  The air detector is designed to stop 
the device right away if air enters the kit and the clamps will close, keeping you away 
from the device.  The bubble trap helps to catch air bubbles to keep air from being 
returned to you.  Other sensors stop the device if there is difficulty in removing blood or 
returning blood.  The sensors will stop the device if the kit becomes blocked.   
Previous testing of the AMICUS RBCx procedures has been done in the lab.   
Testing has shown that the device can reach target fluid balance.  But there is a 
possibility that not enough or too much fluid may be given to you during the procedure.  
If you do not receive enough fluid, you may experience lightheadedness, temporary loss 
of consciousness, weakness, thirst, or low blood pressure.  If you receive too much fluid 
and do not have serious heart, lung, or kidney problems, you would be able to get rid of 
the excess fluid through your urine.  However, if you have serious heart, lung, or kidney 
problems your body may not be able to get rid of the extra fluid.  If you cannot get rid of 
the extra fluid, it is possible that the fluid may enter your lungs and make it difficult for 
you to breathe.  These risks may be greater for you because you have sickle cell 
disease which affects your blood’s ability to carry oxygen throughout your body.  The 
doctor and nurses will monitor the amount of fluid you have throughout the procedure.  
They will also be sure that you do not have heart, lung, or kidney problems that may 
increase your risk for these problems.   
Due to technical reasons, such as your blood clotting in the device or the presence of a 
leak in the tubing, it may not be possible to return all of the red blood cells in the device.  
The maximum amount of red blood cells you would lose if this were to happen would be 
less than half the volume (about ½ pint) compared to a whole blood donation (about 1 
pint).  
The AMICUS Exchange Kits that will be used for the study are the same as the FDA 
approved and commercially available kits used for therapeutic plasma exchange, a 
procedure that takes out some plasma and replaces it with other similar fluid.  The 

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saline, ACD and replacement fluid containers use color-coded spikes to help the 
medical staff attach the solutions correctly.   
The RBCx procedure may involve unforeseeable risks to you or to your embryo or fetus 
should you become pregnant prior to taking part in this study.  If you find out you are 
pregnant during the study and up to 30 days after the procedure is completed, you have 
to tell the study doctor.   
VII. 
WHAT OTHER OPTIONS ARE THERE? 
An alternate option would be for you not to take part in this study.  You could continue 
your RBCx treatments using a commercially available device to treat your condition.   
VIII. 
VOLUNTARY PARTICIPATION/TERMINATION (STOPPING) OF 
RESEARCH 
Your participation in this study is voluntary.  You are free to choose whether or not to 
take part in this study.  If you do choose to be in the study, you may choose to stop 
participating at any time by telling the investigator.  If you stop participating during an 
AMICUS procedure, it may not be possible to return all of the red blood cells in the 
device.   
If you stop taking part in this study, you will receive the usual treatment which your 
doctor would prescribe.  There will be no penalty or loss of benefits to which you are 
otherwise entitled if you choose not to participate.  Fresenius Kabi USA, LLC or the 
Investigator may stop your involvement in this study at any time.  For example, this 
could happen if the doctor feels it would be in your best interest, if you do not follow the 
rules of the study, or if you are no longer eligible to participate.   
IX. 
WHAT ARE THE COSTS? 
You may have to pay for some costs related to this study.  These costs may include 
transportation or parking.  The costs for the research RBCx treatment used will be 
provided to you at no cost.  The related study laboratory tests that are not normally 
done during your treatment will be provided to you at no cost.  
X. 
WILL I BE COMPENSATED FOR MY PARTICIPATION? 
You will receive [$XXX] to refund study-related costs like transportation and parking.  If 
you do not finish the study, you will be paid for the part of the study that you did 
complete.   

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XI. 
WILL I BE TOLD ABOUT NEW INFORMATION? 
If important new information develops during this study that may affect your willingness 
to keep being in the study, the Investigator, ______________ will tell you about this 
information.  If at any time you have questions regarding the research or your 
participation, you should contact the Investigator, [telephone#__________] who will 
answer all your questions.  
If at any time you have questions, comments, or complaints related to how the study is 
run, or you feel that you have suffered a research-related illness or injury, you may 
contact the Institutional Review Board/Ethics Commitee at [telephone#__________].  
A description of this study will be available on http://www.ClinicalTrials.gov, as required 
by US law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this website at any time.  
XII. 
WHAT DO I DO IF I AM INJURED? 
If a bad side effect (also called an adverse reaction) or injury occurs, you will be 
attended to free of charge by the medical professionals in the treatment area.  If 
necessary, you may be treated by the medical professionals designated by the 
institution’s emergency procedures.  However, if you require treatment at an outside 
hospital or medical center, those costs must be paid by you, your insurance company or 
other third party payer.  If at any time you have questions, comments, or complaints 
relating to how the study is run, or if you feel you have suffered a research-related 
illness or injury, you should contact [Investigator] at [telephone#_____].   
XIII. 
WHO WILL KNOW ABOUT WHAT I DID IN THE STUDY OR HAVE 
ACCESS TO MY PRIVATE INFORMATION? 
The purpose of research studies is to collect medical information from a group of 
participants in order to determine how well a medical device or treatment works.  
Therefore, the investigators will need access to the medical records of all of the subjects 
who take part in the study.  
If you sign this consent form, you are giving permission for your physician and 
[hospital/care center] to provide your medical information to the following people, 
agencies or companies to review and use in this research study: 
• Fresenius Kabi USA, LLC 

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• The United States Food and Drug Administration (FDA) 
• Technischer Überwachungs-Verein (Technical Inspection Association, Germany) 
(TÜV) 
• [List researchers and any other recipients]______________________________. 
 
The results of this study will be made available to Fresenius Kabi USA, LLC and will be 
sent to the FDA and TÜV.  Also, your hospital records may be used for data review by 
Fresenius Kabi USA, LLC, the FDA, and TÜV. 
[Name of the hospital/center] and your doctors will keep the records of this study 
confidential, and will release your medical information only to the people or companies 
listed above.  However, you understand that once your doctor or [name of 
hospital/center] releases your medical information to these people or companies, your 
doctor or [name of hospital/center] cannot then ensure that your information will stay 
confidential.  It is possible that these other persons or companies could give your study 
information to others, without your permission.   
The records of this study will be kept confidential with respect to any written or oral 
reports to the profession or the media. Your name will not be used in the study data, 
making it impossible to identify you individually.  
This signed informed consent form will be placed in your medical record at [name of 
hospital/center] with a copy placed in the Investigator’s research file.  If you do not have 
a medical record at [hospital name/center], then this signed consent form will be kept in 
the Investigator’s research file.  
XIV. 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
By signing this consent form, you agree to take part in this study.  You are not giving up 
any of your legal rights or releasing [name of hospital/center] from responsibility or 
carelessness.  
You may cancel your consent and remove yourself from this study at any time without 
penalty or loss of benefits.  Your treatment by, and relationships with the physician(s) 
and staff at [hospital/center], now and in the future, will not be affected in any way if you 
do not want to take part or if you enter into the study and then withdraw from it.   

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At any time, you can tell your doctor or [hospital/center] not to use or give out your study 
information or other information from your medical record to other people or companies.  
Withdrawal of this permission must be in writing.  Any study information or other 
information from your medical record collected before your written notice of permission 
withdrawal may still be used for the study, if that information is necessary for the study.  
Because the purpose of this study is to collect information about the AMICUS 
Separator, if you refuse to release your study information, you may not be able to start, 
or continue taking part in this study.  Your decision will not affect your regular care and 
your doctor will not change his or her feelings about you.   
If you agree to take part in this research study, you may not be able to look at a copy of 
your health information collected only for this study while you are taking part in the 
study.  If you wish, you will be able to ask for this study research information when the 
study is finished.  This does not affect your right to see your medical record or the 
results of tests related to regular medical care that is given during the same time as the 
research study.   
If you have any questions about the research methods, you should contact the 
Investigator, [name], by contacting [telephone# _________] during a workday or 
[telephone #______] at night or on weekends.  
You will be given a signed and dated copy of this consent form.  
 
 

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You agree to let your doctor or [hospital/center] use and give out your health information 
in the way it is described in this consent form until the end of the research study.  
You have read this consent form, and you agree to take part in this study as explained 
in this consent form.  
 
 
Age of Research Subject 
 
 
 
Signature of Research Subject  
(subject is 18 years or older) 
 
 
Date 
 
 
Time 
 
 
 
Printed Name of Research Subject 
 
 
 
I certify that I have explained the above to this research subject and believe that the 
signature was affixed freely.  I also agree to answer any questions that the subject may 
ask.  
 
 
 
 
Signature of Investigator/Designee Obtaining Consent 
 
 
 
 
Date 
 
 
 
Printed Name of Person Obtaining Consent 
 
 
 
 
 

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SAMPLE INFORMED CONSENT FORM 
Italicized writing is for guidance only and should not be included in the final document. 
Parent Consent to allow Child to Participate in a Research Study 
Investigators at (institution’s name) invite you to consider allowing your child to take part 
in a research study entitled: 
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in Sickle Cell Patients 
Sponsored by Fresenius Kabi USA, LLC and carried out by (investigator’s name). 
You are being asked to allow your child to be in a research study of a medical device 
known as the AMICUS Separator. 
The purpose of this form is to help you decide if you want to allow your child to be in this 
study.  Please read this form carefully.  It may contain words that you do not 
understand.  Please ask the study doctor or nurse to explain any words or information 
that you do not clearly understand.  You may take home an unsigned copy of this form 
to think about or discuss with family or friends before making a decision.  
If you sign this form, you are giving your permission (or consent) for your child to be a 
part of this study.  You can agree to allow your child to take part in this study and 
change your mind later without any negative effects to you or your child. 
You should not sign this form if you have any questions that have not been answered.  
I. 
INTRODUCTION  
Blood is made up of four parts:  plasma, platelets, white blood cells, and red blood cells.  
Hemoglobin is a protein found in the red blood cells.  It carries oxygen from the lungs to 
other parts of the body.     
You are being asked to allow your child to take part in this study because your child has 
a hemoglobin disorder called sickle cell disease.  Hemoglobin disorders are passed 
down through families.  They are defined by abnormal production and shape of 
hemoglobin protein.  Abnormal hemoglobin production and shape interfere with the 

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body’s ability to circulate blood and carry oxygen throughout the body.  This causes a 
variety of problems and symptoms that your child may have.  
Removing red blood cells (which contain abnormal hemoglobin) and replacing them with 
healthy red blood cells or another fluid is a procedure called red blood cell exchange 
(also called RBCx).  RBCx is used to treat people with some hemoglobin disorders. 
II. 
WHY IS THIS STUDY BEING DONE? 
This study is being done because a new procedure, red blood cell exchange (also 
called RBCx) has been added to the AMICUS Separator.   
The AMICUS Separator is a blood collection machine called an apheresis device.  It 
collects blood from the patient.  As the blood is collected, the device separates it into its 
four different parts:  plasma, platelets, white blood cells, and red blood cells.  The 
device removes the unwanted blood parts and returns some of the other parts back to 
the patient along with another fluid, like salt water solution (also called saline), to 
replace what was removed.  This is called the replacement fluid.  Replacement fluid is 
needed to keep the patient’s blood level normal.   
In RBCx, the red blood cells that are removed from your child are replaced with a new 
fluid that your child’s doctor will prescribe.  The doctor may use healthy red blood cells 
or a mixture of other fluids that do not contain blood (like saline) and blood to replace 
the red blood cells that were removed.     
The parts of the blood that are removed (also called waste blood material) and any 
samples taken are tested and then discarded after the testing is finished.  
The AMICUS Separator can perform similar types of exchange procedures based on 
the type of replacement fluid the doctor prescribes.  This study will look at two types of 
procedures:  RBC Exchange and RBC Depletion/Exchange. 
The doctor will prescribe the type of RBCx procedure your child needs based on your 
child’s medical condition. 
The AMICUS Separator is approved for treatment procedures.  It is also approved for 
several blood collection procedures in healthy donors. The AMICUS Separator is not 
approved to perform RBCx procedures.  Any RBCx procedures performed on the 
AMICUS Separator are for research purposes only.   

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This study will look at the AMICUS Separator’s RBC Exchange and RBC 
Depletion/Exchange procedures. 
 
 

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III. 
SUBJECT SELECTION 
Your child can take part in this study if: 
• They are 6 years old or older. 
• They have sickle cell disease and require RBC Exchange or RBC 
Depletion/Exchange treatment. 
• They are medically stable and have been previously treated with an RBC 
Exchange or RBC Depletion/Exchange procedure. 
• You give informed consent by signing this form before any activities related to 
this study are started.  
• Your child’s doctor has enough RBC replacement products that are right for your 
child’s blood type. 
• The doctor or nurse can access your child’s veins well enough to run the RBCx 
procedure. 
• They are able to tell the doctor or nurse how they are feeling. 
• They agree to tell the doctor or nurse any bad side effects they feel during the 
procedure and about 18-24 hours after the procedure.  
 
Your child cannot take part in this study if: 
• The RBCx treatment is done during a hospital emergency visit.  
• They were released from the hospital less than a week ago.   
• You are not able to fully understand the rules of the study and give informed 
consent.   
• Your child’s doctor feels there are factors (such as drug or alcohol abuse, etc.) 
that could interfere with your child’s ability to follow his or her instruction or the 
rules of the study. 
• They have experienced a bad side effect with an RBCx procedure in the past.  
• If your child’s doctor feels that they have a life expectancy fewer than 30 days. 
• You refuse blood products for your child. 
• They are pregnant. 
• You do not follow the doctor’s instructions to stop any of your child’s medication 
that he or she tells you to while taking part in this study. 

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WHAT IS INVOLVED IN THE STUDY AND HOW LONG WILL I BE IN THE STUDY? 
Your child will be 1 of up to 130 subjects taking part in this study at up to 7 study sites.   
Your child’s doctor will prescribe the type of RBCx procedure that will be used:   
• RBC Exchange 
• RBC Depletion/Exchange 
 
Your child will be required to complete 1 AMICUS RBCx procedure at 1 Study Visit.   
The following figure shows how this study is designed: 
 
 
RBCx Study Design 
 
During the Study Visit, your child’s doctor or nurse will collect information from your 
child. Your child’s date of birth, age at the time this form is signed, sex, ethnicity, race, 
and the diagnosis of their hemoglobin disorder will be documented.  Your child’s, height, 
and weight will be collected.  Medicines your child has taken up to 7 days before the 
Study Visit will be recorded. 
A. Informed Consent Form is 
understood and signed. 
B. Study Visit 
1 RBCx procedure is done on the 
AMICUS Separator 

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Before the start of the procedure, your child’s doctor or nurse will measure your child’s 
blood pressure, temperature, pulse, and breathing rate.  About 20 milliliters of blood 
(about 1 ½ tablespoons) will be taken from your child to measure their blood cell counts, 
test their hemoglobin, hematocrit, and plasma hemoglobin (to determine if red cells 
have broken).  If your child is female with child bearing ability, she will also be required 
to take a pregnancy test at the beginning of the Study Visit.  If she finds out she is 
pregnant during the study and up to 30 days after the procedure is completed, you have 
to tell the study doctor.     
Two (2) of your child’s veins will be accessed using the method your child’s doctor or 
nurse prescribes.  In an RBCx procedure, your child’s blood will remain within a sterile, 
single use kit during the procedure.  Blood will be taken from one vein and the device 
will separate it into its 4 parts.  Your child’s red blood cells will be collected in a plastic 
bag (waste blood material).  Healthy donor red blood cells will be returned to them along 
with some of their plasma and blood cells in the other vein.  Depending on your child’s 
sex, height, weight, and doctor’s orders, about 3-5 liters of your child’s blood will be 
processed and returned to them during the RBCx procedure.  Only a portion of your 
child’s blood will be removed at one time during the RBCx procedure. 
After the procedure is finished, the doctor or nurse will measure your child’s blood 
pressure, temperature, pulse, and breathing rate again.  They will also take about 15 
milliliters of blood (about 1 ½ tablespoons) to measure your child’s blood cell counts, 
test their hemoglobin, hematocrit, and plasma hemoglobin.   
The waste blood material will be tested after the procedure is finished.  All samples and 
waste red blood cells removed will be discarded after testing is finished.    
For the RBC Depletion/Exchange procedure, about half way through the procedure, the 
doctor or nurse will measure your child’s blood pressure, temperature, pulse, and 
breathing rate again.  They will also take about 10 milliliters of blood (about 1/2 
tablespoon) to measure your child’s blood cell counts and test their hemoglobin, 
hematocrit, and plasma hemoglobin. 
If your child’s doctor or nurse cannot start the procedure for certain reasons, your child 
may come back one more time to try again.  This may happen if your child’s doctor or 
nurse cannot access their veins or if there isn’t enough blood that is right for your child.  
Your child will be able to come back another time to complete the study procedure. 

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Your current working telephone number is: 
____________________________________(enter current working phone number 
and area code).  A member of the study team will call your child about 18-24 hours 
after the procedure is done to see how they are feeling.  The study team will try to call 
up to 2 times.  They will ask your child how they are feeling.  Your child will tell them 
how they are feeling.  If the study team is unable to reach you, they will send you a 
letter in the mail. 
An electronic database will be used.  Your child’s name will not be entered into the 
database.  Your child will be given a unique subject identification number that will be 
used in place of their name.  Your child’s date of birth will be entered into the electronic 
database.  The database will be password protected and only approved people will 
have access to the database.       
IV. 
ARE THERE BENEFITS (GOOD THINGS) TO TAKING PART IN THE 
STUDY? 
Your child may or may not receive any benefit from being in this study.  It is possible 
that they may get better, stay the same, or get worse.  The risks and benefits of the 
AMICUS RBCx procedure are believed to be similar to any RBCx procedure.  If your 
child takes part in this study, other people with sickle cell disease may be helped in the 
future.   
V. 
WHAT ARE THE POSSIBLE RISKS OR SIDE EFFECTS (BAD THINGS) OF 
THE STUDY? 
Your child might experience some side effects and discomfort while taking part in this 
study.  The risks to your child as a participant in this study are similar to the risks related 
with any RBCx procedure.  These risks include damaged red blood cells, air pocket in 
the blood system, blood loss, or blood clotting.  Although very rare, these risks can 
cause serious and even life-threatening problems for your child like back pain, low blood 
pressure, different urine color, and impaired kidney function.  If  your child’s red blood 
cells are damaged from many procedures, it’s possible for your child to have increased 
blood pressure, greater increase in leg ulcers, and if your child is a boy, priapism.  It 
may also cause your child to experience pressure in their lungs.  If air enters their body, 
it may affect their heart, making it harder for it to pump blood throughout their body.  
This may make it difficult for their lungs and other organs to receive the right amount of 
blood flow.  If this happens it could damage those organs, or cause pain in their chest.  

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It may also make your child have shortness of breath and low blood pressure.  In the 
rare case of the procedure causing a blood clot, the blood clot may cause pain, 
swelling, and redness.  It can also cause a stroke or be life-threatening.  These risks are 
rare and your doctors and nurses will be watching your child’s vital signs and lab work 
to reduce the seriousness of these risks if they do occur.  Other risks and discomforts 
that may happen are low blood pressure or blood volume, cooling by the saline or 
replacement fluids may cause your child to feel cold, bruising, allergic reactions, skin 
redness, itching, hives, trouble breathing rate, stomach cramps, sweating, fainting, 
tiredness, fast pulse, feeling dizzy, feeling sick to the stomach, and throwing up.  Your 
child’s blood count may go up or down. 
During the procedure, your child will receive some saline and anticoagulant (also called 
ACD) that is used to keep their blood from clotting.  This is a common anticoagulant 
solution and is often used in platelet and white blood cell collection procedures.  An 
increased risk of bleeding with ACD is very low since your child’s body quickly 
processes the ACD and the ACD keeps your child’s blood from clotting only in the 
machine.  
Your child may have symptoms of low calcium, such as a tingling feeling, around their 
mouth, fingers, or toes.  They may also have feelings of vibrations, unusual taste, or 
brief muscle discomfort.  Your child will be closely monitored during the procedure.  If 
these symptoms happen, it is important for your child to tell the operator.  The operator 
can then slow the return rate of the blood to reduce the symptoms.  If your child does 
not tell the operator the symptoms they have, more serious reactions like muscle 
twitching or convulsions can happen. 
Although donors are tested for numerous diseases, transfusion of blood has can spread 
harmful diseases. 
If your child is using a medicine called an ACE inhibitor and does not follow the doctor’s 
instruction to stop taking the medicine before their procedure, your child may 
experience a reddened face, low blood pressure, or increased anxiety during your 
child’s RBCx procedure.   
The system has been designed to lower the possibility that air will enter the kit.  A 
special air detector and bubble trap are present.  The air detector is designed to stop 
the device right away if air enters the kit.  The clamps will close, keeping your child 

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away from the device.  The bubble trap helps to catch air bubbles to keep air from being 
returned to your child.  Other sensors stop the device if there is difficulty in removing 
blood or returning blood.  The sensors will stop the device if the kit becomes blocked.   
Previous testing of the AMICUS RBCx procedures has been done in the lab.   
Testing has shown that the device can reach target fluid balance.  But there is a 
possibility that not enough or too much fluid may be given to your child during the 
procedure.  If this happens, it will cause improper fluid balance.  If your child does not 
receive enough fluid, he or she may experience lightheadedness, temporary loss of 
consciousness, weakness, thirst, or low blood pressure.  If they receive too much fluid 
and do not have serious heart, lung, or kidney problems, they would be able to get rid of 
the excess fluid through their urine.  However, if your child has serious heart, lung, or 
kidney problems their body may not be able to get rid of the extra fluid.  If your child’s 
body cannot get rid of the extra fluid, it is possible that the fluid may enter their lungs 
and make it difficult for them to breathe.  These risks may be greater for your child since 
they have sickle cell disease which affects the blood’s ability to carry oxygen throughout 
the body.  Your child’s doctor and nurses will monitor the amount of fluid they have 
throughout the procedure.  They will also be sure that your child does not have heart, 
lung, or kidney problems that may increase their risk for these problems.   
The effects of blood loss are more serious in children than they are in adults.  The loss 
of too much blood may cause your child to have reduced blood flow to their skin and 
muscle, low blood pressure, weakness, and in serious cases may be life-threatening.  
Your child’s doctors and nurses will be watching your child’s vital signs and lab work to 
reduce the seriousness of these risks if they do occur. 
It may be more difficult to access a child’s veins for apheresis procedures than for an 
adult since children are smaller and have smaller veins.  Therefore, your child’s doctor 
or nurses may have to use a central line to get venous access in order to use the 
AMICUS exchange kit.  It may be possible, in rare cases, for infections or inflammation 
to happen.  Sometimes the central lines become clogged.  Your child’s doctor and 
nurses will use proper sterile technique to help prevent these risks from happening.  
Your child’s doctor will decide the best way to access your child’s veins based on their 
medical need. 

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Although the kit, needles, and central lines (if appropriate) that are used are sterile and 
proper sterile technique will be used to prevent infections, in rare cases, infections or 
inflammation may happen.  Due to technical reasons, such as your child’s blood clotting 
in the device or the presence of a leak in the tubing, it may not be possible to return all 
of the red blood cells in the device.  The maximum amount of red blood cells your child 
would lose if this were to happen would be less than half the volume (about ½ pint) 
compared to a whole blood donation (about 1 pint).  
The AMICUS Exchange Kits that will be used for the study are the same as the FDA 
approved and commercially available kits used for therapeutic plasma exchange, a 
procedure that removes some plasma and replaces it with similar fluid.  The saline, 
ACD and replacement fluid containers use color-coded spikes to help attach the 
solutions correctly.   
The RBCx procedure may involve unforeseeable risks to your daughter or to your 
daughter’s embryo or fetus should she become pregnant prior to taking part in this 
study.  If you find out your daughter is pregnant during the study and up to 30 days after 
the procedure is completed, you have to tell the study doctor. 
VI. 
WHAT OTHER OPTIONS ARE THERE? 
An alternate option would be for you to not allow your child to take part in this study.  
Your child could continue their RBCx treatments using a commercially available device 
to treat their condition.   
VII. 
VOLUNTARY PARTICIPATION/TERMINATION (STOPPING) OF 
RESEARCH 
Your child’s participation in this study is voluntary.  You are free to choose whether or 
not to allow your child to take part in this study.  If you do allow your child to be in the 
study, you may choose to stop their participation at any time by telling the investigator.  
If you stop your child’s participation during an AMICUS procedure, it may not be 
possible to return all of the red blood cells in the device.  If your child stops taking part in 
this study, your child will receive the usual treatment for their hemoglobin disorder that 
their doctor would prescribe.  There will be no penalty or loss of benefits to which your 
child is otherwise entitled if you choose to not allow your child to participate.  Fresenius 
Kabi USA, LLC or the Investigator may stop your child’s involvement in this study at any 
time.  For example, this could happen if the doctor feels it would be in your child’s best 

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interest, if your child or you do not follow the rules of the study, or if your child is no 
longer eligible to participate.   
VIII. 
WHAT ARE THE COSTS? 
You may have to pay for some costs related to this study.  These costs may include 
transportation or parking.  The costs for the research RBCx treatment used will be 
provided to your child at no cost.  The related study laboratory tests that are not 
normally done during your child’s treatment will be provided to your child at no cost.  
IX. 
WILL I BE COMPENSATED FOR MY PARTICIPATION? 
You will receive [$XXX] per Study Visit to refund study-related costs like transportation 
and parking.  If your child does not finish the study, you will be paid for the part of the 
study your child did complete.   
X. 
WILL I BE TOLD ABOUT NEW INFORMATION? 
If important new information develops during this study that may affect your willingness 
to allow your child to continue in the study, the Investigator, ______________ will tell 
you about this information.  If at any time you have questions regarding the research or 
your child’s participation, you should contact the Investigator, [telephone#__________] 
who will answer all your questions.  
If at any time you have questions, comments, or complaints related to how the study is 
run, or you feel that your child has suffered a research-related illness or injury, you may 
contact the Institutional Review Board/Ethics Committee at [telephone#__________].  
A description of this study will be available on http://www.ClinicalTrials.gov, as required 
by US law.  This Web site will not include information that can identify your child.  At 
most, the Web site will include a summary of the results.  You can search this website 
at any time.  
XI. 
WHAT DO I DO IF I AM INJURED? 
If a bad side effect (also called an adverse reaction) or injury occurs, your child will be 
attended to free of charge by the medical professionals in the treatment area.  If 
necessary, your child may be treated by the medical professionals designated by the 
institution’s emergency procedures.  However, if your child requires treatment at an 
outside hospital or medical center, those costs must be paid by you, your insurance 
company or other third party payer.  If at any time you have questions, comments, or 

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complaints relating to how the study is run, or if you feel you have suffered a research-
related illness or injury, you should contact [Investigator] at [telephone#_____].   
XII. 
WHO WILL KNOW ABOUT WHAT I DID IN THE STUDY OR HAVE 
ACCESS TO MY PRIVATE INFORMATION? 
The purpose of research studies is to collect medical information from a group of 
participants in order to determine how well a medical device or treatment works.  
Therefore, the investigators will need access to the medical records of all of the subjects 
who take part in the study.  
If you sign this consent form, you are giving permission for your child’s physician and 
[hospital/care center] to provide your child’s medical records to the following people, 
agencies or companies to review and use in this research study: 
• Fresenius Kabi USA, LLC  
• The United States Food and Drug Administration (FDA) 
• Technischer Überwachungs-Verein (Technical Inspection Association, Germany) 
(TÜV) 
• [List researchers and any other recipients]______________________________. 
 
The results of this study may be made available to Fresenius Kabi USA, LLC and will be 
sent to the FDA and TÜV.  Also, your child’s hospital records will be used for data 
review by Fresenius Kabi USA, LLC, the FDA, and TÜV. 
[Name of the hospital/center] and your child’s doctors will keep the records of this study 
confidential, and will release your child’s medical information only to the people or 
companies listed above.  However, you understand that once your child’s doctor or 
[name of hospital/center] releases your child’s medical information to these people or 
companies, your child’s doctor or [name of hospital/center] cannot then ensure that your 
child’s information will stay confidential.  It is possible that these other persons or 
companies could give your child’s study information to others, without your permission.   
The records of this study will be kept confidential with respect to any written or oral 
reports to the profession or the media. Your child’s name will not be used in the study 
data, making it impossible to identify them individually.  

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This signed informed consent form will be placed in your child’s medical record at [name 
of hospital/center] with a copy placed in the Investigator’s research file.  If your child 
does not have a medical record at [hospital name/center], then this signed consent form 
will only be kept in the Investigator’s research file.  
XIII. 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
By signing this consent form, you agree to allow your child to take part in this study.  
You are not giving up any of your child’s legal rights or releasing [name of 
hospital/center] from responsibility or carelessness.  
You may cancel your consent and remove your child from this study at any time without 
penalty or loss of benefits.  Your child’s treatment by, and relations with the physician(s) 
and staff at [hospital/center], now and in the future, will not be affected in any way if you 
do not allow your child to take part or if you enter your child into the study and then 
withdraw them from it.   
At any time, you can tell your child’s doctor or [hospital/center] not to use or give out 
your child’s study information or other information from their medical record to other 
people or companies.  Withdrawal of this permission must be in writing.  Any study 
information or other information from your child’s medical record collected before your 
written notice of permission withdrawal may still be used for the study, if that information 
is necessary for the study.  Because the purpose of this study is to collect information 
about the AMICUS Separator, if you refuse to release your child’s study information, 
your child may not be able to start, or continue taking part in this study.  Your decision 
will not affect your child’s regular care and your child’s doctor will not change his or her 
feelings about them.   
If you allow your child to take part in this research study, you may not be able to look at 
a copy of your child’s health information collected only for this study while your child is 
taking part in the study.  If you wish, you will be able to ask for this study research 
information when the study is finished.  This does not affect your right to see your child’s 
medical record or the results of tests related to regular medical care that is given during 
the same time as the research study.   
If you have any questions about the research methods, you should contact the 
Investigator, [name], by contacting [telephone# _________] during a workday or 
[telephone #______] at night or on weekends.  

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You will be given a signed and dated copy of this consent form. 

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You give your permission to let your child’s doctor or [hospital/center] use and give out 
your child’s health information in the way it is described in this consent form.  
By signing, you agree that you have read this consent form and you agree to have your 
child, ___________________________ [clearly print the child’s name) take part in this 
study as explained in this consent form.  
 
 
Age of Child 
 
 
 
Signature of Parent(s) or Legal Representative(s)  
 
 
 
 
Date 
 
 
 
Time 
 
 
 
Printed Name of Parent(s) or Legal Representative(s) 
 
 
 
 
 
_________________________________________________ 
Identify the signatory: e.g., Parent, Legal Representative 
 
 
 
I certify that I have explained the above to this research subject and believe that the 
signature was given freely.  I also agree to answer any questions that the subject may 
have.  
 
 
 
 
Signature of Investigator/Designee Obtaining Consent 
 
 
 
 
Date 
 
 
Printed Name of Person Obtaining Consent 
 
 
 
 

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SAMPLE INFORMED ASSENT FORM 
Italicized writing is for guidance only and should not be included in the final document. 
Adolescent’s Agreement to Participate in a Research Study 
Ages 6-17 
I am being asked to be in a research study called:  
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The study is being done by (investigator’s name) at (name of institution). 
 
I. 
WHY IS THIS STUDY BEING DONE? 
You are being told about a research study at (name of institution).  Research studies 
help explain how medicines and medical devices work.  Research studies are by 
choice, which means that you only have to participate in the study if you want. 
You are being asked to be in this research study because you have sickle cell disease.  
You are being asked to be in this research study to help researchers learn more about a 
medical device called the AMICUS Separator’s Red Blood Cell Exchange (RBCx) 
System. 
II. 
WHAT HAPPENS IN THE STUDY AND HOW LONG WILL I BE IN THE 
STUDY?  
If you want to be in the study, this is what will happen: 
• You will ask any questions that you have.  You would sign this form after all of 
your questions have been answered. 
• Your doctor will check to see if you are able to take part in this study.  
• You will go to 1 study visit.   
• You will complete 1 red blood cell exchange or 1 red blood cell 
depletion/exchange procedure at the visit.  Your doctor will decide what type of 
procedure will be done.   
• You will have 1 procedure using the AMICUS.  
• Your doctor or nurse will ask questions about you such as your birthday, age, if 
you’re a boy or a girl and your family background.  They will record your height, 

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weight, and the type of disease that you have.  They will record any medicine you 
have taken up to 7 days before and during the procedure.   
• Your doctor or nurse will measure your blood pressure, temperature, pulse and 
breathing rate before and after the procedure.  If the red blood cell 
depletion/exchange procedure is used, these measurements will also be done 
about half way through the procedure.    
• You will give a small sample of blood (about 1 ½ tablespoons) to measure your 
blood counts and to see if any of your red blood cells have broken.  They will do 
this before and after the procedure.  If the red blood cell depletion/exchange 
procedure is used, the blood sample and testing will also be done about half way 
through the procedure.    
• If you are a girl and have had your first period, you will give some urine to see if 
you are pregnant at the beginning of the visit.  If you find out you’re pregnant 
during the study and up to 30 days after the procedure is completed, you have to 
tell your doctor.  
• Your doctor or nurse will use 2 of your veins to run the procedure. 
• You understand that your blood will be drawn into a kit.  The kit is attached to the 
device and is made up of tubing and plastic bags.  The kit will only be used one 
time. 
• Blood will be taken from one vein and the device will separate it into its 4 parts.   
• Your red blood cells will be collected in a plastic bag.   
• You will be given healthy donor red blood cells and some of your own blood in 
the other vein.   
• Depending on if you are a boy or girl, height, weight, and doctor’s orders, about 
6-22 cups of your blood will go through the machine and be given back to you.  
Only a portion of your blood will be removed at one time. 
• The blood that the device takes from you will be tested after the procedure is 
done.  The blood will be thrown away after the testing is done.  
• Your doctor or nurse will remove you from the machine as usual when the 
procedure is done.  
• The study staff will call you within a day to see how you are feeling.  You will tell 
them how you are feeling.  
• The AMICUS RBCx System is an experimental device.  This means that the 
Food and Drug Administration has not approved it for use in the clinic or hospital.  

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WHAT ARE THE GOOD THINGS ABOUT THE STUDY?  
Although you may not be helped directly from this study, you may help the researchers 
learn something that could help other children in the future who have sickle cell disease. 
III. 
WHAT ARE THE NOT-SO-GOOD, BAD, OR HARMFUL THINGS THAT 
COULD HAPPEN TO ME IF I AGREE TO BE IN THIS STUDY?  
You might have some side effects and discomfort while in the study.  Some side 
effects are tingling in the lips or fingers; strange smell, feeling, or taste; 
headache; shaking; feeling cold, and in extremely rare cases, your heart may 
stop beating.  It is unlikely, but you may experience skin redness, itching, hives, 
difficulty breathing, or cramps.  It is very rare, but it is possible that air may enter 
your blood; you may lose blood, or your blood may clot.  These rare risks can be 
very bad and serious.  Anytime you receive blood from a healthy donor; there is a 
risk of getting a harmful disease.  But a lot of testing has been done on the blood 
to help keep this from happening.  You may be given too much fluid.  If your 
heart, lungs and kidneys are healthy your body will be able to get rid of the extra 
fluid when you go to the bathroom.  If your heart, lungs, and kidneys are not 
healthy, it may be difficult for your body to get rid of the extra fluid.  If the extra 
fluid stays in your body, it may get into your lungs and make it hard for you to 
breathe.  If not enough fluid is given to you, you may feel dizzy.  Your doctors 
and nurses will watch you and how much fluid you have during the procedure to 
keep these problems from happening.  Your doctor and nurses will also make 
sure that your body is healthy enough for the red blood cell exchange procedure.   
Even though the doctors and nurses will use the right care, it is possible for you 
to get a bruise or an infection where they access your veins.  
If you have any of these or other bad feelings you must tell your doctor or nurses 
right away.  Your doctor and nurses will help you and try to help you feel better.  
The study staff will call you the next day after the procedure to see how you are 
feeling.  You will tell them how you are feeling. 
You will be told if your doctor learns new information that may make you change your 
mind about being in this study.    

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WHAT OTHER OPTIONS ARE THERE? 
You do not have to be in this study if you don’t want to.  Your doctor will still help 
you.   
If you join the study and then change your mind, it is okay for you to leave this 
study.  Your doctors will not be upset with you and will still try to help you feel 
better.  
IV. 
What about keeping my information private? 
Your doctors and nurses will do everything they can to make sure that your medical 
information and records are kept private. 
Unless it’s needed by law, only people from the following groups or organizations can 
see your study records. 
• Fresenius Kabi USA LLC 
• The United States Food and Drug Administration (FDA) 
• Technischer Überwachungs-Verein (Technical Inspection Association, Germany) 
(TÜV) 
• [List researchers and any other recipients]______________________________. 
 
They are required to keep your personal information private. 
 
V. 
WILL I RECEIVE ANY PAYMENT OR GIFTS IF I AM IN THIS 
STUDY?  
You will receive [$XXX] to refund study-related costs like driving and parking.  If you do 
not finish the study, you will be paid for the part of the study that you did finish.   
VI. 
WHAT IF I HAVE QUESTIONS?  
You can ask questions whenever you have them.  You can ask your doctor, nurse or 
other people working with them on the study (insert investigator name and/or study 
team contact information). You can also ask your parents.  
Your parents know about the study.  You don’t have to be in the study if you don’t want 
to.  

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You can ask (PI name) anything about the study. If you are not happy with this 
study and want to talk with someone else, not the doctor or the people working 
with the doctor, you may contact the IRB/EC at (insert IRB/EC contact 
information). 
You will be given a signed and dated copy of this form. 
You have read this assent form, and agree to take part in this study as it is explained in 
this assent form. 
 
______________
Date 
____________ 
Time 
______________________________________ 
Signature of Child (6-17 years old) 
 
______________ 
Age of Child  
 
 
______________________________________ 
Printed Name of Child 
 
 
 
___________________ 
 
Date 
Signature of Person Obtaining Assent 
 
 
 
 
Printed Name of Person Obtaining Assent 
 
 
 

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Appendix D. SUMMARY OF PRIOR NON-CLINICAL STUDIES 

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Summary of Prior Non-Clinical In Vitro Studies 
 
During the development phase of the AMICUS RBCx operating protocol, several internal in 
vitro studies using bagged blood were completed to assess the performance, safety and efficacy 
of RBCx procedures on the AMICUS separator.  This included evaluation of the new RBCx 
application software with the exchange spool/spool holder, AMICUS Exchange Kit (R4R2339) 
and Blood Component Filter Set with Vented Spike and Luer Adapter (R4C2170) (where 
applicable) currently cleared for use in AMICUS TPE procedures (K111702, 3/22/12).  Where 
applicable, it also included evaluation of the new ancillary disposable waste transfer set 
developed for use with AMICUS RBCx procedures.   
 
Feasibility Evaluation of AMICUS RBC Exchange Procedure, 345-REP-018203  
An internal in vitro feasibility study was performed to evaluate the performance of an RBC 
Exchange procedure on the AMICUS separator.  Data was collected concurrently on the COBE 
Spectra RBC Exchange procedure for informational purposes.  In this study, manually collected 
units of whole blood drawn from donors were pooled and processed by both the AMICUS and 
Spectra devices.  Measurements and samples were taken pre-procedure and post-procedure to 
evaluate RBC removal accuracy, end patient Hct accuracy and fluid balance accuracy. 
 
During this study, ten paired procedures were evaluated using pooled whole blood to represent 
the patient.  The pooled blood was warmed for the same amount of time, and mixed using a 
similar method prior to beginning the procedure on each instrument.  The AMICUS inlet flow 
rate was adjusted to the limit set by Spectra based on the input total blood volume.  The average 
total blood volume for each procedure was approximately 2500 mL.  Additional whole blood 
was hematocrit adjusted to simulate packed red blood cells as the replacement fluid.  Patient and 
procedure parameters were entered such that the two instruments removed a similar volume of 
red blood cells, targeted the same end patient Hct, and targeted the same fluid balance.   
 
The RBC removal accuracy was determined by calculating the percentage difference between the 
total actual volume of RBCs removed at the end of the procedure to the targeted RBCs to 
remove.  The values were 5.7% and 6.5% for AMICUS and Spectra, respectively, well within the 
study acceptance criteria of 8% or less.   
 
The end patient Hct accuracy was determined by comparing the end patient Hct value at the end 
of each procedure to the targeted end patient Hct value.  The average end Hct error for AMICUS 
was 1.3 Hct points, and for Spectra it was 0.6 Hct points, well within the study acceptance 
criteria of 5 points or less.  The results showed that when the target end Hct is less than or equal 
to the starting patient Hct, the AMICUS instrument is able to achieve the desired Hct within 2 
Hct points; however, when the target End Hct is greater than the starting patient Hct, the error 
increases to within 3 Hct points.  However, in this version of AMICUS software, the system 
focused on fluid balance as a primary goal and end Hct as a secondary goal.   

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The fluid balance accuracy was determined by comparing the difference between the actual fluid 
volume removed and replaced at the end of the procedure and the targeted fluid volume to be 
removed and replaced, and then dividing it by the total blood volume of the patient.  The actual 
fluid balance error for the AMICUS procedures was 1.4%, well below the study acceptance 
criteria of less than 10%. This was comparable to Spectra’s fluid balance error of -1.4%.   
 
Overall, the averages met the study requirement for RBC removal accuracy, end patient Hct 
accuracy and fluid balance accuracy.  The average results for all three values were within the 
acceptable ranges identified in the acceptance criteria, and established the feasibility of 
performing an RBC Exchange procedure on the AMICUS separator.   
 
The ability to achieve FCR was not evaluated in this study.  It was assumed that if RBC removal 
accuracy, end patient Hct and final fluid balance were similar between AMICUS and Spectra 
procedures, then FCR value would also be comparable.  Following this feasibility study, 
algorithms were implemented in the AMICUS software to include FCR as an endpoint to be 
achieved simultaneously with End Hct and Fluid Balance.  All three endpoints were evaluated in 
the development phase of the program. 
 
Evaluation of RBCx Procedures in Meeting Key Endpoints  
 
The following objectives were evaluated and are described in the in vitro studies referenced 
below. 
 

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Note:  Although the RBC Depletion procedure is not included in this clinical protocol, 
evaluations of this procedure are included in this section for comprehensive purposes. 
 
Objective 
Studies 
Confirm that AMICUS RBC Exchange, 
RBC Depletion/Exchange and RBC 
Depletion procedures meet established 
internal requirements for key endpoints:  
FCR, Hematocrit and Fluid Balance. 
Evaluation of RBCx Protocol: Evaluation 
of Amicus RBC Exchange Procedure,  
345-REP-028411 
 
Evaluation of RBCx Protocol: Evaluation 
of Amicus RBC Depletion/Exchange 
Procedure,  
345-REP-030680 
 
Evaluation of RBCx Protocol: Evaluation 
of AMICUS RBC Depletion Procedure, 
345-REP-030681 
 
Evaluation of Amicus RBCx Procedures: 
Non-Isovolemic Procedures,  
345-REP-031764 
Evaluate the generation of hemolysis 
during AMICUS RBC Depletion and RBC 
Exchange procedures under established 
worst case scenarios. 
Hemolytic Evaluation of AMICUS RBC 
Depletion and Exchange Procedures,  
345-REP-031106 
Perform AMICUS RBC Exchange 
procedures using sickle cell waste blood 
obtained from patient procedures to 
examine flow and pressure characteristics 
and evaluate hemolysis generation.  
Evaluation of AMICUS RBC Exchange 
Procedure Using Sickle Cell Blood,  
345-REP-030759  
 
 
To evaluate the first objective, four separate in vitro protocols were conducted to study a 
combination of FCR, Hct, and Fluid Balance target endpoints.  These studies evaluated the 
performance of the AMICUS RBCx procedures and concurrently collected data on the COBE 
Spectra Apheresis System.   
 
To simulate an abnormal hemoglobinopathy condition, each procedure used a common pool of 
Type A whole blood (WB) units to represent the patient’s abnormal cells, and a common pool of 
Type O, AS-1 red cells as the replacement fluid (RF).  Flow cytometry was used to measure the 
fraction of Type A cells remaining in the patient pool at the end of the procedure.  This value 
was analogous to the FCR at the end of the procedure.  Equivalent patient and procedure 
parameters were entered into the AMICUS and Spectra separators and run under the same 

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environmental conditions.  The units of pooled blood were warmed for the same lengths of time 
and mixed throughout the procedure.  Where applicable, a commercial blood warmer was used in 
both the AMICUS and Spectra procedures.   
 
The internal system requirement specifications for the four studies were: 
 
• The actual FCR shall be within ± 3 of the targeted FCR, on average. 
• The procedure shall achieve the targeted end hematocrit with an accuracy of ± 3, on 
average. 
• The fluid balance error (defined as the difference between the actual fluid removed and 
replaced and the targeted fluid to be removed and replaced, divided by the total blood 
volume of the patient) shall be less than 5%, on average. 
• The difference between the displayed "current fluid balance" and the patient's 
real-time fluid balance shall be within 15% of the total blood volume of the patient.  
(Applicable only to Evaluation of Amicus RBCx Procedures: Non-Isovolemic 
Procedures, 345-REP-031764) 
 
Each of the four studies are summarized below. 
 

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Evaluation of RBCx Protocol: Evaluation of Amicus RBC Exchange Procedure, 
345-REP-028411 
The purpose of this study was to evaluate the performance of the RBC Exchange procedure on 
the AMICUS separator, and to concurrently collect data on an RBC Exchange procedure on 
COBE Spectra for comparison.  Measurements and samples were taken pre and post-procedure 
to evaluate the accuracy of FCR, End Patient Hct and Fluid Balance.  Intra-procedure sampling 
was performed where appropriate.   
 
Table 1: Descriptive Statistics of Fluid Balance, FCR, and Hct 
 
Fluid Balance 
FCR 
Hct 
Amicus 
Spectra 
Amicus 
Spectra 
Amicus 
Spectra 
N 
27 
27 
27 
27 
27 
27 
Average 
2.83 
9.10 
1.65 
2.99 
0.56 
0.98 
Standard Deviation 
1.95 
3.57 
1.46 
2.16 
0.47 
1.03 
Minimum 
0.04 
0.11 
-4.75 
-6.69 
-1.00 
-1.00 
Maximum 
8.50 
16.85 
5.03 
6.92 
1.00 
3.50 
95% Upper Bound 
3.46 
10.27 
2.13 
3.70 
0.71 
1.32 
p value1 
0.00 
1.00 
0.00 
0.49 
0.00 
0.00 
Note: FCR and Hct data were represented as the difference of target to actual values for the minimum and 
maximum.  The absolute difference of target to actual values was presented for all other data. 
1 Statistical significance was taken at p< 0.05. 
 
Since the p-values of the t-test for AMICUS FCR, Hct, and Fluid Balance, and for Spectra Hct, 
were less than 0.05, there was enough statistical evidence to conclude with 95% confidence that, 
for AMICUS, the mean was less than 3 points for FCR and Hct and less than 5% for fluid 
balance.   
 
The results show that the performance of AMICUS, on average, meets the requirements for FCR, 
Hct and Fluid Balance accuracy and that AMICUS is capable of meeting performance targets for 
the RBC Exchange procedure.   The Spectra device, on average, did not pass the internal 
requirements established for Fluid Balance accuracy, but did pass for FCR and Hct accuracy.   
 
 

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Evaluation of RBCx Protocol: Evaluation of Amicus RBC Depletion/Exchange 
Procedure, 345-REP-030680 
This study evaluated the performance of the AMICUS RBC Depletion/Exchange procedure, and 
concurrently collected data on COBE Spectra’s Isovolemic Hemodilution - Red Cell Exchange 
procedure1 for comparison.  The Spectra procedure was performed through the manual 
connection of two functions:  RBC depletion, followed in quick succession by RBC exchange.  
Measurements and samples were taken pre and post-procedure to evaluate accuracy of FCR, 
(post-exchange), patient Hct (post-depletion and post-exchange) and Fluid Balance. 
 
Table 2: Descriptive Statistics of FCR, Hct and Fluid Balance 
 
FCR 
Depletion End Hct 
Exchange End Hct 
Fluid Balance 
Accuracy 
Amicus 
Spectra 
Amicus 
Spectra 
Amicus 
Spectra 
Amicus 
Spectra 
N 
24 
24 
24 
24 
24 
24 
24 
24 
Average 
0.97 
2.04 
0.39 
0.12 
0.22 
0.77 
3.43 
4.21 
Standard Deviation 
0.89 
1.29 
0.38 
0.27 
0.31 
0.78 
1.04 
1.88 
Minimum 
-3.97 
-3.92 
-0.50 
-0.75 
-1.00 
-1.00 
1.14 
1.08 
Maximum 
2.51 
5.31 
1.00 
0.50 
0.50 
3.00 
4.97 
9.16 
95% Upper Bound 
1.28 
2.50 
0.52 
0.27 
0.33 
1.04 
3.79 
4.87 
p value1 
0.000 
0.001 
0.000 
0.000 
0.000 
0.000 
0.000 
0.026 
1 Statistical significance was taken at p< 0.05. 
 
Since the p-values of the t-test for AMICUS and Spectra FCR, Hct, and Fluid Balance for were 
less than 0.05, there was enough statistical evidence to conclude with 95% confidence that the 
AMICUS mean was less than 3 points for FCR and Hct and less than 5% for Fluid Balance.   
 
The results show that the performance of AMICUS, on average, meets the internal requirements 
for FCR, End Hct and Fluid Balance.  The data collected on Spectra meet the internal 
requirements as well.  The averages for AMICUS are overall less than those of Spectra with the 
exception of the depletion End Hct.  Because some depletion replacement fluid was still present 
in the replacement fluid drip chambers at the end of depletion, the Hct was slightly higher in the 
simulated patient than the depletion end target.  The depletion end target was met at the very 
beginning of the exchange portion of the procedure when this remaining depletion fluid was 
returned to the simulated patient.  This short delay in hitting the depletion end hematocrit was 
accounted for by the system which is evidenced by the more accurate exchange end hematocrit.  
Both end hematocrit averages, however, are within the acceptance criterion set in the protocol.  
Overall, the results of the study show that the AMICUS is capable of meeting performance 
targets of the RBC Depletion/Exchange procedure. 

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Evaluation of RBCx Protocol: Evaluation of AMICUS RBC Depletion Procedure,  
345-REP-030681 
The report for the evaluation of the AMICUS RBC Depletion procedure is a compilation of data 
from two in vitro studies conducted for the new RBCx protocol: Evaluation of AMICUS RBC 
Depletion/Exchange Procedure (345-REP-030680) and Hemolytic Evaluation of AMICUS RBC 
Depletion and Exchange Procedures (345-REP-031106).  In the Depletion/Exchange study, the 
simulated patient was depleted 5 or 10 Hct points from its starting Hct.  In the Hemolysis study, 
Depletion procedures were performed with a high Hct simulated patient which was depleted 30 
Hct points from its starting Hct.  The following data was used to evaluate the RBC Depletion 
procedure:  the end Hct data at the end of the depletion phase of the Depletion/Exchange 
procedure performed on AMICUS and the depletion End Hct and Fluid Balance accuracy data 
from the AMICUS Hemolysis study. 
 
Table 3: Descriptive Statistics of Hct and Fluid Balance Accuracy 
 
Depletion/ 
Exchange Study 
Hct 
Hemolysis Study 
Hct 
Overall Hct 
Fluid Balance 
Accuracy 
Hematocrit delta 
-10% or -5% 
-30% 
Replacement Fluid 
PBS2 or Albumin 
Saline 
N 
24 
9 
33 
9 
Average 
0.39 
0.69 
0.47 
2.01 
Standard Deviation 
0.38 
0.39 
0.40 
0.70 
Minimum 
-0.50 
-1.00 
-1.00 
1.05 
Maximum 
1.00 
0.00 
1.00 
3.00 
95% Upper Bound 
0.52 
0.94 
0.59 
2.44 
p value1 
0.000 
0.000 
0.000 
0.000 
Note: Hct data is represented as the difference of target to actual values for the minimum and maximum.  The 
absolute difference of target to actual values was presented for all other data. 
1 Statistical significance was taken at p< 0.05. 
2Phosphate Buffered Saline 
 
Since the P-Values of the t-test for hematocrit is less than 0.05, there was enough statistical 
evidence to conclude with 95% confidence that the mean was less than 3 for Hct. 
 
The results show that the performance of AMICUS, on average, meets the internal requirements 
for Hct and Fluid Balance accuracy. The Hct data taken from the Depletion/Exchange study were 
slightly higher than what the system targeted for the depletion End Hct. This is because some 
depletion replacement fluid was still present in the replacement fluid drip chambers at the end of 

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the depletion portion of the procedure.  The depletion end target was met at the very beginning of 
the exchange portion of the procedure when this remaining depletion fluid was returned to the 
simulated patient.  However, the data taken from the Depletion/Exchange study were still within 
the acceptance criterion set in the protocol.  Overall, the results of this study show that the 
AMICUS is capable of meeting performance targets for the RBC Depletion procedure. 
 
Evaluation of Amicus RBCx Procedures: Non-Isovolemic Procedures, 345-REP-031764 
During some RBCx procedures, the operator may choose to increase or decrease the blood 
volume of the patient by adjusting the target fluid balance.  This study evaluated the performance 
of the AMICUS RBC Exchange procedure with an alteration in patient fluid volume (i.e., non-
isovolemic).  Data was collected for comparison on COBE Spectra.  Measurements and samples 
were taken pre and post-procedure to evaluate the accuracy of FCR, End Patient Hct and FCR. 
 
Table 4: Descriptive Statistics of FCR, Hct and Fluid Balance 
 
FCR 
Hct 
Fluid Balance 
Amicus 
Spectra 
Amicus 
Spectra 
Amicus 
Spectra 
N 
12 
12 
12 
12 
12 
12 
Avg 
1.05 
5.27 
0.42 
1.71 
2.51 
3.44 
SD 
0.78 
3.65 
0.42 
1.44 
1.36 
2.59 
Min 
-2.16 
-5.71 
-1.0 
-3.0 
0.33 
0.26 
Max 
1.10 
12.31 
0.5 
4.0 
4.77 
8.86 
95% Upper Bound 
1.46 
7.16 
0.63 
2.62 
3.21 
4.78 
p value1 
0.000 
0.973 
0.000 
0.005 
0.000 
0.030 
Tolerance Bounds 
NA 
NA 
NA 
NA 
[-6.64,1.82] 
[-14.31,10.03] 
Note: FCR and Hct data were represented as the difference of target to actual values for the minimum and 
maximum.  The absolute difference of target to actual values were presented for all other data. 
1 Statistical significance was taken at p< 0.05. 
 
Since the p-values of the t-test for AMICUS FCR, Hct, and Fluid Balance, and for Spectra Hct 
and Fluid Balance, were less than 0.05, there was enough statistical evidence to conclude with 
95% confidence that the mean was less than 3 points for FCR and Hct and less than 5% for Fluid 
Balance.   
 
A minimum of 95% of the procedure types performed will fall within the tolerance bounds listed 
for Fluid Balance with a confidence level of 95%.  Neither the tolerance interval for AMICUS 
nor Spectra included a value greater than 15.00, so these parameters met the internal 
requirement. 
 
The results showed that the performance of AMICUS on average, meets the requirements for 
FCR, End Hct and Fluid Balance accuracy.  The data collected on Spectra show that it meets the 
requirements for End Hct and Fluid Balance, but not for FCR.  The errors in End Hct and FCR 

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for Spectra appeared to be correlated with the type of run, both by target fluid balance and total 
patient blood volume tested. Overall, both the average errors and the standard deviations of all 
targets were less for AMICUS than for Spectra. 
 
 

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Hemolytic Evaluation of AMICUS RBC Depletion and Exchange Procedures,  
345-REP-031106 
The objective of this in vitro study was to evaluate the amount of hemolysis generated during 
AMICUS RBC Depletion and RBC Exchange procedures under foreseeable worst case 
conditions, including:  
 
• 
Small diameter needles 
• 
Simulated high hematocrit patient blood 
• 
High hematocrit replacement fluids 
• 
Highest allowable whole blood flow rates 
• 
Elevated replacement fluid flow rates 
• 
Use of in-line replacement fluid filters 
• 
No flow conditions through the centrifuge 
 
The elevated Hct levels increased the viscosity of the blood flowing through the disposable that 
may increase the shear force to which the RBCs were exposed.  Therefore, the study primarily 
examined shear force as a potential cause of hemolysis.   
 
The following internal requirements were evaluated during this protocol: 
 
• The allowable mean difference in a patient’s concentration of hemoglobin is less than 
25  mg/dL. 
• The maximum hemoglobin load which can be given to a patient (45 kg) and results in 
none/negligible harm is 900 mg. 
• The maximum hemoglobin load which can be given to a pediatric patient (10 kg) and 
results in none/negligible harm is 200 mg. 
• The maximum hemoglobin load which can be given to a pediatric patient (10 kg) that 
results in minor harm is 400 mg. 
 
Ten in vitro RBC Depletion procedures were performed with whole blood units from healthy 
donors that were pooled, spun and had plasma volume removed to simulate patients with high 
hematocrits.  The whole blood flow rate was maintained at the highest possible rate that did not 
induce inlet pressure related alarms.  The RBC Depletion procedures examined the amount of 
hemolysis generated by the system.  A given red cell only passes once through the disposable 
from the simulated patient to the waste container.  Any plasma hemoglobin created during this 
process was returned to the simulated patient through the separated plasma.  The combination of 
high flow rates, small diameter needles (18 gauge), and high hematocrit blood created a 
reasonably foreseeable worst case scenario for shear force during an RBC Depletion procedure. 
 
The change in the Patient Plasma Hemoglobin Concentration was the difference between pre and 
post-plasma hemoglobin levels.  
 
For each Depletion procedure, patient pre and post-procedure and waste RBC product samples 
were measured for plasma hemoglobin.   

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Table 5: Plasma Hemoglobin Concentration in RBC Depletion Procedures (mg/dL) 
 
Patient Pre 
Patient Post 
Patient Delta 
Waste Product 
N 
10 
10 
10 
10 
Avg 
32.530 
18.520 
-14.0101 
16.860 
SD 
10.882 
6.039 
8.101 
5.170 
Min 
23.900 
10.100 
-34.40 
9.200 
Max 
59.700 
26.700 
-5.40 
23.700 
1 Does not consider the effect of dilution by the RF saline returned to the simulated patient nor the static condition of 
a bagged blood system. 
 
Hemoglobin mass calculations were also performed for each procedure.  The patient delta is the 
difference between the pre and post-hemoglobin mass. 
 
The change in the System Total Hemoglobin Mass was calculated for each procedure using the 
following formula: 
 
(Patient Post + Waste) – Patient Pre = System Delta 
 
 
Additionally, ten in vitro RBC Exchange procedures were performed with high hematocrit 
replacement fluids.  The return flow rates of both the replacement fluid and the plasma were 
intentionally elevated through procedure targets (i.e., increased target end hematocrit, increased 
fluid balance).  The elevated flow rates exposed the replacement fluid to potentially higher shear 
forces and maximized the return of plasma free hemoglobin to the simulated patient.    The 
Exchange procedures examined the amount of hemolysis created by both separation and 
replacement.  A given red cell potentially completed a full circuit through the disposable, passing 
from the RBC replacement fluid container to the simulated patient and then to the waste 
container.  Any free hemoglobin created during this process may eventually be carried back to 
the simulated patient through the separated plasma.  The combination of high hematocrit 
replacement fluid, the use of a replacement line blood component filter, and the targeting of 
elevated return rates created a worst case scenario for shear force during an RBC Exchange 
procedure. 
 
Table 6: Total Hemoglobin Mass in RBC Depletion Procedures (mg) 
 
Patient Pre 
Patient Post 
Patient Delta 
Waste Product 
System Delta 
N 
10 
10 
10 
10 
10 
Avg 
167.30 
218.90 
51.600 
94.600 
146.30 
SD 
77.04 
77.95 
53.158 
34.735 
72.89 
Min 
111.00 
106.00 
-17.000 
44.000 
39.00 
Max 
373.00 
359.00 
124.000 
157.000 
255.00 

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For each Exchange procedure, patient pre and post-procedure, waste plasma, and RF unit 
samples were measured for plasma hemoglobin.  
  
Table 7: Plasma Hemoglobin Concentration in RBC Exchange Procedures (mg/dL) 
 
Patient Pre 
Patient Post 
Patient Delta 
RF 
Waste Plasma 
N 
10 
10 
10 
10 
10 
Avg 
3.1100 
30.270 
27.1701 
77.760 
14.010 
SD 
1.8466 
9.182 
8.362 
33.022 
3.970 
Min 
0.0000 
16.500 
15.100 
37.100 
7.900 
Max 
6.0000 
43.600 
42.000 
132.600 
19.700 
1 Includes the contribution of plasma hemoglobin concentration from the RF. 
 
Hemoglobin mass calculations were also performed for each procedure.  The patient delta is the 
difference between the pre and post-hemoglobin mass.  
 
The change in the System Total Hemoglobin Mass was calculated for each procedure using the 
following formula: 
 
(Patient Post + Waste) – (Patient Pre + RF) = System Delta 
 
 
 
 
Table 8: Total Hemoglobin Mass in RBC Exchange Procedures (mg) 
 
Patient Pre 
Patient Post 
Patient Delta 
RF 
Waste 
System 
N 
10 
10 
10 
10 
9 
9 
Avg 
40.000 
340.30 
300.30 
273.10 
127.67 
149.44 
SD 
23.405 
99.73 
87.12 
89.34 
44.40 
85.89 
Min 
0.000 
190.00 
169.00 
138.00 
72.00 
12.00 
Max 
76.000 
447.00 
426.00 
413.00 
202.00 
279.00 

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The results showed that: 
 
• 
During RBC Depletion procedures, the mean difference in the simulated patient’s 
hemoglobin concentration (-14.010 mg/dL) was significantly less than 25 mg/dL 
(Table 5). 
• 
During RBC Depletion procedures, the mean increase in the simulated patient’s 
hemoglobin mass (51.600 mg) was significantly less than 200 mg (Table 6). 
• 
During RBC Exchange procedures, there was not enough statistical evidence to reject 
the null hypothesis that the hemolysis generation was greater than 25 mg/dL with 
95% confidence.  Since the RBC Exchange procedures used red cell replacement 
fluid that already contained some level of hemolysis, this adds variability to the 
simulated patient’s post-procedure hemoglobin concentration.  To observe the 
hemolysis generated by the AMICUS Separator alone, see 345-REP-030759 
(Table  7). 
• 
During RBC Exchange procedures, the mean increase in the simulated patient’s 
hemoglobin mass (300.30 mg) was significantly less than 400 mg (Table 8). 
 
Since this study simulated the real-use condition of using red cell replacement fluid, it is difficult 
to discern if the hemolysis generated is due to the system or the replacement fluid.  Even if it 
were assumed that all hemolysis generated was due to the system operating under the established 
worst-case conditions, this would still only present a minor risk of harm.   
 
Evaluate RBCx System Using Waste Sickle Cell Blood  
An in vitro protocol was conducted to evaluate the performance of the AMICUS RBCx System, 
including hemolysis generation, using waste sickle cell blood from actual patient RBC Exchange 
procedures. 
 
Evaluation of AMICUS RBC Exchange Procedure Using Sickle Cell Blood,  
345-REP-030759  
The purpose of this study was to evaluate the performance of the AMICUS RBC Exchange 
procedure when processing waste sickle red blood cells obtained from patients who had 
undergone an RBC Exchange procedure using a commercially cleared therapeutics apheresis 
device.  Samples of simulated patient plasma were collected prior to, during, and after running 
the RBC Exchange procedure on the AMICUS instrument.  The study evaluated the hemolysis 
generation of the AMICUS system as well as the functionality of the Amicus RBC Exchange 
procedure when running sickle red blood cells.  
 
Ten procedures were performed using an 18 GA needle and programming the maximum inlet 
rate at 120 mL/min.  Five procedures were performed using an 18 GA needle and programming 
the maximum inlet rate at 10 mL/min.  Additionally, five procedures were performed using a 21 
GA needle and programming a maximum inlet rate of 120 mL/min. Not all procedures were able 
to process blood at the set maximum inlet rate due to low inlet pressure alarms.  In these 
instances, the maximum inlet rate was reduced until the inlet pressure was within the allowable 

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limits.  This is representative of system behavior in normal use and does not affect the validity of 
the data gathered during these procedures. 
 
During the RBC Exchange procedure, the waste sickle cell blood was drawn into the AMICUS 
system while saline was returned as RF.  After the blood was separated, the plasma was collected 
and analyzed for plasma hemoglobin levels.   
 
The following internal requirement was evaluated: 
 
The mean difference (pre to post) in the concentration of hemoglobin shall be less than 25 mg/dL 
in a donor/patient following a procedure.   
 
The data in the following tables demonstrates the change in plasma hemoglobin level from the 
pre-procedure sample to the final inline procedure sample for each needle size/flow rate 
configuration noted above.  
 
Table 9: Plasma Hemoglobin Levels, 120 mL/min Max, 18 GA Needle 
Date 
Actual Inlet 
Rate 
(mL/min) 
Pre Sample 
(mg/dL) 
Final 
Inline 
Sample 
(mg/dL) 
Change in Pls Hb 
Levels (Pre to Final 
Inline Sample, mg/dL) 
1/30/2014 
100 
13.5 
18.7 
5.2 
1/31/2014 
90 
12 
13.7 
1.7 
2/14/2014 
120 
19.1 
13.8 
-5.3 
2/19/2014 
120 
1.8 
1.5 
-0.3 
2/21/2014 
120 
6.9 
7.2 
0.3 
2/26/2014 
120 
7 
8.1 
1.1 
3/6/2014 
120 
8.6 
9.5 
0.9 
3/28/2014 
120 
12.9 
12.6 
-0.3 
4/4/2014 
120 
20.7 
17.5 
-3.2 
4/21/2014 
120 
14.6 
14.5 
-0.1 
 
 
 

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Table 10: Plasma Hemoglobin Levels, 10mL/min Max, 18 GA Needle 
Date 
Actual Inlet 
Rate 
(mL/min) 
Pre Sample 
(mg/dL) 
Final 
Inline 
Sample 
(mg/dL) 
Change in Pls Hb 
Levels (Pre to Final 
Inline Sample, 
mg/dL) 
3/19/2014 
10 
13.2 
14.5 
1.3 
3/26/2014 
10 
12 
10.7 
-1.3 
4/24/2014 
10 
17.5 
17.9 
0.4 
5/14/14 
10 
14.7 
15.8 
1.1 
6/6/14 
10 
121.41 
101.9 
-19.5 
1Retrospectively, it was  confirmed that the patient’s waste product was hemolyzed 
prior to in vitro testing.    
 
Table 11: Plasma Hemoglobin Levels, 120 mL/min, 21 GA Needle 
Date 
Actual 
Inlet Rate 
(mL/min) 
Pre Sample 
(mg/dL) 
Final 
Inline 
Sample 
(mg/dL) 
Change in Pls Hb 
Levels (Pre to 
Final Inline 
Sample, mg/dL) 
4/16/2014 
20 
9.8 
12.6 
2.8 
4/18/2014 
30 
89.71 
81.5 
-8.2 
4/23/2014 
20 
19.9 
17.8 
-2.1 
6/30/14 
20 
11.5 
11.9 
0.4 
7/14/14 
20 
18.4 
17.8 
-0.6 
1Retrospectively, it was confirmed that the patient’s waste product was hemolyzed 
prior to in vitro testing. 
 
The data shows that the pre samples frequently showed less hemolysis than the source blood.  
This can be explained by the dilution of the source blood by saline already present in the kit 
following saline prime.  As the saline is cleared from the kit, it has less of an effect on 
hemoglobin levels.  Thus, for evaluation of hemolysis generated by the system, the pre sample 
was compared to the final sample taken from the plasma line as this will include the least amount 
of saline; while the post-procedure sample will include the saline that has been pumped into the 
plasma collection bag.  
 
The results show that when the AMICUS RBCx Exchange procedure is performed with 18 and 
21 gauge needles at various flow rates, the difference between pre and post procedure plasma 
hemoglobin values is less than the internal requirement of 25 mg/dL.  Additionally, during the 
procedures, no significant issues were encountered and the procedures proceeded as expected.  
From this evaluation, it can be concluded that the AMICUS RBC Exchange procedure does not 
generate hemolysis when processing sickle cell blood at various flow rates through 18 and 21 
gauge needles.

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Appendix E. SUMMARY OF PRIOR PRE-CLINICAL STUDIES 
 
 

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Summary of Pre-Clinical In Vivo Studies 
 
Donor Room Evaluation of the AMICUS Red Blood Cell Exchange (RBCx) System 
AMIC-002-CMD 
 
This exploratory study was the first human use evaluation in the product development process 
for the AMICUS RBCx System.  The study performed utilized investigational software that can 
provide three procedures: RBC Exchange, RBC Depletion/Exchange and RBC Depletion.  The 
study evaluated the RBC Depletion procedure in healthy human adult subjects and collected data 
on the functional operation of the RBCx System (hardware, software, and disposables) prior to 
initiation of external studies.  The protocol enrolled healthy subjects and therefore did not 
evaluate RBC Exchange or RBC Depletion/Exchange procedures, due to ethical considerations. 
EC/IRB approval of the protocol, including the informed consent form was obtained prior to the 
start of the study.  Subjects provided written informed consent prior to participation in the study.   
The in vivo study included two phases; the Phase 1 consisted of one-way pass abbreviated 
procedures that collected a single unit of whole blood, (up to 550 mL without anticoagulant) 
without return of processed fluids or blood components to the subject. The whole blood was 
drawn from the subject and processed in the AMICUS centrifuge, the red blood cells were 
collected in the kit waste containers with the plasma collected in a separate attached sterile 
transfer pack.  The return line was connected to a second attached sterile transfer pack.   
 
Phase 2 of the study consisted of two-way pass procedures that removed a total absolute RBC 
volume up to a maximum of 420 mL, including samples, from subjects and autologous plasma 
(along with some anticoagulant) was returned with saline replacement fluid.  The AMICUS 
Separator System is currently cleared for the collection of an RBC product of approximately 235 
mL in conjunction with a platelet collection (BK000039).  Subjects participating in two-way pass 
procedures were required to meet the eligibility criteria for 2RBC collections using the 
nomogram developed for the FDA cleared ALYX Component Collection System double RBC 
apheresis donations. 
 
 

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Phase 1: One-way Pass Procedure Results 
In the one-way pass procedures, a total of 8 subjects, 7 male and one 1 female with an average 
age of 41.6 ± 15.06 (range: 23-64) participated.  The saline used as replacement fluid was 
diverted to a sterile transfer pack attached to the return line needle.  The pre to post-procedure 
changes in the subjects’ blood pressure measurements, pulse and temperature were 
unremarkable. (Table 1)    
 
Table 1 Summary of Subject Parameters  
(One-way Pass Procedures) 
Parameter 
N 
Mean (SD) 
Median 
Min, Max 
Weight (lbs) (Pre-Procedure) 
8 
192.4 (28.64) 
190.0 
153, 236 
Height (in) (Pre-Procedure) 
8 
69.5 (3.82) 
70.0 
63, 74 
Systolic Blood Pressure 
(mmHg) 
 
 
 
 
          Pre-Procedure 
8 
119.5 (11.77) 
118.0 
103, 140 
          Post-Procedure 
7 
120.7 (14.08) 
122.0 
102, 140 
Diastolic Blood Pressure 
(mmHg) 
 
 
 
 
          Pre-Procedure 
8 
71.1 (11.27) 
68.5 
57, 95 
          Post-Procedure 
7 
77.7 (12.67) 
80.0 
60, 98 
Pulse (bpm) 
 
 
 
 
          Pre-Procedure 
8 
69.1 (8.51) 
70.0 
55, 80 
          Post-Procedure 
7 
71.4 (9.64) 
68.0 
60, 84 
Temperature (°F) 
 
 
 
 
          Pre-Procedure 
8 
97.40 (0.888) 
97.30 
96.4, 98.4 
          Post-Procedure 
7 
97.57 (0.637) 
97.40 
96.8, 98.2 
Fingerstick Hematocrit (%) 
8 
44.06 (4.011) 
43.85 
38.4, 50.5 
Clinical Study Protocol: AMIC-002-CMD 
Note: NA=Not Applicable; UNK=Unknown; ND=Not Done 
Table Status: DRAFT; SAS Program: Table 14.3.sas: 25OCT2014:21:56:15 
Cross reference: Listing 16.3 
 
 
 

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The subjects’ pre to post-procedure changes in hematology (RBC, WBC, platelet counts and 
hematocrit) were within expected values and no clinically significant differences were observed 
during the one-way pass procedures. (Table 2)   
 
Table 2  Summary of Subject Hematology  
(One-Way Pass Procedures)  
Parameter 
N 
Mean (SD) 
Median 
Min, Max 
White Blood Cell Count (WBC) (x103/µL) 
 
 
 
 
          Pre-Procedure 
7 
5.61 (1.785) 
5.10 
4.1, 9.0 
          Post-Procedure 
7 
5.39 (1.792) 
5.10 
3.8, 8.8 
Red Blood Cell Count (RBC) (x106/μL) 
 
 
 
 
          Pre-Procedure 
7 
5.059 (0.5348) 
5.000 
4.42, 5.87 
          Post-Procedure 
7 
4.724 (0.5927) 
4.710 
4.01, 5.60 
Platelet Count (x103/μL) 
 
 
 
 
          Pre-Procedure 
7 
214.7 (15.01) 
212.0 
190, 238 
          Post-Procedure 
7 
214.9 (14.50) 
222.0 
190, 228 
Hematocrit (%) 
 
 
 
 
          Pre-Procedure 
7 
42.41 (3.948) 
41.80 
37.7, 47.9 
          Post-Procedure 
7 
39.53 (4.455) 
39.80 
34.2, 45.6 
Plasma Hemoglobin (mg/dL) 
 
 
 
 
          Pre-Procedure 
7 
7.49 (2.781) 
7.10 
5.0, 13.1 
          Post-Procedure 
7 
7.76 (3.754) 
6.80 
2.4, 13.2 
Clinical Study Protocol: AMIC-002-CMD 
Note: NA=Not Applicable; UNK=Unknown; ND=Not Done 
Table Status: DRAFT; SAS Program: Table 14.4.sas: 26OCT2014:19:48:58 
Cross reference: Listing 16.4 
 
The mean subject pre-procedure plasma hemoglobin value was 7.49 ± 2.781 mg/dL (range: 5.0-
13.1 mg/dL).  Note, the lower level of sensitivity of the plasma hemoglobin assay was 
2.4 mg/mL.  One subject (05002) reported two mild, single adverse events (infiltration and 
hematoma) related to an unsuccessful venipuncture prior to the start of the procedure.  The 
subject was treated, recovered and was released without completing the procedure.  There was no 
relationship to the investigational procedure.  No serious or unexpected adverse events occurred 
during this phase of the study. 
 
The procedures were uneventful and comparable to a whole blood donation with a mean duration 
time of 11.3 ± 1.80 minutes (range: 10-15 minutes). The programmed AC Ratio, citrate infusion 
rate and the mean whole blood flow rate were 12:1, 1.25 mg/kg/min, and 64.9 ± 9.26 mL/min, 
(range: 53-80 mL/min), respectively.  An average anticoagulated whole blood volume of 
495.7 ± 0.49 mL (range: 495-496 mL) was withdrawn from the subjects and separated into 
separate containers for the waste RBC material and plasma collected.  The mean volume of 
plasma collected was 192.93 ± 26.621 mLs (range: 158.7-231.7).  There was no significant 
hemolysis in the plasma collected during the procedure, as demonstrated by the low mean 
plasma hemoglobin concentration, 4.21 ± 2.976 mg/dL (range: 2.4 – 10.4 mg/mL). 

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It was noted that the Fluid Balance from the procedure results had a mean of 9.7 ± 6.24 mL 
(range: 0-19 mL) when the expected Fluid Balance was zero.  Also, the Saline to Subject was 
observed to be the same values reported for Fluid Balance.  Further investigation determined that 
a positive fluid balance can occur when the saline administration feature used after venipuncture, 
is active during the Load Replacement Fluid screen, to allow operators to maintain vein patency.  
As described in the operator’s manual, the needle prime should be stopped using the Stop Needle 
Prime button.  In the study procedures in which a minimal volume of saline delivered was 
reported, the operator did not press the Stop Needle Prime button on the Procedure Setup screen.  
Prior to pressing the Begin Depletion button to start the procedure, the operator opened the roller 
clamps on the inlet and return lines. During this brief period of time, saline was sent to the sterile 
transfer pack that was connected to the return line and was hanging on the side of the instrument 
positioned below the subject’s arm. The AMICUS instrument appropriately reported this saline 
weight scale difference and updated the Fluid Balance accordingly.  Additional training was 
provided to the Donor Room staff prior to the start of two-way procedures, to minimize the 
volume of saline administered following venipuncture.  
 
One cassette pressure limit exceeded alarm was reported (Subject # 05001) and was due to the 
operator forgetting to open a roller clamp on the plasma transfer set.  The roller clamp was 
opened and the procedure was resumed without further incident. 
 
These abbreviated one-way pass procedures verified that the functionality of the RBCx System 
when used with a human subject supported the data obtained during system verification testing.  
The changes observed for the subject parameters pre and post-procedure were not clinically 
significant. No functional issues were identified or unanticipated adverse device effects were 
reported during these procedures.  A procedural observation was made and was addressed with 
additional training of the Donor Room Staff.  Based on the review of these one-way pass 
procedures, the data were acceptable and demonstrated subject safety to proceed to two-way pass 
procedures. 
 
Phase 2: Two-way Pass Procedures 
The second phase consisted of two-way pass RBC Depletion procedures that removed a limited 
volume of RBCs and maintained isovolemia with saline and plasma.   
Participants met the Sponsor’s Donor Room requirements per Standard Operating Procedure for 
subject safety guidelines for whole blood donations.  In addition, the nomogram used with 
double RBC donations, i.e., the FDA cleared ALYX System Double RBC apheresis collection 
(Table 2) was used to further qualify subjects and define the maximum total absolute RBC 
volume that was removed (including samples) based on the subject gender, height, weight, and 
hematocrit or hemoglobin.  The acceptable End Hematocrit was determined prior to the start of 
the procedure by using the subject’s pre-procedure hematocrit, total blood volume, and by 
adjusting the End Hematocrit until the Depletion Red Cell Volume parameter did not exceed the 
maximum RBC volume limit for each subject.  During the procedure, whole blood was drawn 

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from the subject and processed.  Up to the equivalent of a double RBC collection including 
samples (i.e., no more than 420 mL of absolute RBCs) was collected in the kit waste containers.  
Autologous plasma was returned to the subject during the procedure with some anticoagulant 
and saline replacement fluid.  Reinfusion was not performed during any of the procedures.   
 
Table 2  Nomogram for Participation in Two-way Pass Procedures 
Subject Weight 
(lbs) 
Height 
(inches) 
Hematocrit 
(%) 
Hemoglobin 
(g/dL) 
Maximum Total 
Absolute RBC 
Volume (mL) 
Male 
130-149 
≥61 
≥ 40 
≥ 13.3  
360 
150-174 
≥61 
≥ 40 
≥ 13.3 
400 
≥175 
≥61 
≥ 40 
≥ 13.3 
420 
Female 
150-174 
≥65 
≥ 40 
≥ 13.3 
360 
≥175 
≥65 
≥ 40 
≥ 13.3 
400 
 
 
 

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A total of 18 subjects, 17 male and one 1 female with an average age of 39.3 ± 10.4 (range: 23-
56) were enrolled and provided 15 evaluable procedures. All donors met the required 2RBC 
eligibility criteria. The pre to post-procedure changes in the subjects’ blood pressure 
measurements, pulse and temperature were unremarkable. (Table 3) 
Table 3  Summary of Subject Parameters  
(Two-way Pass Procedures) 
Parameter 
N 
Mean (SD) Median Min, Max 
Weight (lbs) (Pre-Procedure) 
18 
204.4 (28.75) 
201.0 
160, 270 
Height (in) (Pre-Procedure) 
18 
71.2 (3.21) 
72.0 
65, 76 
Systolic Blood Pressure (mmHg) 
 
 
 
 
          Pre-Procedure 
18 
125.4 (13.39) 
126.0 
104, 152 
          Post-Procedure 
18 
120.4 (10.39) 
119.0 
102, 142 
Diastolic Blood Pressure (mmHg) 
 
 
 
 
          Pre-Procedure 
18 
78.7 (8.65) 
78.5 
65, 92 
          Post-Procedure 
18 
77.4 (7.88) 
78.0 
64, 94 
Pulse (bpm) 
 
 
 
 
          Pre-Procedure 
18 
76.6 (10.46) 
78.5 
56, 96 
          Post-Procedure 
18 
73.8 (8.26) 
72.0 
60, 92 
Temperature (°F) 
 
 
 
 
          Pre-Procedure 
18 
97.80 (0.803) 
97.80 
96.4, 99.0 
          Post-Procedure 
18 
97.77 (0.676) 
97.80 
96.4, 98.8 
Fingerstick Hematocrit (%) 
18 
45.29 (2.373) 
44.80 
41.3, 50.2 
Clinical Study Protocol: AMIC-002-CMD 
Note: NA=Not Applicable; UNK=Unknown; ND=Not Done 
Table Status; FINAL; SAS Program: Table 14.3.sas: 14NOV2014:12:31:18 
Cross reference: Listing 16.3 
 
 
 

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The subjects’ pre to post-procedure decreases in hematology (WBC, platelet counts, and 
hematocrit) were not clinically significant and within expected values during a RBC Depletion 
procedure.  The post-procedure RBC counts and hematocrit decreased as anticipated with a 
double RBC collection. (Table 4) 
Table 4 Summary of Subject Hematology 
(Two-way Pass Procedures) 
Parameter 
N1 
Mean (SD) 
Median 
Min, Max 
White Blood Cell Count (WBC) (x103/µL) 
 
 
 
 
          Pre-Procedure 
16 
6.12 (1.799) 
6.05 
3.9, 10.4 
          Post-Procedure 
16 
5.16 (1.522) 
4.85 
3.1, 8.7 
Red Blood Cell Count (RBC) (x106/μL) 
 
 
 
 
          Pre-Procedure 
16 
5.094 (0.2843) 
4.980 
4.84, 5.84 
          Post-Procedure 
16 
4.316 (0.2316) 
4.335 
3.99, 4.85 
Platelet Count (x103/μL) 
 
 
 
 
          Pre-Procedure 
16 
234.1 (40.24) 
228.0 
174, 318 
          Post-Procedure 
16 
211.1 (36.05) 
201.5 
153, 309 
Hematocrit (%) 
 
 
 
 
          Pre-Procedure 
16 
44.20 (2.373) 
43.40 
40.8, 49.0 
          Post-Procedure 
16 
37.52 (2.287) 
37.65 
33.9, 43.2 
Plasma Hemoglobin (mg/dL) 
 
 
 
 
          Pre-Procedure 
16 
8.74 (8.655) 
5.95 
2.4, 35.4 
          Post-Procedure 
16 
7.06 (6.237) 
5.40 
2.4, 25.4 
Difference in Plasma Hemoglobin 
(mg/dL)* 
16 
-1.69 (3.424) 
-0.05 
-10.0, 2.3 
Clinical Study Protocol: AMIC-002-CMD 
*Calculated Parameter: 
Difference in Plasma Hemoglobin=Subject Plasma Hemoglobin Post-Procedure - Subject Plasma Hemoglobin Pre-Procedure 
1Subject #05009 had a venous access issue and did not start the procedure; Subject #05024 had an infiltration 
and only Pre-Procedure sample was collected 
Note: NA=Not Applicable; UNK=Unknown; ND=Not Done 
Table Status: FINAL; SAS Program: Table 14.4.sas: 18NOV2014:9:55:56 
Cross reference: Listing 16.4 
 
The mean subject pre-procedure and post-procedure plasma hemoglobin values were 
8.74 ± 8.655 mg/dL (range: 2.4-35.4 mg/dL) and 7.06 ± 6.237 (range: 2.4-25.4 mg/dL), 
respectively.  The general decrease in plasma hemoglobin post-procedure is attributed to a 
dilution effect of the saline replacement fluid. One subject (05019) had elevated plasma 
hemoglobin levels both pre and post-procedure (35.4 mg/dL and 25.4 mg/dL, respectively). Both 
samples were retested and the original results were confirmed, although the operator did not note 
any visible hemolysis.  The sample was also reported to have a high level of lipemia. Plasma 
hemoglobin was measured using a spectrophotometric method and presence of turbidity 
(lipemia) interferes with the measurement.   
 

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One subject (05009) was unable to establish dual venous access. Two subjects (05014, 05024) 
reported one incident each of a mild, single adverse event (AE) return line infiltration. The 
subjects were treated, recovered and were released without completing the procedure. A third 
subject (05017) experienced an infiltration prior to the start of the procedure but was 
recannulated successfully. The infiltration was treated, and the subject completed the procedure.  
There was no relationship to the investigational article for any of the AEs.  No serious or 
unexpected adverse events occurred during this phase of the study.  
 
The procedures were uneventful with a mean duration time of 14.9 ± 1.62 minutes (range: 12-
17 minutes). The programmed AC Ratio, citrate infusion rate and the mean whole blood flow 
rate were 12:1, 1.25 mg/kg/min, and 69.6 ± 6.48 mL/min, (range: 59-80 mL/min), respectively.  
An average anticoagulated whole blood volume of 888.5 ± 87.26 mL (range: 770-1047 mL) was 
withdrawn from the subjects and processed.  The mean target End Hematocrit was 39.3 ± 2.77 
(range: 35-44) with a mean target absolute Red Cell Depletion Volume of 345.1 ± 19.71 (range: 
315-379 mL).  The mean replacement fluid volume of saline and ACD-A returned to the subject 
were 427.9 ± 48.62 mL (range: 381-584 mL) and 49.1 ± 7.19 mL (range: 38-63 mL), 
respectively. The Fluid Balance reported was 21.6 ± 11.11 mL (range: 10-47 mL).   
 
The RBC waste material collected was weighed and resulted in a calculated mean volume of 
476.4 ± 109.85 mL (range: 404-861 mL).  The high value of the range (861 mL) was due to air 
purge volume and additional initial processing saline volume transferred to the waste containers.  
The hematocrit of the waste material was an average of 52.98 ± 4.952% (range: 39.4-60.4%). 
The WBC and platelet count were 7.67 ± 2.102 x 103/uL (range: 5.0-12.9 x 103/uL) and 
263.7 ± 51.56 x 103/uL (range: 190-406), respectively.  
 
Table 5 summarizes the AMICUS Estimator values calculated at the start of the procedure based 
on the subject and procedure input compared to the end of procedure reported values. 
 
Table 5  Summary of Estimated Values and Actual Procedure Parameter Results 
Parameter 
Estimated Value  
Pre-procedure 
Mean (SD), n=15 
Value Reported 
Post-procedure 
Mean (SD), n=15 
Procedure Time (min) 
13.5 (1.60) 
14.9 (1.62) 
AC to Subject (mL) 
51.1 (6.46) 
49.1 (7.19) 
AC Required (mL) 
68.1 (6.65) 
68.3 (6.90) 
Other Replacement Fluid1 (mL) 
414.1 (20.06) 
427.9 (48.62) 
Fluid Balance (mL) 
0.00 
21.6 (11.11) 2 
1 Saline used as Replacement Fluid 
2 Volume due to saline used to keep vein open prior to start of procedure 
 
Table 6 summarizes the End Hematocrit accuracy. The mean difference of actual to target End 
Hematocrit observed may be attributed to the fingerstick hematocrit used to determine study 
eligibility as the input for the procedure, while an automated measurement was used for the post-

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Evaluation of the AMICUS Red Blood Cell Exchange (RBCx) System in Sickle Cell Patients  
Version 09 10 Feb 2017 
 
Page 134 of 134 
 
Fresenius Kabi USA LLC, Confidential 
 
 
 
procedure hematocrit.  In addition, visible dilution for samples taken from the return line in the 
first two procedures was noted despite taking a 10 mL volume to waste.  Subsequent procedures 
used the inlet line for sampling post-procedure.  
 
 
 
 
 
 
 
Fourteen procedures reported no alarms. During one procedure (05019) the operator did not fill 
the replacement fluid drip chamber and did not open the clamp resulting in Check Replacement 
Fluid and Air Detected alarms. The alarms were acknowledged, the roller clamp was opened, 
and the procedure was resumed without further incident. 
 
The two-way pass RBC Depletion procedures demonstrated that removal of up to approximately 
400 mL of RBCs can be safely completed. The AMICUS estimated pre-procedure parameters 
were consistent with the values reported at the end of the procedure.  The changes observed for 
the subject parameters pre and post-procedure were as anticipated clinically. No functional issues 
were identified, unanticipated adverse device effects, or serious adverse events were reported 
during these two-way procedures.  The data generated were acceptable and demonstrated subject 
safety in two-way pass RBC Depletion procedures. 
 
 
References 
1. Matevosyan K, Anderson C, and Sarode R. Isovolemic Hemodilution-Red Cell Exchange 
for Prevention of Cerebrovascular Accident in Sickle Cell Anemia: The Standard 
Operating Procedure. J Clin Aph 2012. DOI: 10.1002/jca.21203. 
 
 
 
Table 6  End Hematocrit Accuracy (n=15) 
Mean Target End 
Hematocrit (%) 
Mean Subject Post-
Procedure Hematocrit 
(%) 
Mean Difference of Actual to 
Target End Hematocrit (%) 
39.3 (2.77) 
37.52 (3.424) 
-1.89 (1.784)