A Multi-Center, Pilot Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device (SCD) for the Treatment of Immunomodulatory Dysregulation Due to Pediatric Acute Kidney Injury (AKI)
Phase: NA
Conditions: Acute Kidney Injury
Sponsor: Children's Hospital Medical Center, Cincinnati

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A Multi-Center, Pilot Study to Assess the Safety and Efficacy of a Selective Cytopheretic 
Device (SCD) for the treatment of immunomodulatory dysregulation due to pediatric 
acute kidney injury (AKI).
 
 
 
Protocol Number: 
SCD-PED-02 
 
 
Date: 
 
March 9, 2022 
Version 1.5 
Sponsor, Principal 
Investigator: 
Lenar Yessayan, MD, University of Michigan 
 
 
 
Co-Principal 
Investigator: 
Stuart Goldstein, MD, Cincinnati Children’s Medical Center 
 
 
 
 
 
 
Signature                                                                        Date 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................. 3 
LIST OF ABBREVIATIONS .......................................................................................... 7 
1. 
INTRODUCTION ..................................................................................................... 9 
2. 
PRIOR CLINICAL EXPERIENCE ...................................................................... 11 
3. 
PILOT STUDY (PROTOCOL SCD-PED-02) OBJECTIVES AND 
ENDPOINTS ................................................................................................................... 26 
4. 
STUDY DESIGN ..................................................................................................... 28 
5. 
SELECTION OF PATIENT POPULATION ....................................................... 28 
6. 
STUDY ACTIVITIES ............................................................................................. 30 
7. 
TREATMENT INTERRUPTIONS – DISCONTINUATION CRITERIA ....... 41 
8. 
CLINICAL TRIAL TERMINATION CRITERIA .............................................. 43 
9. 
SAFETY ................................................................................................................... 43 
10. DEVICE ACCOUNTABILITY ............................................................................. 48 
11. DATA SAFETY MONITORING BOARD ........................................................... 49 
12. PROTOCOL ANALYSIS / SCIENTIFIC SOUNDNESS ................................... 49 
13. DATA COLLECTION – STUDY MONITORING AND AUDIT ...................... 51 
14. INVESTIGATOR’S STATEMENT OF RESPONSIBILITY ............................. 53 
15. REFERENCES ........................................................................................................ 54 
APPENDIX A – PEDIATRIC RISK OF MORTALITY (PRISM II) SCORE [28] ... 57 
APPENDIX B – CRRT MANAGEMENT .................................................................... 60 
APPENDIX C – CRITICAL MEDICATION LIST .................................................... 61 
APPENDIX D –REGIONAL CITRATE ANTICOAGULATION (RCA) 
PROTOCOL EXAMPLE ............................................................................................... 62 
APPENDIX E – SCD/CRRT BLOOD PRIMING PROTOCOL ............................... 67 
APPENDIX F – PLACEMENT OF SCD IN CRRT / ECMO CIRCUIT .................. 69 
 
 

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PROTOCOL SYNOPSIS 
 
Study Title 
A Multi-Center, Pilot Study to Assess the Safety and Efficacy of 
a Selective Cytopheretic Device (SCD) for the treatment of 
immunomodulatory dysregulation due to pediatric acute kidney 
injury (AKI). 
Study Phase 
Pilot Study. 
Product Description 
 
The Selective Cytopheretic Device (SCD) is comprised of tubing, 
connectors, and a synthetic membrane cartridge. The device is 
connected in series to a commercially available Continuous Renal 
Replacement Therapy (CRRT) device. Blood from the CRRT 
circuit is diverted after the CRRT hemofilter through to the extra 
capillary space (ECS) of the SCD. Blood circulates through this 
space and it is returned to the patient via the venous return line of 
the CRRT circuit. Regional citrate anticoagulation is used for the 
entire CRRT and SCD blood circuits.   
 
The SCD
 is a synthetic membrane with the ability to bind 
activated leukocytes and when used in a continuous renal 
replacement extracorporeal circuit in the presence of regional 
citrate anticoagulation modulates inflammation.  
Rationale 
Our primary hypothesis is that up to ten sequential 24-hour SCD 
treatments will improve survival in pediatric patients with Acute 
Kidney Injury (AKI) as compared to CRRT alone (standard of 
care).  Further, SCD therapy will reduce the duration of 
maintenance dialysis secondary to AKI due to acute tubular 
necrosis (ATN).  ATN is an acute reversible process and if not 
reversed in three months, it may not be reversed at all. [1, 2] 
Studies suggest that approximately 10-20% of AKI patients do not 
recover renal function [3, 4] and, therefore, require chronic 
dialysis. 
 
Importantly, acute kidney injury is a highly lethal condition in 
critically ill patients. Despite improvements in acute medical care 
and advances in dialysis therapies, the mortality rate during the 
past four decades of this condition has not improved. Critically ill 
patients with AKI in hospital ICU settings have mortality rates of 
approximately 50%, including pediatric patients [5, 6, 7, 8, 9, 10, 
11, 12] 
 
AKI promotes a systemic inflammatory response syndrome 
(SIRS) which results in systemic microvascular damage and, if 
severe, multi-organ dysfunction. [13, 14] Activated circulating 

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leukocytes play a central role in this process. [15] Leukocytes, 
especially neutrophils, are major contributors to the pathogenesis 
and progression of many inflammatory disorders, including SIRS, 
sepsis, ischemia reperfusion injury, and acute respiratory distress 
syndrome (ARDS). Many therapeutic approaches are under 
investigation to limit the activation and tissue accumulation of 
leukocytes at sites of inflammation to minimize tissue destruction 
and disease progression. [16, 17, 18]  
Primary Objective 
To evaluate the safety of up to ten consecutive 24 hour SCD 
treatments in the pediatric AKI population being treated with 
Continuous Renal Replacement Therapy (CVVH, CVVHD, or 
CVVHDF) with regional citrate anticoagulation. 
Secondary 
Objective 
To assess the effect of SCD treatment on various measures of 
pediatric patient clinical outcomes and to evaluate the integrity of 
the SCD device and patient safety in SCD treatments from the 
time of initiation of therapy to as many as ten consecutive 24-hour 
SCD treatments. 
 
Study Endpoints 
In this Pilot study four domains of interest have been designated. 
The four domains are: 
• Patient Safety: Safety Endpoint Measures include adverse 
events, laboratory safety parameters, vital signs, EKG, 
ventilation status and hemodynamic variables.  
• Clinical Efficacy: The Primary Clinical Efficacy Endpoint 
Measure is in-hospital; 28 and 60-day all-cause mortality. Time 
to renal recovery and necessity for chronic dialysis up to day 60 
will also be determined. Additional efficacy endpoints include 
time to intensive care unit (ICU) discharge, and time to hospital 
discharge.  
• Device Integrity and Performance: The Endpoint Measure is 
SCD use without failure. This measure will help assess the 
integrity and performance of the SCD device.  
• SCD Mode of Action: Exploratory Endpoint Measures will 
include inflammatory cytokines, cell activation parameters and 
biomarkers at clinical sites with this capability. The analysis 
will be performed at a central laboratory. 
Assessment of 
Device Integrity and 
Performance 
Criteria for assessment of device integrity and performance 
include: 
• Significant Clotting within the Device as assessed by visual 
inspection. 
• Evidence of leakage (i.e., cracking/breakage of a port, 
connector, hemofilter cartridge or tubing). 

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• Any unforeseen malfunction that results in the need for 
discontinuation. 
Study Populations 
Pediatric patients with a body weight (BW) between ≥10 and ≤ 
20kg receiving care in the Intensive Care Units of each 
participating hospital will be screened daily and identified for 
participation in the trial. 
Study Design 
This is an open-label, multi-center Pilot study.  
Approximate 
Number of Subjects 
Up to 10 patients will be enrolled in this study. 
Approximate 
Number of Centers 
Up to 7 Clinical Centers in the United States will participate in 
this study. 
Duration of Subject 
Participation 
Each patient will be followed for 60 days following enrollment. 
Inclusion Criteria 
1. 
A patient, or legal representative, has informed consent 
form. 
2. 
Must be receiving medical care in an intensive care unit 
(e.g., PICU, CICU). 
3. 
Age less than 18 years. 
4. 
Body weight   ≥10 and ≤ 20kg. 
5. 
Intent to receive full supportive care through aggressive 
management utilizing all available therapies for a minimum 
of 96 hours.  
6. 
Clinical diagnosis of AKI requiring CRRT. AKI is defined 
as acute kidney injury with any one of the following: 
• 
Increase in SCr by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 
hours or; 
• 
Increase in SCr to ≥1.5 times baseline, which is known 
or presumed to have occurred within the prior 7 days or; 
• 
Urine volume <0.5ml/kg/h for 6 hours   
7. 
At least one non-renal organ failure (defined as receiving 
mechanical ventilation or at least one vasoactive medication 
to treat hypotension) OR presence (proven or suspected) of 
sepsis.  
Exclusion Criteria 
 
 
 
1. 
Threshold blood pressure of 80/40 mmHg-- patients with 
both a systolic blood pressure of less than 80 mmHg and a 
diastolic blood pressure of less than 40 mmHg. 
2. 
Patients with a solid organ transplant or those with a bone 
marrow or stem cell transplant in the previous 100 days or 
who have not engrafted. 
3. 
Acute or chronic use of circulatory support device other than 
ECMO such as LVADs, RVADs, BIVADs. 

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4. 
Presence of preexisting advanced chronic renal failure (i.e., 
ESRD) requiring chronic renal replacement therapy prior to 
this episode of acute kidney injury or with pre-existing 
chronic kidney disease (CKD) defined as an eGFR<30 
ml/min/1.73m2. Patients who have never seen a pediatric 
nephrologist will be assumed not to have pre-existing CKD. 
5. 
AKI occurring in the setting of burns, obstructive uropathy, 
scleroderma renal crisis, atheroembolism, functional or 
surgical 
nephrectomy, 
cyclosporine, 
or 
tacrolimus 
nephrotoxicity. 
6. 
Metastatic malignancy which is actively being treated or 
may be treated by chemotherapy or radiation during the 
subsequent three month period after study therapy. 
7. 
Chronic immunosuppression with the exception of 
corticosteroids up to a dose of 10 mg per day.  
8. 
Known positive HIV or AIDS or COVID-19 
9. 
Current Do Not Attempt Resuscitation (DNAR), Allow 
Natural Death (AND), or withdrawal of care status, or 
anticipated change in status within the next 7 days. 
10. Patient not expected to survive 28 days because of an 
irreversible medical condition. (This is not restrictive to 
AKI, and may include situations such as the presence of 
irreversible 
brain 
damage, 
untreatable 
malignancy, 
inoperable life threatening condition, or any condition to 
which therapy is regarded as futile by the PI.) 
11. Any medical condition that the Investigator thinks may 
interfere with the study objectives. 
12. Treating clinician does not feel it is in the best interest of the 
patient  
13. Platelet count <15,000/mm3 at time of screening.  
14. Concurrent enrollment in another interventional clinical 
trial. Patients enrolled in clinical trials where only 
measurements and/or samples are taken (NO TEST 
DEVICE OR TEST DRUG USED) are allowed to 
participate. 
15. Use of any other investigational drug or device within the 
previous 30 days. 
16. Use of an AN-69 hemofilter membranes 
Evaluation Plan 
The primary evaluation of this study will be safety and all-cause 
mortality or dialysis dependency through 60 days post-
enrollment.  Additional endpoints will be time on CRRT, total 
ICU and hospital days.  Mortality and dialysis dependency rates 
will be compared to historical controls.  
 

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LIST OF ABBREVIATIONS 
 
ACD-A 
Anticoagulant Citrate Dextrose- Formula A 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
AIDS 
Acquired Immunodeficiency Syndrome 
AND 
Allow Natural Death 
ARDS 
Acute Respiratory Distress Syndrome 
ARF 
Acute Renal Failure 
ASHD 
Atherosclerotic heart Disease 
ATN 
Acute Tubular Necrosis 
BRS 
Bradykinin Release Syndrome 
BW 
Body Weight 
CV 
Cardio-Vascular disease 
CBC 
Complete Blood Count 
CCC 
Clinical Coordinating Center 
CCHMC 
Cincinnati Children’s Hospital Medical Center 
CICU 
Cardiac Intensive Care Unit 
CKD 
Chronic Kidney Disease 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRRT 
Continuous Renal Replacement Therapy 
CTICU 
Cardiothoracic Intensive Care Unit 
CVVH 
Continuous Veno-Venous Hemofiltration 
CVVHD 
Continuous Veno-Venous Hemodialysis 
CVVHDF 
Continuous Veno-Venous Hemodiafiltration 
DCC 
Data Coordinating Center 
DNAR 
Do Not Attempt Resuscitation 
DSMB 
Data Safety Monitoring Board 
ECMO 
Extra-corporeal Membrane Oxygenation 
ECS 
Extra Capillary Space 
ECV 
Extracorporeal Circuit Volume 
ESRD 
End Stage Renal Disease 
FDA 
Federal Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCS 
Glasgow Coma Score 

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GFR 
Glomerular Filtration Rate 
HD 
Hemodialysis 
HIV 
Human Immunodeficiency Virus 
HRS 
Hepatorenal Syndrome 
iCa or ionCa 
Ionized Calcium 
ICU 
Intensive Care Unit 
IRB 
Institutional Review Board 
LAR 
Legal Authorized Representative 
LTFU 
Long Term Follow Up 
LVAD 
Left Ventricular Assist Device 
MAP 
Mean Arterial Pressure 
MICU 
Medical Intensive Care Unit 
MOF 
Multiple Organ Failure 
nriCa 
Non Recommended Ionized Calcium Range 
PEEP 
Positive End Expiratory Pressure 
pH 
Power of Hydrogen 
PICU 
Pediatric Intensive Care Unit 
ppCRRT 
Prospective Pediatric CRRT Registry 
PRISM 
Pediatric Risk of Mortality 
RAD 
Renal Assist Device 
RCA 
Regional Citrate Anticoagulation 
riCa 
Recommended Ionized Calcium Range 
SAE 
Serious Adverse Event 
SaO2 
Saturation of Oxygen 
SCD 
Selective Cytopheretic Device 
SCr 
Serum Creatinine 
SICU 
Surgical Intensive Care Unit 
SIRS 
Systemic Inflammatory Response Syndrome 
SOFA 
Sequential Organ Failure Assessment 
WBC  
White Blood Cell 
UADE 
Unanticipated Adverse Device Effect 
 

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1. INTRODUCTION 
 
The Selective Cytopheretic Device (SCD) is comprised of tubing, connectors, and 
a synthetic membrane cartridge.  The device is connected in series to a 
commercially available Continuous Renal Replacement Therapy (CRRT) device.  
Blood from the CRRT circuit is diverted after the CRRT hemofilter through to the 
extra capillary space (ECS) of the SCD.  Blood circulates through this space and 
it is returned to the patient via the venous return line of the CRRT circuit.  
Regional citrate anticoagulation is used for the entire CRRT and SCD blood 
circuits.   
 
The SCD
 is a synthetic membrane with the ability to bind activated 
leukocytes and when used in a continuous renal replacement extracorporeal 
circuit in the presence of regional citrate anticoagulation modulates inflammation.  
See Figure 1. 
 
Figure 1:  Schematic of the CRRT circuit and SCD 
 
 
1.1 RATIONALE FOR THERAPY 
Our primary hypothesis is that up to ten sequential 24-hour SCD treatments will 
improve survival in patients with Acute Kidney Injury (AKI) as compared to 
CRRT alone (standard of care).  Further, SCD therapy will reduce the duration 
of maintenance dialysis secondary to AKI due to acute tubular necrosis (ATN).  
ATN is an acute reversible process and if not reversed in three months, it may 
not be reversed at all. [1, 2] Studies suggest that approximately 10-20% of AKI 
patients do not recover renal function [3, 4] and, therefore, require chronic 
dialysis. 
 
 
Importantly, acute kidney injury is a highly lethal condition in critically ill 
patients. Despite improvements in acute medical care and advances in dialysis 

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therapies, the mortality rate during the past four decades of this condition has 
not improved. Critically ill patients with AKI in hospital ICU settings have 
mortality rates of up to 50%, including pediatric patients [5, 6, 7, 8, 9, 10, 11, 
12] 
 
AKI promotes a systemic inflammatory response syndrome (SIRS) which 
results in systemic microvascular damage and, if severe, multi-organ 
dysfunction. [13, 14] Activated circulating leukocytes play a central role in this 
process. [15] Leukocytes, especially neutrophils, are major contributors to the 
pathogenesis and progression of many inflammatory disorders, including SIRS, 
sepsis, ischemia reperfusion injury, and acute respiratory distress syndrome 
(ARDS). Many therapeutic approaches are under investigation to limit the 
activation and tissue accumulation of leukocytes at sites of inflammation to 
minimize tissue destruction and disease progression. [16, 17, 18] Preclinical 
studies utilizing a porcine model of septic shock have demonstrated that SCD 
therapy immunomodulates activated circulating leukocytes.  This effect is 
associated with improvement of multiorgan dysfunction. [19] 
 
1.2 RATIONALE FOR NUMBER OF SCD TREATMENTS FOR UP TO 10 
DAYS  
In prior studies, 10-35% of patients were still on CRRT at 7 days, including the 
recently completed SCD-PED-001 pediatric trial. Since the safety profile of the 
SCD in all the prior clinical studies have demonstrated no device related 
adverse events, the immunomodulatory effects on circulating white cells will 
maintain a beneficial response in a subject still requiring CRRT. The 
understanding of the mechanism of action of the SCD have demonstrated that 
the low iCa environment in the blood perfusion circuit initiates the natural 
apoptotic process of the bound neutrophils, thereby suppressing the excessive 
neutrophil inflammatory activity of the circulating innate immunologic system. 
The risk of neutropenia and immunosuppression is prevented due to this natural 
process. In addition, the treatment of four COVID-19 patients with the SCD 
under expanded access emergency use from 14-17 days had no SCD related 
adverse events. 
 
In the recently completed SCD-PED-001 pediatric clinical trial, 5 of 14 patients 
required the full 7 day SCD treatment course, suggesting a subset of patients 
require more than 7 days of SCD treatment to recover and would benefit for 
longer duration of SCD treatment. 
 
 
 
 
 
 
 
 

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2. PRIOR CLINICAL EXPERIENCE 
 
2.1 
PHASE II RENAL ASSIST DEVICE STUDY (RAD003 IND 
NUMBER 11077)[20] 
 
2.1.1 STUDY SUMMARY  
The poor outcomes in patients with acute kidney injury (AKI) and 
end-stage renal disease (ESRD) on chronic dialysis are due to 
immune dysregulation associated with these disorders. Evolving 
evidence suggests that the kidney, and specifically renal epithelial 
cells, plays an important role in the immunological response of 
leukocytes under disease states. Method: In this regard, the 
development of therapeutic approaches utilizing renal epithelial 
cells has been tested in preclinical animal models and clinical 
trials. Results: These approaches have been demonstrated in phase 
II human trials to improve the survival of intensive care unit 
patients with AKI and multiorgan failure.   
 
2.1.2 
SAFETY RESULTS 
All serious adverse events (SAEs) occurring during the first 28 
days after randomization were consistent with a seriously ill ICU 
patient population with AKI receiving CVVH.  
 
 
2.2 ESRD SAFETY AND BIOINFLAMMATORY ASSAY STUDY 
 
2.2.1 
STUDY SUMMARY  
A study of the SCD was conducted at the Henry Ford Hospital in 
Detroit, Michigan entitled “A Phase I/II Trial of a Two-Cartridge 
Hemodialysis System on Inflammatory Markers in Chronic 
Hemodialysis Subjects”. This study was designed to determine 
what effect one treatment with the SCD would have on the 
reduction of bioinflammatory markers such as cytokines IL-2, IL-
6, IL-8 and IL-10 and white cell activation in chronically inflamed 
End Stage Renal Disease (ESRD).  The study enrolled fifteen 
subjects at one site, with four of the original 15 subjects re-enrolled 
in what was called “Amendment 2”. 
 
2.2.2 
SAFETY RESULTS 
Fifteen chronic hemodialysis (HD) subjects with elevated CRP 
levels were treated for four hours under standard HD with systemic 
heparin anticoagulation and, at their next dialysis treatment 
session, received standard HD plus SCD therapy with regional 
citrate anticoagulation. The 15 subjects have completed the study 
treatment period and safety data is shown in Table 1 as follows: 
 

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Table 4 delineates the Summary of Site-reported Serious Adverse 
Events (SAEs) using site-reported category and term.  None of the 
SAEs were considered ‘definitely’ device related per the Principal 
Investigator. 
 
 

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approval of a new clinical trial protocol (no changes to the SCD 
device) designed to achieve statistical significance of a death or 
dialysis dependence composite endpoint.   
 
2.6 
Clinical Study: SCD-PED-001 (Pilot Safety and Efficacy of SCD 
treatment in Pediatric Patients with AKI) IDE 
 
This was a single treatment arm, open-label multi-center pilot study, grant 
funded by the FDA, designed to enroll 16 subjects across 4 clinical sites in 
the United States. The study assessed the safety of the SCD and outcomes in 
pediatric patients (>15 kg, ≤22 years) with AKI and multiorgan failure 
receiving CRRT. Sixteen subjects were enrolled between December 2016 
and January 2020. In these subjects, the SCD was integrated post CRRT 
membrane, changed daily, and circuit ionized (i)Ca maintained <0.4 
mmol/L. Subjects received SCD treatment for up to 7 days or CRRT 
discontinuation.  
 
Of the 16 subjects treated in this study, 8 were male and 8 were female.  
Mean subject age was 12 years (range 4-21yr), weight was 53 kg (range 19-
111 kg) and Pediatric Risk of Mortality (PRISM II) score was 7 (range 2-
19). Two subjects received ECMO concurrently with CRRT and SCD. The 
most common ICU diagnosis was shock. Circuit iCa were maintained at 
<0.4 mmol/L for 90.2% of assessments. Median SCD duration was 6 days 
(range 1 to 7). Fifteen subjects survived SCD therapy, and 12 subjects 
survived to ICU discharge. All 12 ICU survivors were dialysis independent 
at 60 days. No SCD related adverse events were noted. One subject died 
during treatment as a result of Influenza myocarditis. The 3 subjects who 
died after SCD treatment was completed but before ICU discharge included 
one who died as a result of a post op complication and two who died as a 
result of ECMO complications (intracerebral hemorrhage, withdrawal of 
care). Further important observations were noted, including the fact that 8 
subjects had septic shock or severe pneumonia but only 1 subject death in 
this group. This 12.5% mortality rate compares to 50% mortality rate in 
ppCRRT data registry in similar patients with 3 organ failures. Half of the 
SCD treated subjects in this cohort required CRRT for less than 5 days 
compared to 9.6 days from the ppCRRT database. This data suggest the 
SCD is safe in critically ill children who require CRRT. While efficacy 
claims cannot be made statistically, the 75% survival rate and 100% renal 
recovery rate in surviving children suggest a favorable benefit to risk ratio. 
 
Over the course of this study, a total of 12 Serious Adverse Events (SAEs) 
were reported. All 12 of these SAEs were determined by the site PI and 
confirmed by the PI of the CCC/DCC, to be related to previous medical 
history or underlying disease processes. Summary of the SAEs from this 
study are provided in Table 10 below. 
 

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2.8 
Ongoing SCD Trials 
2.8.1 Investigator Initiated Feasibility Study: “Immunomodulatory 
Biomimetic Device to Treat Myocardial Stunning in ESRD Patients”   
• IDE 
, IRB approved 
• 10 subjects, single site, one 4 hours SCD treatment in chronic 
hemodialysis patients with recurrent hemodialysis hypotension due 
to rapid large volume removal rates. 
• SCD treatment vs. control treatment in same subject; myocardial 
ischemia as measured with Echocardiogram. 
• If effective, reduce chronic heart failure progression (5-10% 
ejection fraction loss annually).   
2.8.2 Investigator Initiated Pilot Study to Assess the Safety and Efficacy of a 
Selective Cytopheretic Device (SCD) to Treat ICU Patients with Acute 
on Chronic Systolic Heart Failure with Cardiorenal Syndrome 
Awaiting Left Ventricular Assist Device (LVAD) Implantation or 
Diuretic Resistant (2 clinical protocols) 
• IDE 
; IRB approved 
• 10 subjects, single site, non-control trial.  Stage 4 CHF patients 
with worsening renal function from CRS are not eligible for 
LVAD. 
• Daily 6 hour SCD treatment (up to 7 days) to assess improvement 
in renal function and LV systolic function to become eligible for 
LVAD implantation.   
• Positive efficacy study would be proof of concept of SCD effects 
to improve LV function and renal function.      
• Recent Supplement to include CRS diuretic resistant patients 
requiring ultrafiltration: 3 treatments during 4 hour UF treatments.  
2.8.3 Investigator Initiated Pilot Study to Assess the Safety and Efficacy of a 
Selective Cytopheretic Device (SCD) to Treat ICU Patients with Acute 
Kidney Injury (AKI) and Hepatorenal Syndrome (HRS) Type I  
• IDE 
, IRB approved 
• 10 subjects, single site trial in ICU patients with AKI and HRS not 
on liver transplant list. Prognosis is 80 percent mortality in 90 
days.   
• Daily 24 hour SCD treatment up to 7 days to assess improvement 
in renal function and volume removal.  
2.8.4 A Multi-Center Pilot Study to Assess the Safety and Efficacy of a 
Selective Cytopheretic Device (SCD) in Patients Developing Acute 
Kidney Injury (AKI) or Acute Respiratory Distress Syndrome (ARDS) 
Associated with COVID-19 Infection (Sponsor: SeaStar Medical)  
• IDE 
 S34; IRB approved 

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• 
35 subjects, up to 10 clinical sites, treatment arm only, ICU 
patients with COVID 19 with ARDS and/or AKI requiring CRRT. 
• 
Daily 24 hour SCD treatment up to 10 days to assess safety and 
efficacy on 60 day mortality and renal recovery. 
 
 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
 
3.1 
PRIMARY OBJECTIVE 
To evaluate the safety of up to ten consecutive 24 hour SCD treatments 
compared to historic data on in-hospital mortality and on all-cause 
mortality and dialysis dependency at day 28, and day 60 in the pediatric 
AKI population being treated with Continuous Renal Replacement 
Therapy (CVVH, CVVHD, or CVVHDF) with regional citrate 
anticoagulation. 
 
3.1.1 SECONDARY OBJECTIVE 
To assess the effect of SCD treatment on various measures of pediatric 
patient clinical outcome and to evaluate the integrity of the SCD 
device and patient safety in SCD treatments from the time of initiation 
of therapy to as many as ten consecutive 24-hour SCD treatments. 
 
3.2 
STUDY ENDPOINT 
In this Pilot study four (4) domains of interest have been designated. The 
four (4) domains are: 
1. 
Patient Safety: Safety Endpoint Measures include adverse events, 
laboratory safety parameters, vital signs, EKG, ventilation status and 
hemodynamic variables.  
2. 
Clinical Efficacy: The Primary Clinical Efficacy Endpoint Measure 
is in-hospital; 28 and 60-day all-cause mortality. Time to renal 
recovery and necessity for chronic dialysis up to day 60 will also be 
determined. Additional efficacy endpoints include time to intensive 
care unit (ICU) discharge, and time to hospital discharge.  
3. 
Device Integrity and Performance: The Endpoint Measure is SCD 
use without failure. This measure will help assess the integrity and 
performance of the SCD device.  
4. 
SCD Mode of Action: Exploratory Endpoint Measures will include 
inflammatory cytokines, cell activation parameters and biomarkers at 
clinical sites with this capability. 
 
Endpoints are defined as: 
 
ALL-CAUSE MORTALITY: 
All-cause mortality is defined as in-hospital, 28-day and 60-day all-cause 
mortality. 
 

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DIALYSIS DEPENDANCY AT DAY 60: 
Dialysis dependency at day 60 is defined as patient not receiving any form 
of intermittent or continuous renal replacement therapy at or within 3 days 
of 60 days post enrollment in the study with no plans for additional 
intermittent or continuous renal replacement therapy. 
 
PATIENT SAFETY: 
Adverse events, laboratory safety parameters, vital signs, EKG, ventilation 
status and hemodynamic variables. 
 
DURATION OF RENAL SUPPORT: 
The duration of renal support will be defined as the numbers of days from 
the initiation of renal replacement therapy (start of observation period) to 
final dialysis treatment.  Duration of renal support will be censored if the 
patient is still dialysis dependent at the time of death or are dependent at 
day 60.   
 
RECOVERY OF RENAL FUNCTION: 
Recovery of renal function will be defined as lack of need for continuous 
dialysis support on day 28, and will be classified as yes or no at day 28.  
Subjects who were alive at day 28 will be included in the analysis.  
Patients who remain dialysis dependent at study completion (day 60) or 
time of death will be categorized as having no recovery of renal function. 
 
ASSESSMENT OF DEVICE INTEGRITY AND PERFORMANCE 
Criteria for assessment of device integrity and performance include: 
• Significant Clotting within the Device as assessed by visual 
inspection 
• Evidence of leakage (i.e., cracking/breakage of a port, connector, 
hemofilter cartridge or tubing). 
• Any unforeseen malfunction that results in the need for 
discontinuation. 
 
This trial is an early safety efficacy study but is not powered for statistical 
significance.  Insights into a comparison of historical controls matched to 
SCD treated subjects will utilize the ppCRRT Registry to match for: etiology 
of AKI, co-morbidities, CRRT modality, dose and form of anticoagulant, 
adverse events. [10] 
 
The ppCRRT Registry has data fields for the primary reason for CRRT, 
including AKI and its cause, as well as co-morbidities which will be matched 
for primary organ system involvement. The CRRT modality was evenly 
distributed between convective and diffusive modality, with 60% of the 
convective modalities provided as CVVH and 40% as CVVHDF. The 
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used the same protocol in ppCRRT Registry as outlined in this study protocol. 
Thus, the ppCRRT Registry dataset will be able to be matched to our study 
subject cohort. Also as noted above, subjects will be matched for age, size and 
PRISM II score. 
 
 
4. 
STUDY DESIGN 
This is an open-label, multi-center Pilot Study. 
 
5. 
SELECTION OF PATIENT POPULATION 
 
5.1 
STUDY POPULATION 
Up to 10 pediatric patients with a clinical diagnosis of AKI requiring CRRT 
will be enrolled in this study, in up to 7 Clinical Centers in the United States. 
 
Pediatric patients with a body weight (BW) between ≥10 and ≤ 20kg 
receiving care in the Intensive Care Units of each participating hospital will 
be screened daily and identified for participation in the trial.  
 
5.2 
INCLUSION CRITERIA 
1. 
The patient’s parent or legal representative has provided informed 
consent.  
2. 
Must be receiving medical care in an intensive care unit (e.g., PICU, 
CICU). 
3. 
Age less than 18 years. 
4. 
Body weight between ≥10 and ≤ 20kg  
5. 
Intent to receive full supportive care through aggressive management 
utilizing all available therapies for a minimum of 96 hours.  
6. 
Clinical diagnosis of AKI requiring CRRT. AKI is defined as acute 
kidney injury with any one of the following: 
• Increase in SCr by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 hours 
or; 
• Increase in SCr to ≥1.5 times baseline, which is known or 
presumed to have occurred within the prior 7 days or;  
• Urine volume <0.5ml/kg/h for 6 hours   
7. 
At least one non-renal organ failure (defined as receiving mechanical 
ventilation or at least one vasoactive medication to treat 
hypotension) OR presence (proven or suspected) of sepsis. Sepsis is 
defined as at least two of the following criteria in the setting of a 
probable or documented infection[29]:  
 

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11. Any medical condition that the Investigator thinks may interfere with 
the study objectives. 
12. Treating clinician does not feel it is in the best interest of the patient. 
13. Platelet count <15,000/mm3. 
14. Concurrent enrollment in another interventional clinical trial. 
Patients enrolled in clinical trials where only measurements and or 
samples are taken (NO TEST DEVICE OR TEST DRUG USED) are 
allowed to participate. 
15. Use of any other investigational drug or device within the previous 
30 days. 
16. Use of AN-69 hemofilter membranes 
 
6. 
STUDY ACTIVITIES 
 
6.1 
SCREENING PERIOD 
The screening period is the time period up to 48 hours before enrollment 
when a patient is identified, informed consent is obtained, and the patient 
is evaluated for inclusion in the clinical trial. Parental permission will be 
obtained from parents and/or legally authorized representatives (LAR) on 
a written informed consent document. Because of the critically ill nature 
of the study population, it is expected that most children will not be able to 
provide assent. Only adverse events directly related to the screening 
procedures will be reported during this time. 
 
Medical history and test results must be examined to ensure the patient 
meets all eligibility criteria. Tests that are specific to this protocol (i.e. not 
standard of care) require the patient or legal representative to have 
provided written consent for participation.  
 
Any patients that do not meet study criteria, will not be enrolled into the 
study. These patients will not be counted in the overall study enrollment 
numbers, but will be listed on the screening log. 
 
Prior to enrollment please contact the study sponsor or designee 
below to validate that the patient has met all inclusion and exclusion 
criteria.  
 
Lenar Yessayan, MD 
 
University of Michigan 
Internal Medicine-Nephrology 
3916C TC 
Ann Arbor, MI 48109 
 
OR 
 
 
Stuart Goldstein MD 
 

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Cincinnati Children’s Hospital Medical Center (CCHMC) 
3333 Burnet Avenue MLC 7022 
Cincinnati, OH 45229 
 
 
6.2 
CRRT PARAMETERS 
 
6.2.1 CITRATE ANTICOAGULATION 
Each participating clinical site will use their regional citrate 
anticoagulation protocol.  The clinical site is responsible to achieve 
and maintain a serum post filter ionized calcium level of <0.40 
mmol/L throughout the entire SCD treatment period (day and 
night).  The serum post filter ionized calcium level will be 
collected from the CRRT Circuit post SCD
. Examples of 
regional citrate anticoagulation protocols are included in Appendix 
D. If the site has difficulty in maintaining post-fiter iCa levels 
<0.4mM from prior experience with patients in this body weight 
between 10 and 20 kg body weight, the Sponsor and Lead 
Investigator will discuss options of citrate protocols to be used in 
enrolled patients to meet post filter iCa levels <0.4 mM as required 
during SCD treatment. 
 
See the RCA example protocol in Appendix D.  
Clinical sites will utilize the following parameters to alleviate the 
metabolic derangements associated with regional citrate based 
anticoagulation: 
 
a) Alkalosis: Patients with an arterial pH <7.40 at enrollment will 
initiate CRRT with solutions containing either 25 or 35 meq/L 
of base as directed by local standard of care.  During the study, 
if the patient’s arterial pH increases to >7.45 OR the patient’s 
serum bicarbonate increases to >35 meq/L, the CRRT solution 
will be changed to a base concentration of 25 meq/L, OR 0.9% 
NaCl will be added dialysis fluid to correct the alkalosis per 
local standard of care. 
 
b) Citrate lock: If the patient develops citrate lock, as defined by a 
serum ionCa <0.95 mmol/L and a total serum Ca >12.5 meq/L, 
the citrate infusion will be discontinued OR the CRRT 
clearance will be increased by 50% or per local standard of 
care, AND CRRT circuit Ca and patient Ca will be checked at 
least every one hour.  For centers that stop citrate, once the 
patient ionCa is >1.0 mmol/L, the citrate will be restarted at a 
lower rate determined by the site investigator, and hourly 
ionCa pairs will be rechecked x 3 to ensure a stable patient 
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Of importance the clinical plan is to monitor the perfusion circuit 
iCa levels at least q1h ±30min at the initiation of regional citrate 
anticoagulation (RCA) until a steady state iCa range is between 
0.25 to 0.40 mmol/L.  Once established, iCa levels both in the 
circuit and in the patient will be monitored q6h ±1hr.  If the iCa is 
outside the targeted range or alterations in citrate or calcium 
infusion rates are made, iCa levels are measured at least q1h 
±30min until targeted ranges are once again achieved.  Of 
importance, for efficacy of SCD treatment, iCa levels must be 
maintained in the recommended range at least 90% of the time, 
based on a sensitivity analysis showing that the mortality endpoint 
difference was lower with target iCa 80-85% of total treatment in 
clinical trial SCD-003. 
 
The protocol example identified in Appendix D may be utilized.  
 
6.2.2 BLOOD CIRCUIT VOLUME 
The additional blood volume for the SCD is 120 ml. This 
additional circuit blood volume for the standard SCD in enrolled 
patients can be handled with blood priming with matched blood 
similar to the standard practice in neonates. Blood prime will occur 
if the total extracorporeal circuit volume (ECV) is greater than 
10% of the patient’s blood volume, based on an estimate of blood 
volume = 70 ml/kg x patient body weight (kg) [25]. The situation 
is most commonly encountered in neonatal CRRT, where circuit 
ECV can represent nearly 50% of patient blood volume, yet the 
same principles apply for this clinical study. [26] 
 
Hypotension associated with blood priming can occur from 
transient dilution of vasoactive medications (e.g., norepinephrine), 
or from exposure to the hyperkalemic, hypocalcemic acidotic 
nature of blood banked blood, which can cause a bradykinin 
release syndrome (BRS) when the blood is exposed to the CRRT 
membrane.  The BRS is usually associated with AN-69 membranes 
that will not be used in this study.  Each center has its own blood 
priming protocol to mitigate the potential for this reaction.  
However, minimum standards for blood priming in this trial are 
detailed in Appendix E to ensure patient safety. [27]   
 
Patients with AKI requiring CRRT are often hypotensive prior to 
initiation of CRRT.  Initiation of CRRT itself can improve 
hemodynamics by correcting acidosis and hypocalcemia.  Most 
patients with hemodynamic instability receive vasoactive 
medications.  Since the age range and associated normal blood 
pressure parameters is wide for this pediatric study, it is difficult to 

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mandate an age specific lower blood pressure threshold to preclude 
CRRT initiation, especially if CRRT can address the instability as 
noted above.  However, a threshold BP of 80/40 mmHg-- patients 
with both a systolic blood pressure of less than 80 mmHg and a 
diastolic blood pressure of less than 40 mmHg will not be entered 
into the study. 
 
If a patient develops hypotension or experiences worsening 
hypotension during CRRT/SCD initiation (defined as a > 10 
mmHg decrease in mean arterial pressure (MAP) during the first 
15 minutes of CRRT initiation or integration of the SCD into the 
circuit), the patient, depending on the site PI’s judgement, will 
receive a either a 10 ml/kg crystalloid bolus over 10 minutes or 
vasoactive medications will either have their dose increased (if 
already prescribed) or will be initiated.  Each center will select the 
vasoactive medication that is best suited for the clinical indication. 
 
6.2.3 SCD PLACEMENT IN CRRT / ECMO CIRCUIT 
 
Appendix F illustrates the integration of the CRRT circuit and 
SCD into the ECMO circuit.  The CRRT return will be post pump. 
 
Patients who receive CRRT on ECMO almost always develop their 
AKI, and hence their need for CRRT, after they have been on 
ECMO for at least 24 hours. Thus, the additional extracorporeal 
volume (ECV) associated with the CRRT circuit is not a factor, as 
the blood volume from ECMO is stable. In fact, the contribution of 
the CRRT circuit is decreased (in terms of percent of ECV) since 
the ECMO circuit adds to the patient blood volume. The 
requirement for blood priming will be left to the clinical team 
treating the patient, as these cases will differ significantly from one 
another.  
 
The pressure gradients are not an issue with CRRT on ECMO. In 
the most standard configurations, the CRRT circuit draws blood 
from the ECMO circuit post‐pump and returns blood to the ECMO 
circuit pre‐membrane, which is the safest configuration. The 
CRRT circuit will therefore see positive pressure from the ECMO 
circuit, and the current CRRT machines are designed to handle 
this. The CRRT pumps however, regulate the pressures within the 
CRRT circuit, so the SCD will see similar pressures compared to a 
non‐ECMO situation. 
 
6.2.4 Concomitant Medications 
 

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Since clearance or adsorption of medications have not been 
completely studied with SCD therapy, dosing of concomitant 
medications as per other extracorporeal therapies should be 
employed and evaluated during SCD treatment. In this regard: 
 
• Subjects are permitted to take prescribed medications only.  
• Continuously administered intravenous medications should 
be administered without interruption during SCD therapy 
• Essential oral medications should be administered without 
adjustment of their dosing schedule 
• Emergent intermittent intravenous and oral medications 
will be administered when required, without regard to the 
timing of SCD therapy 
• For antibiotics, subjects will receive standard of care anti-
infective dosing according to published schedules adjusted 
for CRRT [30]. Antibiotic serum levels will also be 
measured as per standard of care guidelines to ensure 
effective dosing and avoidance of toxicity. 
• For vasopressors, dose adjustments will be made to achieve 
targeted mean arterial pressure. 
 
A list of critical medications is listed in Appendix C. The clinical 
investigators will be alerted to evaluate dosing schedules for these 
medications carefully for potential adjustments to achieve desired 
effects during SCD therapy. 
 

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1SCD Treatment Period lasts 240 hours or until termination criteria are met per Section 7 
2The Post SCD Period lasts 120 hours or until ICU discharge, whichever comes first 
3Window for follow up visits is day from SCD initiation +7 days 
4Blood for research biomarkers should be completed before SCD initiation (or 6 hours prior), as well as 48h, 96h, 144h, 192h, end of 
SCD, and 120 hours post SCD ±6 hours  
5Post filter iCa only need recorded in the pre-SCD time period if patient was on CRRT with RCA prior to SCD initiation  
6Post filter iCa should be obtained Q1Hr± 30min until <0.40 mmol/L for two consecutive measurements within the first 12 hours of 
SCD 
7Post filter iCa should be obtained Q1Hr± 30min until post filter iCa level<0.40 mmol/L for two consecutive measurements after any 
CRRT recirculation or restart, citrate or calcium rate change, and then Q6Hr±1Hr after 
8An arterial blood gas is only required if the patient is receiving invasive mechanical ventilation and has an arterial line per standard of 
care 
9Only SAEs need to be reported on Day 28 and Day 60 
 
 

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6.4 
BASELINE PERIOD 
The Baseline Period begins at enrollment and ends at the start of the SCD 
Treatment Period (when the subject starts treatment). The following 
information will be recorded as close to the start of the SCD Treatment 
Period as possible. Data from standard of care tests may be used as 
baseline data, as long as it is captured within the time frames noted.  
 
• Demographic Data 
a) Date of birth 
b) Gender 
c) Race/ethnicity 
• Hospitalization Data 
a) Hospital Admission Date 
b) Hospital Admission Diagnosis 
c) ICU Admission Date 
d) ICU Admission Diagnosis 
e) Medical History 
• Vital Signs/Physical Assessment (within 12 hours prior to the start 
of SCD Treatment Period unless otherwise indicated) 
o Temperature 
o Blood Pressure and heart rate  
o Body weight at ICU admission 
o PRISM II Score 
o Physical Exam 
o Urine Output (previous 24 hours) 
o ICU percent fluid overload at CRRT initiation (Defined as [(Fluid 
In (liters) – Fluid Out (liters))/ICU admission weight (kg)] x 100% 
where Fluid In and Fluid Out are calculated from ICU admission to 
CRRT initiation. 
• Clinical Laboratory Tests (within 12 hours prior to the start of 
SCD Treatment Period) 
o CBC with differential  
o BUN/Creatinine 
o Na, K, Cl, HCO3, Ca, Mg, Ionized Ca, PO4 
o ALT, AST, Bilirubin, ALP, Total Protein, Albumin, Glucose 
• Respiratory  
o Status – Ventilator support (yes/no; date of intubation) 
o If on Vent:  FiO2 
o If on Vent with an arterial line: Arterial Blood Gas (12 hours prior 
to start of SCD Treatment Period) 
o If on Vent without an arterial line: Arterial Blood Gas (if available 
within 12 hours of start of Observation Period per standard of care)  
o ECMO Status (yes/no; date of cannulation) 
• Blood for Research 
o Blood sample should be collected within 6 hours before the start of 
the SCD Treatment Period 

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o Blood sample will be sent to an outside laboratory for testing of 
biomarkers. The research laboratory is Innovative BioTherapies 
located at 650 Avis Dr., Ann Arbor, MI 48108. 
• Other (Event-driven) 
o Acknowledgement (yes/no) to critical medications, vasopressors, 
and blood products administered to the patient in the 24 hours prior 
to start of SCD Treatment Period 
o Adverse Events occurring since enrollment 
o Microbiology/culture data (within the last 72 hr.) 
 
6.5 
SCD TREATMENT PERIOD 
The SCD Treatment Period begins when the subject starts treatment and 
will continue up to a maximum of 240 hours from the time of Treatment 
Start.   A subject may begin CRRT therapy and SCD treatment at the same 
time, which would also mark the beginning of the SCD Treatment Period. 
 
This treatment period has been broken into ten 24 hour time periods.  It 
ends when the subject has reached 240 hours in the treatment period or 
when the subject meets the termination criteria outlined in Section 7.2 as 
determined by the Principal Investigator or Medical Team at the 
participating Clinical Site. 
 
All tests are scheduled on a 24 hour cycle, or once a day, and can be 
scheduled to be drawn around each participating site’s ICU blood drawing 
schedule, with the exception of any test that requires a specific draw 
frequency. 
 
The following information will be obtained for subjects enrolled during 
the SCD treatment period on a daily basis unless otherwise specified: 
 
• Vital Signs/Physical Assessment 
o Temperature 
o Blood Pressure, heart rate  
o Urine Output (previous 24 hours) 
o Net Fluid Balance (previous 24 hours) 
• Clinical Laboratory Tests 
o CBC with differential  
o BUN, Creatinine 
o Na, K, Cl, HCO3, Ca, ionized Ca, Mg, PO4 
o ALT, AST, Bilirubin, ALP, Total Protein, Albumin, Glucose 
• Respiratory  
o Status – Ventilator support (yes/no; date of intubation or 
extubation, as applicable) 
o If on Vent: FiO2   
o If on Vent with an arterial line: Arterial Blood Gas  

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o If on Vent without an arterial line: Arterial Blood Gas (if 
completed as standard of care) 
o ECMO Status (yes/no; date of cannulation or decannulation as 
applicable) 
• Blood for Research 
o Collect at hours 48, 96, 144, 192 and end of SCD treatment (± 6 
hours). Blood for biomarkers will be collected as close as possible 
to the time of SCD scheduled changes in the days required (± 6 
hours) if practical and within window. 
o Blood sample will be sent to an outside laboratory (Innovative 
Therapies) for testing of biomarkers 
• CRRT Parameters (Start at hour 0)  
o Parameters include modality, blood flow rate, net fluid removal, 
dialysate or replacement solution flow rate, citrate infusion rate, 
calcium replacement rate. 
o System performance (circuit survival - event driven) 
o Post filter ionized calcium  
 
Therapy Initiation 
Q 1 hr±30min. until post filter 
iCa level 
<0.40 mmol/L; for two 
consecutive measurements 
within the first 12 hours of SCD 
then Q 6hr±1hr.  
After any Calcium or Citrate 
rate change 
Q 1 hr±30min. until post filter 
iCa level  
<0.40 mmol/L; then Q 6hr±1hr. 
After any Interruption: 
Recirculation, Procedure, 
Restart 
Q 1 hr±30min. until post filter 
iCa level 
 <0.40 mmol/L; then Q 6hr±1hr. 
 
• SCD Performance (Start at hour 0) 
o SCD
 performance (event driven) 
o SCD and SCD Blood Tubing Set Change every 24 hour (± 4 hours) 
 
• Other (Event Driven) 
o Acknowledgement (yes/no) to critical medications, vasopressors, 
and blood products administered to the patient 
o Adverse Events 
o Diagnostic/Therapeutic Procedures 
o Microbiology/culture data 
 
6.6 
STUDY FOLLOW UP PERIOD 
 
6.6.1 POST SCD TREATMENT PERIOD 

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This Study Follow Up period has been broken into five 24 hour 
time periods.  It starts when the subject has reached 240 hours in 
the treatment period or when the subject meets the termination 
criteria outlined in Section 7.2.  It ends at 120 hours post SCD or 
ICU discharge, whichever comes first.  Record the following data 
daily in the Study Follow-up Period unless otherwise noted: 
 
• Vital Signs/Physical Assessment 
o Blood pressure, heart rate, temperature 
o Physical Exam (first 24 hours only)  
o Urine Output (from previous 24 hours) 
o Net fluid balance (from previous 24 hours) 
• Clinical Laboratory Tests (first 24 hours only) 
o CBC with differential  
o BUN, Creatinine  
o Na, K, Cl, HCO3, Ca, Mg, Ionized Ca, PO4  
• Blood for Research 
o Collect at 120 hours post SCD ± 6 hours 
o Blood sample will be sent to an outside laboratory 
(Innovative Biotherapies) for testing of biomarkers 
• Respiratory  
o Status – Ventilator support (yes/no)  
o If on Vent:  FiO2 
o If on Vent with an arterial line: Arterial Blood Gas (first 24 
hours only)  
o If on Vent without an arterial line: Arterial Blood Gas (if 
completed as standard of care, first 24 hours only) 
o ECMO Status (yes/no) 
• Renal Replacement Therapy status 
o RRT status  
• Other (Event Driven) 
o Microbiology/culture data  
o Adverse Events 
o Acknowledgement (yes/no) to antibacterial agents 
administered to the patient. 
o Concomitant treatments or procedures 
 
6.6.2 DAY 28 POST ENROLLMENT 
This visit may be done via telephone call or office visit. Please 
record the following information on day 28 (+7 days) following 
enrollment: 
o Presence / date and setting of mechanical ventilation (since last 
visit) 
o Presence / date and settings of renal replacement therapy (since 
last visit) 
o Serious Adverse events (since last visit) 

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o Serum creatinine (if an office visit takes place) 
o ICU discharge date 
o Hospital discharge date 
 
6.6.3 DAY 60 POST ENROLLMENT 
This visit may be done via telephone call or office visit. Please 
record the following information on day 60 (+7 days) following 
enrollment: 
o Presence / dates of mechanical ventilation (since last visit) 
o Presence / dates of renal replacement therapy (since last visit) 
o Serious Adverse events (since last visit) 
o Serum creatinine (if an office visit takes place) 
 
7. 
TREATMENT INTERRUPTIONS – DISCONTINUATION CRITERIA 
 
7.1. 
TREATMENT DISCONTINUATION CRITERIA 
Subjects may be withdrawn from therapy prior to hour 240 for a variety of 
reasons.  When therapy is discontinued prior to hour 240, the follow-up 
period will immediately begin and data will continue to be collected per 
protocol. 
 
The Principal Investigator will assign a primary reason for therapy 
termination utilizing the categories listed in 7.2 and 7.3 below, and if 
appropriate, one or more subcategories. The Principal Investigator will 
notify the Sponsor or designee within 24 hours of withdrawal of 
participation. 
 
7.2. 
CLINICAL CRITERIA: 
 
1. Improvement in Clinical Status 
If a subject’s condition improves (e.g. renal condition has improved to 
the extent that CRRT can be discontinued or hemodynamic status has 
improved so that the dialysis modality can be changed from CRRT to 
IHD) treatment may be discontinued before the 240 hour treatment 
period. The decision to discontinue treatment based upon improvement 
in clinical status will be made by the Principal Investigator. 
 
2. CRRT related events 
Such as inability to maintain vascular access based upon PI’s clinical 
assessment. Includes failure of the CRRT device and/or circuit that 
requires treatment to be discontinued prior to hour 240 of therapy. 
 
3. SCD related medical events 
Such as persistent leukopenia, neutropenia or thrombocytopenia based 
upon PI’s clinical assessment of relationship to SCD.  
 

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4. SCD Failure/Malfunction 
Any failure of the SCD that requires treatment to be discontinued prior 
to hour 240 of therapy e.g. clotting or evidence of leakage in the SCD 
or inability to maintain a patent circuit. 
 
5. Death or withdrawal of life support 
 
6. Regional Citrate Anticoagulation Intolerance 
All subjects must be able to tolerate and achieve satisfactory regional 
citrate anticoagulation. Tolerance of regional citrate anticoagulation is 
defined as achieving: 
 Two (2) consecutive circuit ionized calcium levels of < 0.40 mmol/L 
(or < 1.6 mg/dL), 
 At least 30 minutes apart, and 
 Within the first 12 hours of SCD initiation. 
 
If unable to achieve the specific circuit ionized calcium levels within 
the time frame above, treatment with the SCD must be discontinued. 
The subject will progress on to the post-SCD follow up period, unless 
the subject and/or legal guardian withdraws consent for the study. 
 
7. Hematologic Events 
 Persistent leucopenia, neutropenia, thrombocytopenia based 
upon PI’s clinical assessment 
 Absolute neutrophil count less than 500 mm3 will be an 
indicator for therapy termination 
 Platelet count less than 30,000 mm3 after transfusion of 6 units 
of platelets 
 
8. Other 
Any other reason that the Principal Investigator deems appropriate for 
discontinuation from the SCD Treatment period must be documented. 
 
7.3. 
NON-CLINICAL CRITERIA: 
 
• Withdrawal of participation from SCD treatment period 
Subjects may withdraw their consent to participate in the study 
observation period at any time. If the subject wishes to remain in the 
clinical study, the follow-up period will immediately begin at the 
termination of SCD treatment period. All data will continue to be 
collected per protocol. 
 
The Principal Investigator will notify the Sponsor or designee within 
24 hours of withdrawal of participation. 
 
• Withdrawal of consent 

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If a subject or legal representative withdraws consent, all protocol 
related activities will be immediately discontinued. If study therapy 
(CRRT+SCD) is being administered at the time of withdrawal, normal 
procedures will be followed for CRRT+SCD therapy discontinuation 
(please see SCD Operator’s Manual).  No further study activity will be 
conducted. 
 
The Principal Investigator will notify the Sponsor or designee within 24 
hours of withdrawal of consent. 
 
8. 
CLINICAL TRIAL TERMINATION CRITERIA 
The Sponsor reserves the right to terminate the clinical trial for safety or 
administrative reasons at any time.  If the Sponsor, Principal Investigator, Data 
Safety Monitoring Board (DSMB), Institutional Review Board (IRB), or Food 
and Drug Administration (FDA) officials discover conditions during the study 
indicating that the trial or participation by a clinical site should be discontinued, 
this action may be taken after appropriate consultation between the Sponsor and 
the Investigators. 
 
Conditions that may warrant discontinuation of the trial at a specific clinical site 
may include the following: 
 
• Failure of the Investigator to enroll patients into the trial at an acceptable rate 
(as defined and agreed upon between the Investigator and the Sponsor). 
• Failure of the Investigator to comply with the pertinent FDA regulations. 
• Submission of false information by the Investigator from the research facility 
to the Sponsor or the FDA. 
• Failure to achieve and maintain post filter iCa levels of <0.40 mmol/L 
 
Conditions that may warrant discontinuation of the trial may include, but are not 
limited to, the following: 
 
• Discovery of an unexpected, serious or unacceptable risk to the patients 
enrolled in the study. 
• Decision on the part of the Sponsor to suspend or discontinue testing, 
evaluation or development of the study product at any time. 
 
9. 
SAFETY 
 
9.1. 
ADVERSE EVENTS 
An Adverse Event is any sign, symptom, illness, clinically significant 
abnormal laboratory value or other adverse medical event that appears for 
the first time or worsens in a subject during this clinical study, regardless 
of whether or not it is considered related to the device. 
 
Anticipated adverse events that may occur during CRRT include: 

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• thrombocytopenia 
• hypo- or hypernatremia 
• hypo- or hyperkalemia 
• hypo- or hypercalcemia 
• hypo- or hyperglycemia 
• other electrolyte imbalance 
• air embolism 
• hypotension 
• hypertension 
• hemolysis 
• increased oxygenation requirements 
• fatigue 
• dyspnea 
• muscle spasm 
• myalgia 
• nausea 
• vomiting  
• fluid imbalance 
• leukopenia 
• arrhythmias 
• hypothermia 
• hyperthermia 
• lactic acidosis 
• temporary decrease in cardiac output or cardiac index 
• disruption of skin integrity 
• paresthesia 
• tetany 
• altered mental status 
• bleeding 
• shock 
• infection 
• bacteremia 
• laryngospasm 
• seizure 
• death 
 
Anticipated AEs associated with the addition of SCD to CRRT include: 
• neutropenia 
• thrombocytopenia 
• hypotension 
• hypo- or hypercalcemia 
• alkalosis 
• clotting within the device 
• leakage due to cracking or breakage 

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9.2. 
SERIOUS ADVERSE EVENTS 
Any Adverse Event, whether considered study-treatment related or not, 
which fits any of the criteria below, is considered a serious adverse event 
(SAE): 
• Results in death 
• Is life-threatening (meaning that the patient was at risk of death at the 
time of the event; this does not refer to an event which might have 
caused death if it had occurred in a more severe form) 
• Requires in-patient hospitalization or prolongs the existing 
hospitalization 
• Is a persistent disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is considered an important medical event by the Principal Investigator 
(e.g., surgery, return to ICU, emergency procedures)   
 
9.3. 
UNANTICIPATED ADVERSE DEVICE EFFECT 
Unanticipated adverse device effect (UADE) is any serious adverse effect 
on health or safety, any life-threatening problem or death caused by, or 
associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the 
application; or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.  The 
Sponsor-Investigator will report UADEs to the FDA as they occur (e.g., 
no later than 10 working days after the Sponsor Investigator first receives 
notice of the effect), as mandated by 21 CFR 812.150(b)(1).   
 
9.4. 
ANTICIPATED ADVERSE EVENT 
Co-morbidities and symptoms/laboratory/physiological deviations 
normally associated with pre-existing conditions (e.g., diabetes, ASHD, 
other CV conditions, pneumonia, dialysis shunt problems, neurologic 
deficits) are considered “anticipated adverse reactions.” The investigator is 
required to take special care in differentiating concomitant illness events 
from those related to the therapy by use of subject history, relationship to 
treatment time and cartridge integrity, and other characteristics of clinical 
circumstances present at the time of the adverse experience, including 
drug interactions of concomitant medications and effects of surgical 
and/or medical procedures.  
 
Adverse events associated with CRRT or underlying critical illness are 
also to be considered “anticipated”.  Such events include but are not 
limited to the list in Section 9.1 above. 

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Any questions as to the expectedness of an adverse event will be discussed 
with Drs Yessayan and Goldstein.  Final review and assessment will be 
made by the Sponsor-Investigator, Dr. Yessayan and the DSMB. 
 
9.5. 
CAUSALITY 
All enrolled subjects must have all AEs assessed for causality (probability 
that the AE may have been caused by the study treatment) by the Principal 
Investigator. The following definitions for causality assessment will be 
used in this study: 
 
9.5.1. DEFINITELY RELATED 
A clinical event, including a significant change in a laboratory test, 
that occurs in a plausible time relationship to the SCD treatment or 
other protocol-required activity, and which cannot be explained by 
concurrent disease or other drugs, chemicals, or procedures and 
that follows a clinically reasonable response upon withdrawal of 
the SCD treatment. 
 
9.5.2. PROBABLY RELATED 
A clinical event, including a significant change in a laboratory test, 
that occurs within a reasonable time sequence in relationship to the 
SCD treatment or other protocol-required activity that is unlikely 
to be attributed to concurrent disease, other drugs, chemicals, or 
procedures, and that follows a clinically reasonable response upon 
withdrawal of the SCD treatment. 
 
9.5.3. POSSIBLY RELATED 
A clinical event, including a significant change in a laboratory test, 
that occurs within a reasonable time sequence in relationship to the 
SCD treatment or other protocol-related activity that could also be 
explained by concurrent disease, drugs, chemicals, or procedures. 
The clinical course after withdrawal of the SCD treatment may be 
unclear with respect to the contribution of the SCD treatment to the 
AE. 
 
9.5.4. UNRELATED 
An AE, including a significant change in a laboratory test, that 
occurs with a temporal relationship to the SCD treatment or 
protocol-required activity that makes an association with the SCD 
treatment or study activity improbable, and in which other drugs, 
procedures or underlying disease(s) provide likely explanation.  
 
9.6. 
SEVERITY – INTENSITY 
The intensity of all adverse events should be evaluated using the following 
definitions: 

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9.6.1. MILD 
An event that requires minimal clinical treatment or an adverse 
event requiring monitoring but no intervention or treatment; causes 
slight discomfort. 
 
9.6.2. MODERATE 
An event that requires non-routine intervention, (i.e., a new clinical 
treatment or diagnostic procedure), administered within an hour of 
the event; causes annoying discomfort. 
 
9.6.3. SEVERE 
An event requiring immediate intervention; causes significant 
discomfort. 
 
9.7. 
ADVERSE EVENT REPORTING 
Adverse event reporting requirements will be based on the time period in 
which the adverse event occurs.  It is understood that many of the signs 
and symptoms observed with ICU patients are expected. However, these 
should still be reported as adverse events if they meet the definitions of the 
Protocol. A “clinical care” event should therefore be reported as an 
adverse event if it meets any of the definitions. A group of symptoms that 
can be combined under one diagnosis, should be reported as a single 
adverse event. If a group of symptoms cannot be combined under one 
diagnosis, the symptoms should be reported as separate adverse events.  
These events will be reported as the number of events per time of 
exposure to the device. 
 
9.7.1. SCREENING AND ENROLLMENT PERIOD  
Only adverse events, serious and not serious, directly related to the 
screening procedures will be captured during this period. Unrelated 
clinical adverse events that occur prior to SCD treatment will be 
considered part of the medical history. 
 
9.7.2. TREATMENT PERIOD THROUGH END OF STUDY 
All adverse events that occur from the time of SCD start will be 
recorded as follows: 
• Serious Adverse Events (identified in Section 9.2) will be 
recorded until Day 60 after enrollment, death, or subject 
withdrawal of study consent, whichever occurs first. 
• Non-serious adverse events will be recorded until end of 120 
hours after the SCD Treatment Period ends, death, subject 
withdrawal of study consent or until ICU discharge, whichever 
occurs first. 
 
Any serious adverse event (regardless of relationship to the 

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treatment) occurring from the time of enrollment through end of 
study must be reported to the CCC and DCC at Cincinnati 
Children’s Hospital, within 24 hours of knowledge of the event.  
 
Each clinical trial site will be supplied with written SAE reporting 
instructions, SAE reporting forms and contact information for 
reporting of serious adverse events. 
 
For any AE that is ongoing at the time of the initial report, periodic 
follow-up information will be required until the adverse event is 
resolved or the patient is no longer in the study, whichever occurs 
first. 
 
The Investigator is responsible for all adverse events reporting to the 
Institutional Review Board (IRB) according to the requirements of 
the IRB and for providing clinical trial monitors with all medical 
records needed to source-verify the adverse events.  
 
9.8. 
SPONSOR INVESTIGATOR RESPONSIBILITIES  
The Sponsor-Investigator will review documented serious adverse 
effects and abnormal test findings to determine 1) if the abnormal 
test finding should be classified as an adverse effect; 2) if there is a 
reasonable possibility that the adverse effect was caused by the 
investigational device or, if applicable, other study treatment or 
diagnostic product(s); and 3) if the adverse effect meets the criteria 
for a serious adverse effect. 
 
In accordance with 21 CFR Part 812.150(a)(1) and (b)(1), the 
sponsor shall promptly report the results of an evaluation of any 
serious and unanticipated adverse device effect to FDA, the 
University of Michigan IRBMED and participating investigators 
(if any) as soon as possible, but not later than 10 working days 
after the sponsor first receives notice of the effect.  Thereafter, the 
sponsor shall submit such additional reports concerning the effect 
as the FDA requests.  Complications and non-serious or anticipated 
adverse events should be documented and tabulated but need not 
be submitted by the sponsor to the FDA as individual reports.  
10. DEVICE ACCOUNTABILITY 
All use of the SCD will be under the direct supervision of the principal 
investigator or his/her designee. The investigational devices will be clearly 
labeled as investigational use only and have a clearly marked serial number for 
each device. The receipt date and lot number will be recorded, and package 
sterility confirmed.  The devices will be stored in a secure location with access 
limited to the study team. 
 

S C D -P E D - 0 2 I n v esti gati o nal Pr ot oc ol 
Versi o n 1. 5  
 
U ni versit y of Mic hi g a n  
C o nfi d e ntial  
Pa g e 4 9  of 6 9  
All rec or ds of recei pt, use, a n d dis p ositi o n of t he de vices will be mai ntai ne d b y 
t he st u d y tea m. At t he c o m pleti o n of t he st u d y, t here will be a fi nal rec o nciliati o n 
b y st u d y pers o n nel of de vices s hi p pe d, use d, a n d de vices re mai ni n g. A n y 
discre pa n cies n ot e d will be i n vesti gate d, res ol ve d, a n d d oc u me nte d pri or t o ret ur n 
or destr ucti o n of u n use d de vices.   
1 1.  D A T A S A F E T Y M O NI T O RI N G B O A R D  
 
A n i n de pe n de nt D ata Safet y M o nit ori n g B oar d ( D S M B) will re vie w safet y res ults 
o ver t he c o urse of t he st u d y o n a sc he d ule s et b y Drs. Yessa y a n a n d G ol dstei n a n d 
t he D S M B.  T he D S M B will c o m pl y wit h t he F D A G ui da nce: “ G ui da nce f or 
Cli nical Trial S p o ns ors o n t he Esta blis h me nt a n d O perati o n of Cli nical Tri al Data 
M o nit ori n g C o m mittees”. T he D S M B will be f or me d t o pr o vi de scie ntific a n d 
me dical fee d bac k f or t he st u d y.  
 
T he D S M B will f oc us o n t he f oll o wi n g areas:  
 
 Perf or m a nce – t o ass ess st u d y c o n d uct a n d c o m plia nce 
 
 Effective ness – t o assess m ortalit y a n d dial ysis de pe n de nc y  
 S afety – t o assess t he i nci de nce, se v erit y, rel ati o ns hi p, a n d ti mi n g of  
a d verse e ve nts a n d t o i de ntif y safet y c o ncer ns; a n d  
 C o ntext – t o assess t he st u d y relati ve t o t he A KI literat ure.  
 
T he D S M B will r eflect t he disci plines a nd m e dical specialti es necessar y t o 
i nter pret t he data fr o m t he c linica l st u d y a nd t o f u lly e val uat e partici pa nt safet y. 
T h e S C D -P E D - 0 2 D S MB wil l b e ma de u p of a t least 2 me dical practiti o ne rs wit h 
e x pertise i n A KI a n d critical care me dici n e.  T he D S M B will o perate u n der a 
c harter a n d will i de ntif y pr os pecti ve dat a dis pla y s pecificati o ns t o c o n d uct 
i n de pe n de nt data re vie ws.  T he D S M B will ma ke rec o m me n dati o ns t o t he 
S p o ns or t o c o nti n ue t he st u d y as pla n ne d or t o st o p t he st u d y d ue t o safet y. T he 
D S M B will meet t o perf or m safet y e v al uati o ns a n d t o pr o vi de fee d b ac k t o t he 
S p o ns or I n v esti gat or at least q uarterl y .    T he D S M B reser ves t he ri g ht t o re q uest 
m ore fre q u e nt e val u ati o ns.  
1 2.  P R O T O C O L A N A L Y SI S / S CI E N TI FI C S O U N D N E S S  
T his st u d y deri ves fr o m t he h y p ot hesis t hat u p t o te n or less se q ue ntial 2 4 h o ur 
S C D treat me nts will i m pr o ve s ur vi val  i n patie nts wit h AKI re q uiri n g C R R T as 
c o m pare d t o hist orical d ata.  F urt her, S C D t hera p y ma y re d uce t he d urati o n of 
mai nte na nce dial ysis sec o n dar y t o ac ute re n al fail ure ( A R F) d ue t o ac ute ki d ne y 
i nj ur y ( A KI).  
 
T he precise mec h a nis m of acti o n of t he S C D is bec o mi n g better u n derst o o d a n d 
a p pears t o b e a n i m m u n o m o d ulat or y pr ocess w hic h i n hi bits le u k oc yte acti vati o n, 
a tri g ger of s yste mic i nfl a m mat or y res p o nse s y n dr o me ( SI R S) a n d m ulti- s yste m 
or ga n fail ur e. T he m o d ul ati o n of t he pr o- i nfla m m at or y state is belie ve d t o als o 
all o w rec o v er y of r e nal f u ncti o n i n A KI a n d ot her or ga n fail ure.  T he cartri d ge i n 

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the presence of citrate anticoagulant acts as a selective cytopheretic device to 
sequester and inhibit potentially damaging circulating leukocytes.  
 
Recent data have demonstrated, that the inflammatory response of neutrophils 
adhered to a 
 membrane in the presence of low iCa and citrate 
are released with a normalized apoptotic life span, compared to a delayed 
apoptotic rate promoted in systemic inflammation.  Leukocytes, especially 
neutrophils, are major contributors to the pathogenesis and progression of clinical 
inflammatory disorders, including SIRS, sepsis, ischemia/reperfusion injury and 
ARDS. Further data have demonstrated that monocytes with a proinflammatory 
phenotype, binds more avidly than monocytes with a reparative phenotype to the 
membrane in low iCa environment.  This selective binding results in a less 
inflammatory circulating monocyte population in disorders of inflammation.  The 
protocol has been carefully constructed with precise AKI diagnostic criteria, 
CRRT or comparable mode treatment and definition of patient’s age, need to 
tolerate citrate anticoagulation and placement in the ICU during SCD therapy.  
Subject exclusion criteria are also detailed so as to provide a well characterized 
and standardized subject population.  Observational periods and a complete 
schedule of events in the protocol delineate specific efficacy measurements as 
required to test the study hypothesis, including bio-inflammatory assay markers, 
and WBC activation studies.   
 
Besides the test of the hypothesis the study is focused on observable, empirical 
and laboratory determinations of subject safety while on the SCD.  Previous 
human trials have been conducted on the SCD device and the protocol contains a 
review of AE and SAE data from all SCD human studies and findings from those 
studies contributed to constructing the investigative safety profile. Safety endpoint 
measures specified in the protocol include adverse events, laboratory safety 
parameters, vital signs, ventilation status and hemodynamic variables. Device 
integrity and performance measurements are also defined as are circumstances 
which demand premature termination of SCD treatment.   
 
Prolonged exposure to the SCD is anticipated to result in superior outcomes, 
although as noted above, this pilot study is not designed to assess for efficacy.  
However, we understand that a minimum amount of exposure to the SCD will be 
required for an appropriate safety analysis and for making any inference regarding 
efficacy.  The ppCRRT experience demonstrated that the majority of patients 
(201/370) received CRRT for 1 to 7 days and exhibited 65% survival (Symons et 
al CJASN 2007 Table7).  
 
This trial is an early safety efficacy study but is not powered for statistical 
significance.  Insights into a comparison of historical controls matched to SCD 
treated subjects will utilize the ppCRRT Registry to match for: etiology of AKI, 
co-morbidities, CRRT modality, dose and form of anticoagulant, adverse events. 
[10] 
 

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The ppCRRT Registry has data fields for the primary reason for CRRT, including 
AKI and its cause, as well as co-morbidities which will be matched for primary 
organ system involvement. The CRRT modality was evenly distributed between 
convective and diffusive modality, with 60% of the convective modalities 
provided as CVVH and 40% as CVVHDF. The anticoagulant protocol will be 
standardized with ACD-A/CaCl2 and all centers used the same protocol in 
ppCRRT Registry as outlined in this study protocol. Thus, the ppCRRT Registry 
dataset will be able to be matched to our study subject cohort. Also as noted 
above, subjects will be matched for age, size and PRISM II score. 
 
The Prospective Pediatric CRRT (ppCRRT) database will be used as a control for 
the CRRT treatment related factors including: patient age, gender, primary cause 
of AKI, total treatment duration, CRRT modality (CVVH, CVVHD, CVVHDF), 
CRRT small solute clearance (ml/1.73m2/hour), baseline estimated GFR (using 
the original Schwartz formula, which was used in the ppCRRT), urine output in 
the 24 hours prior to CRRT initiation (ml/kg/hour), percent fluid overload at 
CRRT initiation based on admission ICU weight, vasoactive medication number 
at time of CRRT initiation and mean airway pressure at CRRT initiation. 
An additional analysis will also evaluate patients who have achieved targeted iCa 
levels during 90% of treatment time and those who do not. 
 
In summary this protocol meets all criteria necessary for clinical scientific inquiry 
related to a test of hypothesis in a well monitored environment focused on subject 
safety during the conduct of the study.  Basic statistics will be performed on the 
data sets along with historical data comparisons and subjected to subset analysis 
where appropriate.   The results will help to guide the design of a future pivotal 
study of this device. 
 
The rational for therapy, study objectives and endpoints, design, inclusion and 
exclusion criteria are explicitly defined.  Subject safety parameters are well 
documented including safety reporting, safety observations and assays, 
procedures for subject withdrawal and study discontinuation criteria along with 
monitoring device integrity and performance.  Lastly, a review of all prior SCD 
human study safety data is included in the protocol for full disclosure to study 
investigators and the informed consent document includes a full description of all 
known and potential risks of the device treatment.     
13.  DATA COLLECTION – STUDY MONITORING AND AUDIT 
The Principal Investigator at each clinical site is responsible for assuring the 
accuracy and completeness of all study documentation. To assure adequate 
protection of the rights of human subjects, per 21 CFR §812.40, 812.43 and 
812.46, this study will be monitored by the Clinical Coordinating Center (CCC) 
and the Data Coordinating Center (DCC) at Cincinnati Children’s Hospital. 
Monitoring will be conducted within ICH/GCP Guidelines. Clinical Monitoring 
Plan to ensure the following: 

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• The facilities continue to be acceptable. 
• The protocol is appropriately followed. 
• Any agreed upon changes to the protocol have been approved by the IRB  
• Accurate, complete and current records are maintained and available for all 
patients. 
• For each subject. collection of protocol-required data and entry of that data 
into the CRFs must be completed as soon as reasonably possible following 
that subject’s last day in each study period. 
• The information recorded and submitted to the CCC and the DCC is 
representative of the patient’s record and other supporting documentation. 
• Accurate, complete and timely adverse event reports for serious adverse 
events are submitted to the CCC and the DCC. 
• The Principal Investigator continues to assume primary responsibility for the 
study. 
 
The Investigator or designee must, upon request, provide to the CCC and the 
DCC monitors or FDA Investigator the necessary study records for a thorough 
review of the study’s progress.  These records include, but are not limited to, 
original documents and records, such as hospital and clinic charts, consent forms, 
and laboratory records.  The Principal Investigator is required to notify the 
Sponsor Investigator immediately of the following: 
 
• Withdrawal of IRB Approval 
• Any protocol violations or protocol deviations related to study device use 
• Notification that Informed Consent was not obtained or consent was 
withdrawn 
• Any other instance in which the Investigator or Sponsor deems it necessary 
 
Additional visits can be scheduled at the request of the Sponsor-Investigator. 
 
 

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14. INVESTIGATOR’S STATEMENT OF RESPONSIBILITY 
 
By my signature, I confirm that my staff and I have carefully read and understand 
this protocol and agree to comply with the conduct of the specified therein, In 
particular we have agreed to: 
 
• Conduct the study according to the protocol, amendments, and study guides. 
• Obtain Institutional Review Board approval of the study, any amendments to 
the study and periodic-re-approval, as required. 
• Obtain written consent from each study participant or their legal 
representative. 
• Report all serious adverse events to and to the IRB, as required by the 
protocol and IRB regulations. 
• Assure access by study monitors to original source documents. 
• Cooperate fully with CCC and the DCC Monitors, or the Food and Drug 
Administration (FDA). 
• Maintain confidentiality and assure security of confidential documents such as 
the protocol, consent form, case report form, SCD Operator’s Manual, final 
study reports, manuscript, and/or unpublished data and correspondence. 
• Achieve and maintain serum post filter ionized calcium levels of <0.40 
mmol/L. 
 
 
 
______________________________________ 
 
 
_______________ 
Principal Investigator Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________ 
Printed Name  
 
 
 
 

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2019. A guide to understanding antimicrobial drug dosing in critically ill 
patients on renal replacement therapy. Antimicrob Agents Chemother 
63:e00583-19. https://doi.org/10 .1128/AAC.00583-19 
 
. 
 

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APPENDIX A (Continued) 
PEDIATRIC RISK OF MORTALITY (PRISM II) SCORE [28] 
 
GLASGOW COMA SCORE 
 
The Glasgow Coma Score (GCS) is scored between 3 and 15, 3 being the worst and 15 
the best.  It is composed of the three parameters listed below:  
 
Best Eye Response (4) 
 
 
 
Best Verbal Response (5) 
1. No eye opening  
 
 
1.   No verbal response 
2. Eye opening to pain  
 
2.   Incomprehensible sounds 
3. Eye opening to verbal command 
3.   Inappropriate words 
4. Eyes open spontaneously 
 
4.   Confused 
5. Oriented 
 
Best Motor Response (6) 
1. No motor response 
2. Extension to pain 
3. Flexion to pain 
4. Withdrawal from pain 
5. Localizing pain 
6. Obeys commands 
 
A Coma Score of 13 or higher correlates with a mild brain injury, 9 to 12 is a moderate 
injury and 8 or less a severe brain injury. 
 
 

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APPENDIX A (Continued) 
PEDIATRIC RISK OF MORTALITY (PRISM II) SCORE [28] 
 
 
PULMONARY SYSTEM CONVERSION TABLE 
 
O2 Saturation Conversion Table 
 
Conversion Table for FiO2 
Pulse oximetry O2 saturation may 
be used for calculating PaO2/FiO2 
ratio when ABG not available 
 
When measured on mask or nasal cannula 
 
SaO2 (%) 
Calculated PaO2 
 
Nasal Cannula 
80 
44 
100% O2 Flow Rate 
(L/min) 
FiO2 (%) 
81 
45 
1 
24 
82 
46 
2 
28 
83 
47 
3 
32 
84 
49 
4 
36 
85 
50 
5 
40 
86 
52 
6 
44 
87 
53 
 
 
88 
55 
Oxygen Mask 
 
89 
57 
100% O2 Flow Rate 
(L/min) 
FiO2 (%) 
90 
60 
5-6 
40 
91 
62 
6-7 
50 
92 
65 
7-8 
60 
93 
69 
9 
90 
94 
73 
10 
99+ 
95 
79 
 
 
96 
86 
Mask with Reservoir Bag 
97 
96 
100% O2 Flow Rate 
(L/min) 
FiO2 (%) 
98 
112 
6 
60 
99 
145 
7 
70 
 
 
8 
80 
 
 
 

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APPENDIX B – CRRT MANAGEMENT 
 
 
Continuous Renal Replacement will be provided to all subjects enrolled in the SCD-PED-
02 Trial using automated equipment with integrated ultrafiltration control.   
 
 
CRRT Modality: 
 
 
Continuous 
 
 
 
 
Blood Flow Rate: 
 
 
Prescribed by Investigator Team – Treating Team 
Dialysate Type: 
 
 
Prescribed by Investigator Team – Treating Team 
Dialysate Rate: 
 
 
Prescribed by Investigator Team – Treating Team 
Replacement Fluid Type: 
 
Prescribed by Investigator Team – Treating Team 
Ultrafiltration:  
 
 
Prescribed by Investigator Team – Treating Team 
Anticoagulation: 
 
 
Regional Citrate Anticoagulation 
Anticoagulation Prescription:  
Prescribed by Investigator Team – Treating Team 
CRRT Device 
Baxter PrismaFlex or PrisMax 
Hemofilter:* 
Baxter Prismaflex HF 1000 or HF20  
CRRT System Change: 
 
Per participating center protocol 
SCD
 Change: 
 
 
Every 24 hours ± 4 hours and as needed 
SCD Blood Tubing Set Change 
 with each SCD change 
 
*Hemofilters can be provided to site by sponsor upon request.   The clinical site will 
agree to use one of the protocol approved hemofilters for therapy.   
 
 
 
 
 
 
 

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APPENDIX D –REGIONAL CITRATE ANTICOAGULATION (RCA) 
PROTOCOL EXAMPLE 
 
1. Purpose: The purpose of the guidelines is to standardize, to the extent possible, 
the provision of regional citrate anticoagulation to patients who require CRRT.  
While these guidelines should govern the CRRT prescription provided to most 
patients, there will be special circumstances (e.g. inborn errors of metabolism, 
exogenous toxin removal) that will require deviation from these guidelines. 
 
2. Regional citrate anticoagulation: All CRRT circuits will receive regional citrate 
anticoagulation.  The initial prescription and calcium level monitoring will be 
based on the size of patients and the presence, or lack thereof, of significant 
hepatic dysfunction. REMEMBER TO ACCOUNT FOR THESE FLUIDS IN 
THE PATIENT REMOVAL RATE AS THESE ARE EXTERNAL TO THE 
CRRT MACHINE. 
a. Patients > 1 year of age and with normal hepatic function:  
i. Order ACD-A™ and CaCl2 (8 grams/1 liter NS) to bedside 
ii. Initial ACD-A™ rate = 1.5 x CRRT blood pump rate x min/hour 
(e.g., f blood pump rate is 100 ml/minute; the ACD-A™ rate is 
150 ml/hour).  This is to be infused at a stopcock or y-connector on 
access line. 
iii. Initial CaCl2 rate = 0.6 x blood pump rate x min/hour (e.g., if blood 
pump rate is 100 ml/minute; the CaCl2 rate is 60 ml/hour). 
iv. Calcium monitoring schedule 
1. Check patient total and ionized calcium prior to CRRT 
initiation. 
2. Check patient and system ionized calcium 5 minutes after 
CRRT settings at prescribed rates. 
3. Check patient and system ionized calcium 1 hours after 
CRRT settings at prescribed rates. 
4. Check patient and system ionized calcium every 6 hours 
thereafter 
5. Check patient total calcium daily 
6. Check patient and system ionized calcium one hour after 
any change in ACD-A™ or CaCl2 rate 
b. Desired Calcium Concentration ranges 
i. Circuit ionized calcium = 0.25 to <0.40 mmol/L 
ii. Patient ionized calcium = 1.1 to 1.3 mmol/L (a higher level may be 
requested by ICU/CICU service if clinically indicated) 
iii. Patient systemic calcium = 8 to 12 mg/dL 
c. Citrate anticoagulation management 

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i. Bedside RN to call for patient ionCa < 1 mmol/L or >1.5 mmol/L, 
or circuit ionCa < 0.25 mmol/L or ≥ 0.40 mmol/L 
ii. Circuit ionCa managed with ACD-A™ rate 
1. For circuit ionCa < 0.25 mmol/L, decrease ACD-A™  10% 
2. For circuit ionCa ≥ 0.40 mmol/L, increase ACD-A™ 10% 
iii. Patient ionCa managed by CaCl2 rate 
1. For patient ionCa < 0.9, increase CaCl2 20% 
2. For patient ionCa  0.9- 1, increase CaCl2 10% 
3. For patient ion Ca 1.3-1.5, decrease CaCl2 10% 
4. For patient ion Ca> 1.5, decrease CaCl2 20% 
 
 
 

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APPENDIX E – SCD/CRRT BLOOD PRIMING PROTOCOL 
 
The blood volume for the Prismaflex HF1000 is 165 ml and for the SCD is 120 ml, 
leading to a total extracorporeal circuit volume (ECV) is 285 ml.  The blood volume for 
the Prismaflex HF20 is 58mL leading to a total ECV of 178mL. Blood prime will occur if 
the ECV total is greater than 10% of the patient’s blood volume, based on an estimate of 
blood volume = 70 ml/kg x patient body weight (kg) [25]. As such, regardless of the use 
of the HF1000 or HF20 filter, all circuits will need to be blood primed, as estimated 
total blood volume for eligible patients would be 700 – 1400mL, where the ECVs above 
would account for >10%. The priming volumes for prismaflex and prismax are the same 
with the same set of filters. The Thermax heater of the Primsax if used will require 
additional 27 ml.   
 
This additional circuit blood volume can be handled with blood priming with matched 
blood similar to the standard practice in neonates. The situation is most commonly 
encountered in neonatal CRRT, where circuit ECV can represent nearly 50% of patient 
blood volume, yet the same principles apply for this clinical study. [26] 
 
The recommendation for all patients, except when concurrently treated with ECMO: 
 
• A crystalloid primed SCD circuit will be placed in line with a crystalloid primed 
CRRT circuit. For the initial CRRT/SCD circuit, the entire CRRT + SCD circuit 
will then be primed with blood per local standard of care prior to initiating CRRT 
/SCD therapy with the patient. Given the relatively large blood ECV to patient size 
in this population, the following patient lab parameters should be achieved prior to 
initiating CRRT/SCD therapy to prevent severe acidosis or hypocalcemia 
o Patient pH of at least 7.20 
o Patient ionized calcium of at least 1.1 mmol/L 
• Patient should be given calcium gluconate IV (at least 300 mg) at the start of 
CRRT/SCD therapy. 
o An equivalent about of IV calcium can be given in a different formulation 
(ex. 100 mg of IV calcium chloride). 
• Once the CRRT+SCD therapy is initiated, patient ionized calcium and pH should 
be obtained no later than 15 minutes after achievement of final CRRT blood flow 
and effluent rates. 
• For the daily SCD circuit change, one of four options will be available: 
o A completely new CRRT circuit can be used with the SCD circuit with a 
repeat of the procedure in the paragraph above 
o A circuit to circuit prime can be performed per local standard of care 
whereby the blood in the previous CRRT + SCD circuit is used to prime a 
new CRRT + SCD circuit 
o 60 to 120 mL of blood will be rinsed back to the patient. The old SCD and 
tubing will be removed from the CRRT circuit, and a new crystalloid primed 
SCD filter and tubing will be connected. The volume that was rinsed back 
to the patient will be removed over the next 3 hours, unless otherwise 
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o The circuit will be placed into a saline prime, by rinsing the blood to a waste 
bag. The old SCD will be removed and a new crystalloid primed SCD will 
be connected in line post filter. The entire CRRT+SCD circuit will be re-
primed with blood, and then connected back to the patient. 
 
 

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APPENDIX F – PLACEMENT OF SCD IN CRRT / ECMO CIRCUIT