A Multi-Center, Pilot Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device (SCD) in Pediatric Patients With Acute Kidney Injury (AKI)
Phase: NA
Conditions: Acute Kidney Injury
Sponsor: CytoPherx, Inc



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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................. 2 
PROTOCOL SYNOPSIS .............................................................................................................................. 3 
LIST OF ABBREVIATIONS ....................................................................................................................... 8 
1. 
INTRODUCTION ................................................................................................................................ 9 
2. 
PRIOR CLINICAL EXPERIENCE ................................................................................................. 10 
3. 
PILOT STUDY (PROTOCOL SCD-PED-01) OBJECTIVES AND ENDPOINTS ..................... 18 
4. 
STUDY DESIGN ................................................................................................................................ 19 
5. 
SELECTION OF PATIENT POPULATION .................................................................................. 19 
6. 
STUDY ACTIVITIES ........................................................................................................................ 22 
7. 
TREATMENT INTERRUPTIONS – DISCONTINUATION CRITERIA ................................... 30 
8. 
CLINICAL TRIAL TERMINATION CRITERIA ......................................................................... 32 
9. 
SAFETY .............................................................................................................................................. 32 
10. DATA SAFETY MONITORING BOARD ...................................................................................... 39 
11. PROTOCOL ANALYSIS / SCIENTIFIC SOUNDNESS ............................................................... 40 
12. DATA COLLECTION – STUDY MONITORING AND AUDIT ................................................. 42 
13. INVESTIGATOR’S STATEMENT OF RESPONSIBILITY ........................................................ 43 
14. REFERENCES ................................................................................................................................... 44 
15. APPENDICES .................................................................................................................................... 46 
APPENDIX A – PEDIATRIC RISK OF MORTALITY (PRISM II) SCORE [27]................................. 46 
APPENDIX B – DEFINITIONS OF ACUTE KIDNEY INJURY .......................................................... 49 
APPENDIX C – DEFINITIONS OF ORGAN FAILURE AND SEPSIS [28] .......................................... 50 
APPENDIX D – ENDPOINT DEFINITIONS .......................................................................................... 51 
APPENDIX E – CRRT MANAGEMENT ................................................................................................ 52 
APPENDIX F – SCD-PED-01 Study Schedule of Events ........................................................................ 53 
APPENDIX G – SCD-PED-01 Study Schedule of Events: Follow-up Period ........................................ 54 
APPENDIX H – SCD-PED-01 Study Schedule of Events: Day 28 and Day 60 ..................................... 55 
APPENDIX I – INFORMED CONSENT TEMPLATE .......................................................................... 56 
CHILD ......................................................................................................................................... 56 
ADULT ....................................................................................................................................... 64 
APPENDIX J – CRITICAL MEDICATION LIST .................................................................................. 72 
APPENDIX K – CRRT PRESCRIPTION GUIDELINE and REGIONAL CITRATE 
ANTICOAGULATION (RCA) PROTOCOL EXAMPLE ...................................................................... 73 
APPENDIX L – SCD/CRRT BLOOD PRIMING PROTOCOL ............................................................ 76 
APPENDIX M – PLACEMENT OF SCD IN CRRT / ECMO CIRCUIT ............................................. 79 
 
 

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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) In Pediatric Patients 
with 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-F40 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 seven 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 
leukocytes play a central role in this process. [15] Leukocytes, 

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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 the SCD treatment up to seven 
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 evaluate the effect of up to seven consecutive 24 hour SCD 
treatments 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. These outcomes 
will be compared to a historical data set. 
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. 
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 

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discontinuation. 
Study Populations 
Pediatric patients with a body weight (BW) greater than or equal 
to 15 kg 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 30 patients will be enrolled in this study. 
Approximate 
Number of Centers 
Up to 10 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 signed a written 
informed consent form. 
2. 
Must be receiving medical care in an intensive care unit 
(e.g., PICU, MICU, SICU, CTICU, Trauma). 
3. 
Age less than 22 years. 
4. 
Females of child bearing potential who are not pregnant 
(confirmed by a negative serum pregnancy test) and not 
lactating if recently post-partum. 
5. 
Intent to deliver full supportive care through aggressive 
management utilizing all available therapies for a minimum 
of 96 hours.  
6. 
Clinical diagnosis of AKI due to etiologies requiring CRRT 
(see Appendix B). 
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. (Appendix C). 

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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. 
Irreversible brain damage based on available historical and 
clinical information. 
3. 
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. 
4. 
Acute or chronic use of circulatory support device other 
than ECMO such as LVADs, RVADs, BIVADs. 
5. 
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 a eGFR<30 
ml/min/1.73m2. Patients who have never seen a pediatric 
nephrologist will be assumed not to have pre-existing 
CKD. 
6. 
AKI occurring in the setting of burns, obstructive uropathy, 
vasculitis, scleroderma renal crisis, atheroembolism, 
functional or surgical nephrectomy, cyclosporine, or 
tacrolimus nephrotoxicity. 
7. 
Received >12 hour of CRRT (not including SCUF on 
ECMO) during this hospital admission or prior to transfer 
from an outside hospital. 
8. 
Received >1 hemodialysis treatment during this hospital 
admission or prior to transfer from an outside hospital. 
9. 
Metastatic malignancy which is actively being treated or 
may be treated by chemotherapy or radiation during the 
subsequent three month period after study therapy. 
10. Chronic immunosuppression with the exception of 
corticosteroids up to a dose of 10 mg per day.  
11. HIV or AIDS. 
12. Severe chronic liver failure as determined by standard 
diagnostic requirements. 
13. 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. 
14. 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.) 
15. Any medical condition that the Investigator thinks may 
interfere with the study objectives. 
16. Physician refusal. 

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17. Dry weight of <15 kg. 
18. Platelet count <15,000/mm3 at time of screening.  
19. 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. 
20. Use of any other Investigational drug or device within the 
previous 30 days. 
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 
 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ARDS 
Acute Respiratory Distress Syndrome 
ARF 
Acute Renal Failure 
ATN 
Acute Tubular Necrosis 
BW 
Body Weight 
iCa 
Ionized Calcium 
CBC 
Complete Blood Count 
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 
ECS 
Extra Capillary Space 
ICU 
Intensive Care Unit 
MICU 
Medical Intensive Care Unit 
nriCa 
Non Recommended Ionized Calcium Range 
ppCRRT 
Prospective Pediatric CRRT Registry 
PRISM 
Pediatric Risk of Mortality 
RAD 
Renal Assist Device 
riCa 
Recommended Ionized Calcium Range 
SAE 
Serious Adverse Event 
SCD 
Selective Cytopheretic Device 
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-F40 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 seven 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 therapies, the mortality rate during the past four decades of this 
condition has not improved. Critically ill patients with AKI in hospital 

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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] 
 
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 two therapeutic approaches utilizing renal 
epithelial cells and ‘smart’ immunomodulatory membranes has 
been tested in preclinical animal models and clinical trials. Results: 
These two approaches have been demonstrated in phase II human 
trials to improve the survival of intensive care unit patients with 
AKI 
and 
multiorgan 
failure. 
The 
use 
of 
a 
‘smart’ 
immunomodulatory membrane is also being evaluated in a small 
exploratory clinical trial to assess its effects on immunoregulation 
in ESRD patients requiring chronic hemodialysis. Conclusions: 
The use of renal progenitor/stem cell therapy and/or cytopheretic 
membranes may result in effective treatments to alter the 
dysregulated immunological state of acute or chronic renal failure 
and improve the outcomes of these diseases. 
 
2.1.2 SAFETY RESULTS 
All serious adverse events (SAEs) during the first 28 days after 
randomization were reported to the Medical Monitor within 24 

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hours of the event.  The reported SAEs 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 patients re-enrolled 
in what was called “Amendment 2”. 
 
2.2.2 SAFETY RESULTS 
Fifteen chronic hemodialysis (HD) patients 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 patients have completed the study 
treatment period and safety data is shown in Table 1 as follows: 
 
Table 1:  Report of Adverse Events - ESRD trial 
Adverse Event 
Number of 
Mild Severity 
Events 
Number of 
Moderate 
Severity Events 
Fever 
1 
0 
Chills 
2 
0 
Headache 
1 
0 
Nausea 
3 
0 
Vomiting 
2 
1 
Diarrhea 
1 
0 
Dizziness 
1 
1 
Visual Disturbances 
0 
1 
Lethargy 
0 
1 
Itching 
1 
0 
Latent TB infection 
1 
0 
Cough 
1 
0 
Left cheek swelling 
1 
0 
Decreased hemoglobin 
1 
1 
Increased CRP level 
2 
0 
Neck swelling cellulites 
0 
1 
Ankle sprain 
0 
1 
Replacement of left dysfunctional IJ 
catheter for HD 
1 
0 
Dialysis catheter fell off during sleep 
0 
1 
Muscle cramp 
0 
1 

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Adverse Event 
Number of 
Mild Severity 
Events 
Number of 
Moderate 
Severity Events 
Chest pain 
0 
1 
Clotted extracorporeal system. 350 ml 
blood loss 
0 
1 
L Upper quadrant pain 
0 
1 
Decreased WBC 
0 
1 
 
2.3 
AKI SAFETY, MORTALITY AND DEVICE INTEGRITY STUDY 
(CHINA)[21] 
 
2.3.1 STUDY SUMMARY 
Despite decades of improvements in the provision of renal 
replacement therapy, the morbidity and mortality associated with 
acute kidney injury (AKI) in the intensive care unit (ICU) setting 
remains extremely high. Much of the morbidity and mortality of 
this disorder is the consequence of systemic cellular damage that 
results from immune dysregulation. This was a prospective, single-
arm, single-center study designed to evaluate the safety and 
efficacy of treatment with a selective cytopheretic device (SCD) on 
clinical outcomes in AKI requiring renal replacement therapy in 
the ICU. The patients enrolled in the trial were compared with 
historical case-matched controls with respect to age and Sequential 
Organ Failure Assessment (SOFA) score. The mortality for the 
case-matched controls was 77.78%, whereas the mortality in the 
SCD treatment group was 22.22% (p = 0.027). Multiple regression 
analysis identified treatment with SCD as the only significant 
variable affecting mortality among age, SOFA score, and average 
change in urine output over the first 7 days during or after 
treatment.  Mean total urine output in the 10 subjects receiving 
SCD treatment increased from a baseline of approximately 500 
ml/d to more than 2,000 ml/d by day 7 of treatment. 
 
2.3.2 SAFETY RESULTS 
A total of 12 patients were enrolled in this study. There were no 
SAEs reported.  
 
In the 9 subjects analyzed on SCD treatment, no neutropenic 
events were reported. Mean WBC counts remained normal 
throughout treatment, with a mild decline noted upon initiation of 
therapy that was shown to rebound by day 7. No bleeding events 
were reported. Average platelet counts remained in the functional 
range (above 50,000) throughout treatment, with a mild decline 
noted upon initiation of therapy that was shown to plateau by day 4 
to an average platelet count of 75,000. A summary of all adverse 
events (AEs) observed in the 9 subjects on SCD treatment is 
presented in Table 2. These events were not attributed to the 

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device by the investigator, as they commonly occur with CRRT 
treatment. 
 
Table 2:  Adverse event reporting – China Study – n=9 patients 
Adverse Event 
(n=9 patients) 
Number of Mild 
Severity Events 
Number of Moderate 
Severity Events 
Hypercalcemia 
6 
2 
Thrombocytopenia 
1 
0 
Hypocalcemia 
0 
1 
Allergic Reaction 
1 
0 
Hypophosphatemia 
2 
0 
Hypernatremia 
1 
0 
 
2.4 
PILOT STUDY USA ARF-002 - IDE G090189[22] 
 
2.4.1 STUDY SUMMARY 
Acute kidney injury (AKI) is characterized by deterioration in 
kidney function resulting in multisystem abnormalities. Much of 
the morbidity and mortality associated with AKI result from a 
systemic inflammatory response syndrome (SIRS).  This study 
described herein was a prospective, single-arm, multicenter US 
study designed to evaluate the safety and efficacy of the Selective 
Cytopheretic Device (SCD) treatment on AKI requiring continuous 
renal replacement therapy (CRRT) in the ICU.  The study enrolled 
35 subjects.  The mean age was 56.3 ± 15.  With regard to race, 
71.4% of the subjects were Caucasian, 22.9% were Black, and 
5.7% were Hispanic.  Average SOFA score was 11.3 ± 3.6.  Death 
from any cause at Day 60 was 31.4%.  Renal recovery, defined as 
dialysis independence, was observed in all of the surviving 
subjects at Day 60.  The results of this pilot study indicate the 
potential for a substantial improvement in patient outcomes over 
standard of care therapy, which is associated with a greater than 
50% 60-day mortality in the literature.  The SCD warrants further 
study in scientifically sound, pivotal trial to demonstrate 
reasonable assurance of safety and effectiveness. 
 
2.4.2 SAFETY RESULTS 
A summary of all adverse events (AEs) observed in the 35 subjects 
is presented in Table 3.  The AEs observed were those expected for 
a critically ill patient population with acute renal failure and/or in 
an ICU setting.  
 
 

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Table 3:  Summary of Adverse Events ARF-002 
Adverse Events 
Number of Subjects with Events 
N (% of 35) 
Number of Events 
% of 199 (n/199) 
Total adverse events 
33 (94%) 
199 
 Serious adverse event 
23 (66%) 
14.1% (28/199) 
 Unanticipated Adverse Device Effect 
0 (0%) 
0.0% (0/199) 
 Relationship to Study* 
 
 
     Unrelated to study therapy 
32 (91%) 
93.5% (186/199) 
     Possibly related to study therapy 
8 (23%) 
6.0% (12/199) 
     Probably related to study therapy 
0 (0%) 
0.0% (0/199) 
     Definitely related to study therapy 
1 (3%) 
0.5% (1/199) 
 Outcome 
 
 
     Resolved w/ sequelae 
14 (40%) 
13.6% (27/199) 
     Resolved w/out sequelae 
25 (71%) 
64.3% (128/199) 
     Continuing 
11 (31%) 
11.1% (22/199) 
     Death 
11 (31%) 
5.5% (11/199) 
     Reported as Unknown 
3 (9%) 
5.5% (11/199) 
 Frequency 
 
 
     Single Episode 
29 (83%) 
54.3% (108/199) 
     Intermittent 
16 (46%) 
21.1% (42/199) 
     Continuous 
16 (46%) 
24.1% (48/199) 
     Reported as Unknown 
1 (3%) 
0.5% (1/199) 
 Severity 
 
 
     Mild 
21 (60%) 
34.7% (69/199) 
     Moderate 
25 (71%) 
51.8% (103/199) 
     Severe 
19 (54%) 
13.6% (27/199) 
*Subjects experienced more than one AE, therefore, numbers do not add up to N=22 (number of 
subjects experiencing any adverse event). 
 
2.5 
PIVOTAL STUDY (PROTOCOL SCD-003) - IDE G090189[23] 
 
2.5.1 STUDY SYNOPSIS 
Per the SCD-003 Protocol, our primary hypothesis is that up to 
seven 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 may 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% 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 50 to 80%. [5, 6, 7, 8, 9, 10, 11, 12] 
 
The SCD requires regional citrate anticoagulation be used for the 
entire CRRT and SCD blood circuits.  Per SCD-003, Section 5.1:  

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Each participating clinical site is to use their regional citrate 
anticoagulation protocol for the CRRT and SCD-ARF circuits 
(Study Arm) and for the CRRT only (Control Arm).  The 
recommended ionized calcium level (measured post SCD-ARF) in 
the CRRT and SCD-ARF blood circuit should be between 0.25 and 
0.40 mmol/L.   
 
2.5.2 SAFETY RESULTS AT INTERIM ANALYSIS 
The planned interim analysis was initiated at subject 134 and 
subject enrollment paused on May 24, 2013, to assess the clinical 
impact on study endpoints.  On September 3, 2013, the Data Safety 
Monitoring Board (DSMB) convened and reviewed the SCD-003 
data.  Upon completion of their meeting, they stated that there 
were no safety concerns with the outcomes presented in the 
following tables. 
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.   
Table 4:  Summary of Site-reported Serious Adverse Events (SAEs) 
All Subjects  N=132* 
 
CRRT + SCD 
N = 69 
CRRT Alone 
N = 63* 
 
Total 
N =132* 
Category 
Ets 
Pts 
% (n/N) 
Ets 
Pts 
% (n/N) 
Fisher's 
Exact 
P-Value 
Ets 
Pts 
% (n/N) 
Total 
80 
65.2% (45/69) 
71 
63.5% (40/63) 
0.857 
151 
64.4% (85/132) 
Blood and lymphatic system disorders 
9 
11.6% (8/69) 
4 
4.8% (3/63) 
0.212 
13 
8.3% (11/132) 
Cardiac disorders 
15 
17.4% (12/69) 
11 
15.9% (10/63) 
1.000 
26 
16.7% (22/132) 
Gastrointestinal disorders 
5 
5.8% (4/69) 
7 
9.5% (6/63) 
0.518 
12 
7.6% (10/132) 
General disorders and administration site 
conditions 
4 
5.8% (4/69) 
7 
11.1% (7/63) 
0.350 
11 
8.3% (11/132) 
Infections and infestations 
14 
17.4% (12/69) 
11 
15.9% (10/63) 
1.000 
25 
16.7% (22/132) 
Injury, poisoning and procedural complications 
1 
1.4% (1/69) 
0 
0.0% (0/63) 
1.000 
1 
0.8% (1/132) 
Investigations 
0 
0.0% (0/69) 
1 
1.6% (1/63) 
0.477 
1 
0.8% (1/132) 
Metabolism and nutrition disorders 
2 
2.9% (2/69) 
2 
3.2% (2/63) 
1.000 
4 
3.0% (4/132) 
Musculoskeletal and connective tissue disorders 
1 
1.4% (1/69) 
1 
1.6% (1/63) 
1.000 
2 
1.5% (2/132) 
Nervous system disorders 
6 
7.2% (5/69) 
1 
1.6% (1/63) 
0.211 
7 
4.5% (6/132) 
Other 
2 
2.9% (2/69) 
6 
7.9% (5/63) 
0.258 
8 
5.3% (7/132) 
Psychiatric disorders 
0 
0.0% (0/69) 
1 
1.6% (1/63) 
0.477 
1 
0.8% (1/132) 
Renal and urinary disorders 
1 
1.4% (1/69) 
3 
4.8% (3/63) 
0.348 
4 
3.0% (4/132) 
Respiratory, thoracic and mediastinal disorders 
13 
14.5% (10/69) 
10 
15.9% (10/63) 
1.000 
23 
15.2% (20/132) 
Skin and subcutaneous tissue disorders 
0 
0.0% (0/69) 
2 
3.2% (2/63) 
0.226 
2 
1.5% (2/132) 
Vascular disorders 
7 
10.1% (7/69) 
4 
6.3% (4/63) 
0.536 
11 
8.3% (11/132) 
*Two subjects enrolled to CRRT alone arm (012-002, 003-015) however not treated. 
 

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60 Day Mortality based on the SCD-003 protocol intent to treat is 
presented in Table 5.   
 
Table 5:  60 Day Mortality 
60 Day Mortality 
CRRT + SCD 
N= 69 
CRRT Alone 
N= 65 
Overall 
N=134 
All Subjects Enrolled 
100.0% (69/69) 
100.0% (65/65) 
100.0%(134/134) 
Alive 
61% (42/69) 
64% (38/59*) 
63% (80/128) 
Dead 
39% (27/69) 
36% (21/59*) 
38% (48/128) 
*Does not include six subjects LTFU (002-003, 011-002, 004-007, 011-004, 013-002, 007-025) 
 
2.5.3 EFFICACY RESULTS AT INTERIM ANALYSIS 
As a result of the mortality in Control Arm (CRRT alone) being 
approximately 10% lower than published levels of 45-50%, further 
analysis was undertaken.  As a result of the analysis, it was 
discovered that amount of time the patient was maintained in the 
recommended ionized calcium range (0.25-0.40 mmol/L per SCD-
003 protocol) presented a difference in efficacy outcomes.  One 
reason for the deficiency in clinical trial execution to ensure the 
protocol’s riCa target range of ≤0.40 mmol/L be maintained could 
be attributed to the national shortage of injectable calcium.  If the 
patient did not experience circuit clotting, the PIs emphasis of 
achieving and continuously maintaining the patient in the 
recommended ionized calcium range was not consistently adhered 
to.  In addition, the injectable calcium shortage resulted in 9 of the 
21 open clinical sites unable to enroll subjects due to low hospital 
inventories of injectable calcium.   
 
Of the 134 subjects enrolled in the SCD-003 protocol at the time of 
the interim analysis, 19 SCD subjects (CRRT+SCD) and 31 
control subjects (CRRT alone) were maintained in the protocol’s 
recommended range ((≤0.40 mmol/L) ≥90% of the therapy time). 
 
Table 6 details all cause mortality at day 60 (primary endpoint) of 
the treated subjects which received the recommended ionized 
calcium (riCa) and Table 7 details all cause mortality at day 60 of 
the treated subjects which did not receive the recommended 
ionized calcium (nriCa).   
 
Table 6:  60 Day Mortality of Subjects – Recommended Ionized 
Calcium Range (riCa) 
60 Day Mortality 
riCa 
CRRT + SCD 
N= 19 
CRRT Alone 
N= 27* 
Overall 
N=46 
Alive 
84% (16/19) 
59% (16/27) 
70% (32/46) 
Dead 
16% (3/19) 
41% (11/27) 
30% (14/46) 
Pearson chi2(1) =   3.2793   Pr = 0.070 
      *Three subjects LTFU (004-007, 007-025, 011-004).  One subject withdrew consent (013-002). 
 
 

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Table 7:  60 Day Mortality of Subjects – Non Recommended 
Ionized Calcium Range 
60 Day Mortality 
nriCa 
CRRT + SCD 
N= 50 
CRRT Alone 
N= 32* 
Overall 
N=82 
Alive 
52% (26/50) 
69% (22/32) 
59% (48/82) 
Dead 
48% (24/50) 
31% (10/32) 
42% (34/82) 
Pearson chi2(1) =   2.2555   Pr = 0.133 
*Two subjects LTFU (002-003, 011-002).  Two subjects enrolled to CRRT alone arm 
(012-002, 003-015) however not treated. 
 
A borderline statistically significant difference in 60-day all cause 
mortality (primary endpoint) was found in the cohort where the 
patient was maintained for ≥90% of the treatment in the protocol’s 
recommended ionized calcium (riCa) target range of ≤0.40 
mmol/L over those that were maintained ≤90% of the treatment 
duration.   
 
The secondary endpoints of renal replacement therapy dependency 
at day 60, mortality at day 28, number of ventilator free days at 
day 28 and mortality of the sub population of severe septic patients 
at day 60 were analyzed.  No statistical significance was shown 
except for the secondary endpoint of dialysis dependency.  Dialysis 
dependency showed a statistically significant difference between 
the patients maintained for ≥90% of the treatment in the protocol’s 
riCa target range of ≤0.40 mmol/L over those at ≤90% of the 
treatment duration.  See Table 8. 
 
Table 8:  Dialysis Dependency at Day 60 – Recommended Ionized 
Calcium Range 
Dialysis Dependency at Day 60 
riCa 
CRRT + SCD 
CRRT Alone 
N 
0/16 
4/16 
p-value 
0.033 
 
When a composite endpoint of all cause mortality (primary 
endpoint) or renal replacement therapy dependency (a secondary 
endpoint) at day 60 is analyzed, a statistical significance is 
observed. See Table 9. 
 
Table 9:  60 Day Combined End Point of All Cause Mortality or 
Dialysis Dependency – Recommended Ionized Calcium Range 
60 Day Combined End Point of All Cause 
Mortality or Dialysis Dependency -- riCa 
CRRT + SCD 
N=19 
CRRT Alone 
N=27 
15.8% 
55.6% 
N 
3/19 
15/27 
p-value 
0.007 
 

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2.5.4 CONCLUSION AT INTERIM ANALYSIS 
The SCD-003 Protocol included one formal interim effectiveness 
analysis on the primary endpoint of time to all-cause mortality by 
60 days for review by the DSMB.  On September 3, 2013, 
CytoPherx received concurrence from the DSMB that they would 
have recommend continuing the SCD-003 study (with appropriate 
corrective action to ensure the protocol’s riCa target range of <0.40 
mmol/L be maintained).  However, due to the existing statistical 
deficit, an increase in sample size to achieve a statistically 
significant treatment difference on the primary endpoint would 
have been required.  This increase in sample size would be 
prohibitive for CytoPherx to finance.   
 
Rather than continue SCD-003, CytoPherx terminated the study 
and intends to submit to FDA a supplement to IDE G090189 for 
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.   
 
3. 
PILOT STUDY (PROTOCOL SCD-PED-01) OBJECTIVES AND 
ENDPOINTS 
 
3.1 
PRIMARY OBJECTIVE 
To evaluate the safety of the SCD treatment up to seven 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 seven 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 

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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 in Appendix D. 
 
3.3 
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. 
 
4. 
STUDY DESIGN 
This is an open-label, multi-center Pilot Study. 
 
5. 
SELECTION OF PATIENT POPULATION 
 
5.1 
STUDY POPULATION 
Up to 30 pediatric patients will be enrolled in this study, in up to 10 
Clinical Centers in the United States. 
 
Pediatric patients with a body weight (BW) greater than or equal to 15 kg 
receiving care in the Intensive Care Units of each participating hospital 
will be screened daily and identified for participation in the trial. See 
Appendix E, CRRT Management. 
 
5.2 
INCLUSION CRITERIA 
1. 
A patient, or legal representative, has signed a written informed 
consent form. 
2. 
Must be receiving medical care in an intensive care unit (e.g., ICU, 
PICU, CICU, Trauma). 
3. 
Age less than 22 years. 
4. 
Females of child bearing potential who are not pregnant (confirmed 
by a negative serum pregnancy test) and not lactating if recently 
post-partum. 
5. 
Intent to deliver full supportive care through aggressive management 
utilizing all available therapies for a minimum of 96 hours.  

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6. 
Clinical diagnosis of AKI due to etiologies requiring CRRT (see 
Appendix B).  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  
(Appendix C). 
 
5.3 
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. 
Irreversible brain damage based on available historical and clinical 
information. 
3. 
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. 
4. 
Acute or chronic use of circulatory support device, other than 
ECMO, such as LVADs, RVADs, BIVADs. 
5. 
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 a eGFR<30 ml/min/1.73m2.  Patients who have 
never seen a pediatric nephrologist will be assumed not to have pre-
existing CKD. 
6. 
AKI occurring in the setting of burns, obstructive uropathy, 
vasculitis, scleroderma renal crisis, atheroembolism, functional or 
surgical nephrectomy, cyclosporine or tacrolimus nephrotoxicity. 
7. 
Received >12 hour of CRRT (not including SCUF on ECMO) 
during this hospital admission or prior to transfer from an outside 
hospital. 
8. 
Received >1 hemodialysis treatment during this hospital admission 
or prior to transfer from an outside hospital. 
9. 
Metastatic malignancy which is actively being treated or may be 
treated by chemotherapy or radiation during the subsequent three 
month period after study therapy. 
10. Chronic immunosuppression with the exception of corticosteroids up 
to a dose of 10 mg per day.  
11. HIV or AIDS. 
12. Severe chronic liver failure as determined by standard diagnostic 
requirements. 

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13. 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.  
14. 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.) 
15. Any medical condition that the Investigator thinks may interfere with 
the study objectives. 
16. Physician refusal. 
17. Dry weight <15 kg. 
18. Platelet count <15,000/mm3. 
19. 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. 
20. Use of any other interventional drug or device within the previous 30 
days. 
 
 

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6. 
STUDY ACTIVITIES 
 
6.1 
SCREENING PERIOD 
The screening period is the time period when a patient is identified, 
informed consent is obtained, and the patient is evaluated for inclusion in 
the clinical trial. Because of the critically ill nature of the study 
population, it is expected that the majority of patients will not be able to 
provide informed consent. Where subjects are unable to consent 
themselves, surrogate informed consent will be sought from the subject’s 
healthcare proxy or other equivalent legal representative. 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, whether consent was obtained 
or not, 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 to validate that 
the patient has met all inclusion and exclusion criteria.  
 
Chief Medical Officer:  David Humes, MD (734) 417-6825  
OR  
Stuart Goldstein MD (513) 803-3295, (713) 492-8001 
Cincinnati Children’s Hospital Medical Center (CCHMC) 
 
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 observation period (day and 
night).  The serum post filter ionized calcium level will be 
collected from the CRRT Circuit post SCD-F40. 
 
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 

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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% 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 50% of 
the previous rate, and hourly ionCa pairs will be rechecked x 3 
to ensure a stable patient ionCa >1 mmol/L and stable circuit 
ionCa <0.40 mmol/L. 
 
Of importance the clinical plan is to monitor the perfusion circuit 
iCa levels at least q1h 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.  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 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 K 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 >20 kg 
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) [24]. 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. [25] 
 

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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 L to ensure patient safety. [26]   
 
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 
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 will receive a 10 ml/kg crystalloid bolus over 
10 minutes.  If this bolus does not lead to improvement of MAP 
within 5 minutes, 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 M 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 

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the CRRT circuit is decreased (in terms of percent of ECV) since 
the ECMO circuit adds to the patient blood volume. 
 
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. 
 
6.3 
BASELINE PERIOD 
The Baseline Period begins at enrollment and ends at the start of the 
Observation Period. It is expected that the patient will begin the 
Observation Period before the patient has reached 12 hours of CRRT. The 
following information will be recorded as close to the start of the 
Observation 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.  
 
 

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• 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 Observation Period unless otherwise indicated) 
o Temperature 
o Blood Pressure, heart rate,  
o Body weight (within 24 hours if available) 
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 
Observation 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 
o PT, PTT, INR 
o Urinalysis (if urine available) 
• 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 Observation Period) 
o If on Vent without an arterial line: Arterial Blood Gas (if available 
within 12 hours of start of Observation Period)  
• Blood for Research 
o Blood sample will be sent to an outside laboratory for testing of 
biomarkers 
• Other (Event-driven) 
o Acknowledgement (yes/no) to critical medications administered to 
the patient in the 24 hours prior to start of Observation Period 
o Adverse Events occurring since enrollment 
o Microbiology/culture data (within the last 72 hr.) 
 

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6.4 
STUDY OBSERVATION PERIOD 
The Study Observation Period begins when the patient starts treatment and 
will continue up to a maximum of 168 hours from the time of Observation 
Start.  Patient will begin the Observation Period before the patient has 
reached 12 hours on CRRT. A patient may begin CRRT therapy and 
SCD treatment at the same time, which would also mark the beginning of 
the Study Observation Period. 
 
This observation period has been broken into seven 24 hour time periods.  
It ends when the patient has reached 168 hours in the observation period 
or when the patient 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 patients enrolled during the 
study observation 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 – every 12 hours (+/- 4 hours) 
o BUN, Creatinine 
o Na, K, Cl, HCO3, Ca, ionized Ca, Mg, PO4 
o ALT, AST, Bilirubin, ALP, Total Protein, Albumin, Glucose 
o PT, PTT, INR 
• Respiratory  
o Status – Ventilator support (yes/no; date of extubation) 
o If on Vent: FiO2   
o If on Vent with an arterial line: Arterial Blood Gas  
o If on Vent without an arterial line: Arterial Blood Gas (if available) 
• Blood for Research 
o Collect at hours 48, 96, 144, and end of study (+/- 4 hours). If 
study observation period ends prior to hour 168, collect at end of 
study observation period. Blood for biomarkers will be collected as 
close as possible to the time of SCD scheduled changes in the days 
required (+/- 4 hours) if practical. 
o Blood sample will be sent to an outside laboratory for testing of 
biomarkers 

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• 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 (+/- 1 hour) 
 
Therapy Initiation 
Q 1 hr. until post filter iCa level 
<0.40 mmol/L; then Q 6hr.  
After any Calcium or Citrate 
rate change 
Q 1 hr. until post filter iCa level  
<0.40 mmol/L; then Q 6hr. 
After any Interruption: 
Recirculation, Procedure, 
Restart 
Q 1 hr. until post filter iCa level 
 <0.40 mmol/L; then Q 6hr. 
 
• SCD Performance (Start at hour 0) 
o SCD-F40 performance (event driven) 
o SCD and SCD Blood Tubing Set Change every 24 hour (+/-4 hour) 
 
• Other (Event Driven) 
o Acknowledgement (yes/no) to critical medications administered to 
the patient 
o Adverse Events 
o Diagnostic/Therapeutic Procedures 
o Microbiology/culture data 
 
6.5 
STUDY FOLLOW UP PERIOD 
 
6.5.1 POST END OF STUDY TREATMENT PERIOD 
This Study Follow Up period has been broken into five 24 hour 
time periods.  It starts when the patient has reached 168 hours in 
the observation period or when the patient meets the termination 
criteria outlined in Section 7.2.  It ends at 120 hours 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  

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• 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 
available, first 24 hours only) 
• 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. 
 
6.5.2 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 of mechanical ventilation (since last visit) 
o Presence / date of renal replacement therapy (since last visit) 
o Serious Adverse events (since last visit) 
o Serum creatinine (if an office visit takes place) 
 
6.5.3 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 ICU discharge date 
o Hospital discharge date 
o Serious Adverse events (since last visit) 
o Serum creatinine (if an office visit takes place) 
 
 
 

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7. 
TREATMENT INTERRUPTIONS – DISCONTINUATION CRITERIA 
 
7.1. 
TREATMENT INTERRUPTION CRITERIA 
The SCD is to be used continuously along with CRRT and changed every 
24 hours and at any time the circuit exhibits significant clotting that 
impairs the functionality of the circuit.  
 
In the event that a procedure is needed (e.g. CT-Scan, MRI), SCD 
treatment may be interrupted for a maximum of 12 hours (cumulative) per 
24 hour period for these indications.  In the event a patient needs to initiate 
ECMO in the middle of the SCD course, SCD treatment may be 
interrupted for up to 24 consecutive hours.  Cumulative interruption of 
greater than 12 hours (or 24 hours for ECMO) will trigger the end of 
Observation Period and immediate initiation of the Follow-up period.  
These patients will not be removed from the study unless consent is 
withdrawn. 
 
7.2. 
TREATMENT DISCONTINUATION CRITERIA 
Patients may be withdrawn from therapy prior to hour 168 for a variety of 
reasons.  When therapy is discontinued prior to hour 168, 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 7.3 and 7.4 below, and if 
appropriate, one or more subcategories. 
 
7.3. 
CLINICAL CRITERIA: 
 
1. Improvement in Clinical Status 
If a patient’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 168 hour treatment 
period. The decision to discontinue treatment based upon improvement 
in clinical status will be made by the Principal Investigator. 
 
2. CRRT related medical events 
Such as persistent leukopenia, neutropenia or thrombocytopenia based 
upon PI’s clinical assessment. 
 
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. CRRT Failure/Malfunction 
Failure of the CRRT device and/or circuit, including inability to 
maintain vascular access that requires treatment to be discontinued 
prior to hour 168 of therapy. 
 
5. SCD Failure/Malfunction 
Any failure of the SCD-F40 that requires treatment to be discontinued 
prior to hour 168 of therapy e.g. clotting or evidence of leakage in the 
SCD-F40 or inability to maintain a patent circuit. 
 
6. Death 
 
7. Withdrawal of life support 
 
8. Concomitant Medical Conditions 
Need for medical, surgical or diagnostic procedures that necessitate 
discontinuation of SCD treatment for longer than the allowable 12 
hours per 24 hour period. 
 
9. Regional Citrate Anticoagulation Intolerance 
All patients 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 CRRT initiation. 
 
If unable to achieve the specific circuit ionized calcium levels within 
the time frame above, treatment with the SCD must be discontinued. 
The patient will progress on to the post-SCD follow up period, unless 
the patient and/or legal guardian withdraws consent for the study. 
 
10. Other 
Any other reason that the Principal Investigator deems appropriate for 
discontinuation from the Study Observation period must be 
documented. 
 
7.4. 
NON-CLINICAL CRITERIA: 
 
• Withdrawal of participation from study observation period 
Patients may withdraw their consent to participate in the study 
observation period at any time. If the patient wishes to remain in the 
clinical study, the follow-up period will immediately begin at the 
termination of study observation period. All data will continue to be 
collected per protocol. 

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The Principal Investigator will notify the Sponsor’s Chief Medical 
Officer or designee within 24 hours of withdrawal of participation. 
 
• Withdrawal of consent 
If a patient 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’s Chief Medical 
Officer 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 

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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 (control or treatment arm) during this 
clinical study, regardless of whether or not it is considered related to the 
device. 
• Blood and lymphatic system disorders (e.g., anemia, disseminated 
intravascular coagulation (DIC), heparin-induced thrombocytopenia 
(HIT), 
hypercoagulation, 
leukocytosis, 
thrombocytopenia, 
and 
thrombocytosis);  
• Cardiac disorders (e.g., atrial fibrillation, atrial flutter, bradycardia, 
cardiogenic shock, non-ST segment elevation myocardial infarction, 
sinus tachycardia, ventricular fibrillation, and ventricular tachycardia);  
• Gastrointestinal disorders (i.e., blood in stool, constipation, distended 
abdomen, gastrointestinal bleeding, ileus, nausea, pancreatitis, 
vomiting)  
• General disorders and administration site conditions (i.e., chest pain, 
generalized aching, high temperature, hypothermia, multi-organ 
failure)  
• Infections and infestations (i.e., candidiasis, gangrene, klebsiella 
pneumonia infection, methicillin-resistant staphylococcus aureus 
(MRSA) infection, pneumonia, sepsis, septic shock, and urinary tract 
infection (UTI));  
• Injury, poisoning and procedural complications (e.g., post procedural 
pain);  
• Metabolism 
and 
nutrition 
disorders 
(i.e., 
hypercalcemia, 
hyperglycemia, 
hyperkalemia, 
hypernatremia, 
hypervolemia, 
hypocalcemia, 
hypoglycemia, 
hypokalemia, 
hypomagnesemia, 
hyponatremia, hypophosphatemia, malnutrition, metabolic acidosis, 
and metabolic alkalosis);  
• Musculoskeletal and connective tissue disorders (e.g., muscle spasm) ;  
• Nervous System Disorders (e.g., encephalopathy, mental deterioration, 
stroke); 
• Psychiatric disorders (e.g., agitation, anxiety, confusion, insomnia, 
mental status changes);  
• Renal and urinary disorders (e.g., acute retention of urine, renal 
failure);  
• Respiratory, thoracic and mediastinal disorders (e.g., acute respiratory 
failure, aspiration pneumonia, atelectasis, hypoxemia, pleural effusion, 
pneumothorax, pulmonary thromboembolism, respiratory failure, and 
thoracic hemorrhage);  
• Skin and subcutaneous tissue disorders (e.g., macular rash, skin ulcer); 
and  
• Vascular disorders (e.g., deep vein thrombosis, hypertension, 
hypotension, and jugular vein thrombosis). 
 
9.2. 
SERIOUS ADVERSE EVENTS 

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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.  UADEs are 
reported to FDA as they occur (e.g., no later than 10 working days after 
CytoPherx 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 C-V 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 patient 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: thrombocytopenia, hyponatremia, hypokalemia, hypo- or 
hypercalcemia, hypo- or hyperglycemia, air embolism, hypotension, 
hemolysis, increased oxygenation requirements, leukopenia, arrhythmias, 
hypothermia, lactic acidosis, temporary decrease in cardiac output or 
cardiac index, disruption of skin integrity, bleeding, shock, bacteremia, 
hypotension, seizure, and death. 
 

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In addition, the following adverse events were experienced in the SCD-
003 clinical trial and are considered anticipated:   
 
• 
Blood and lymphatic system disorders (i.e., Anemia, Disseminated 
intravascular coagulation (DIC), Heparin-induced thrombocytopenia (HIT), 
Hypercoagulation, Leukocytosis, Thrombocytopenia, Thrombocytosis) 
 
• 
Cardiac disorders (i.e., Atrial fibrillation, Atrial flutter, Bradycardia, 
Cardiogenic shock, Non ST segment elevation myocardial infarction, Sinus 
tachycardia, Ventricular fibrillation, Ventricular tachycardia)  
 
• 
Gastrointestinal disorders (i.e., Blood in stool, Constipation, Distended 
abdomen, Gastrointestinal bleeding, Ileus, Nausea, Pancreatitis, Vomiting)  
 
• 
General disorders and administration site conditions (i.e., Chest pain, 
Generalized aching, High temperature, Hypothermia, Multi organ failure)  
 
• 
Infections and infestations (i.e., Candidiasis, Gangrene, Infection Klebsiella 
pneumonia, Infection MRSA, Pneumonia, Sepsis, Septic shock, UTI)  
 
• 
Injury, poisoning and procedural complications (i.e., Post procedural pain)  
 
• 
Metabolism and nutrition disorders (i.e., Hypercalcemia, Hyperglycemia, 
Hyperkalemia, Hypernatremia, Hypervolemia, Hypocalcemia, 
Hypoglycemia, Hypokalemia, Hypomagnesemia, Hyponatremia, 
Hypophosphatemia, Malnutrition, Metabolic acidosis, Metabolic alkalosis)  
 
• 
Musculoskeletal and connective tissue disorders (i.e., Muscle spasm)  
 
• 
Nervous system disorders (i.e., Encephalopathy, Mental deterioration, stroke)  
 
• 
Psychiatric disorders (i.e., Agitation, Anxiety, Confusion, Insomnia, Mental 
status changes)  
 
• 
Renal and urinary disorders (i.e., Acute retention of urine, Renal failure)  
 
• 
Respiratory, thoracic and mediastinal disorders (i.e., Acute respiratory 
failure, Aspiration pneumonia, Atelectasis, Hypoxemia Pleural effusion, 
Pneumothorax, Pulmonary thromboembolism, Respiratory failure, Thoracic 
hemorrhage)  
 
• 
Skin and subcutaneous tissue disorders (i.e., Macular rash, Skin ulcer)  
 
• 
Vascular disorders (i.e., Deep vein thrombosis, Hypertension, Hypotension, 
Jugular vein thrombosis).   
 
Any questions as to the expectedness of an adverse event will be discussed 
with CytoPherx’s CMO and/or the DSMB. 
 

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9.5. 
CAUSALITY 
All enrolled patients 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: 
 
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. 

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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 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 enrollment will be 
considered part of the medical history. 
 
9.7.2. ENROLLMENT PERIOD THROUGH END OF STUDY 
All adverse events that occur from the time of enrollment will be 
recorded as follows: 
• Serious Adverse Events (identified in Section 9.2) will be 
recorded until Day 60 after enrollment, death, or patient 
withdrawal of study consent, whichever occurs first. 
• Non-serious adverse events will be recorded until end of study 
follow-up period after enrollment, death, patient withdrawal of 
study consent or until hospital discharge, whichever occurs 
first. 
 
Any serious adverse event (regardless of relationship to the 
treatment) occurring from the time of enrollment through end of 
study must be reported to CytoPherx Inc, or designee, within 24 
hours of knowledge of the event.  
 
Each clinical trial site will be supplied with written SAE reporting 

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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.  
 
 

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10. 
DATA SAFETY MONITORING BOARD  
 
An independent Data Safety Monitoring Board (DSMB) will review safety results 
over the course of the study on a schedule set by CytoPherx, Inc. and the DSMB.  
The DSMB will comply with the FDA Guidance: “Guidance for Clinical Trial 
Sponsors on the Establishment and Operation of Clinical Trial Data Monitoring 
Committees”. The DSMB will be formed to provide scientific and medical 
feedback for the study.  
 
The DSMB will focus on the following areas:  
 
• Performance – to assess study conduct and compliance;  
 
• Effectiveness – to assess mortality and dialysis dependency;  
• Safety – to assess the incidence, severity, relationship, and timing of 
adverse events and to identify safety concerns; and  
• Context – to assess the study relative to the AKI literature.  
 
The DSMB will reflect the disciplines and medical specialties necessary to 
interpret the data from the clinical study and to fully evaluate participant safety. 
The SCD-PED-01 DSMB will be made up of at least 2 medical practitioners with 
expertise in AKI and critical care medicine. The DSMB will operate under a 
charter and will identify prospective data display specifications to conduct 
independent data reviews.  The DSMB will make recommendations to the 
Sponsor to continue the study as planned or to stop the study due to safety. The 
DSMB will meet to perform safety evaluations and to provide feedback to the 
Sponsor at least annually as well as after 5, 10 and 16 of the cohort has completed 
60 day follow-up.  An efficacy evaluation to historical controls will be 
accomplished after all 16 enrolled patients have completed 60 day follow-up.  The 
DSMB reserves the right to request more frequent evaluations. 
 
 

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11. 
PROTOCOL ANALYSIS / SCIENTIFIC SOUNDNESS 
This study derives from the hypothesis that up to seven or less sequential 24 hour 
SCD treatments will improve survival in patients with AKI requiring CRRT as 
compared to historical data.  Further, SCD therapy may reduce the duration of 
maintenance dialysis secondary to acute renal failure (ARF) due to acute kidney 
injury (AKI).  
 
The precise mechanism of action of the SCD is becoming better understood and 
appears to be an immunomodulatory process which inhibits leukocyte activation, 
a trigger of systemic inflammatory response syndrome (SIRS) and multi-system 
organ failure. The modulation of the pro-inflammatory state is believed to also 
allow recovery of renal function in AKI and other organ failure.  The cartridge in 
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 polysulfone dialysis 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.  
Patient exclusion criteria are also detailed so as to provide a well characterized 
and standardized patient 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 patient 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.   
 

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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).  Assuming our trial includes patients with similar illness 
severity, we have established a 72 minimum number of hours a patient will be 
treated with the SCD to be included in the final outcome analysis. 
 
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 patients 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 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 patient cohort. Also as noted 
above, patients 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 patient 
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. 

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The rational for therapy, study objectives and endpoints, design, inclusion and 
exclusion criteria are explicitly defined.  Patient safety parameters are well 
documented including safety reporting, safety observations and assays, 
procedures for patient 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.     
12.  
DATA COLLECTION – STUDY MONITORING AND AUDIT 
The Principal Investigator is responsible for assuring the accuracy and 
completeness of all study documentation.  Monitoring will be conducted within 
ICH/GCP Guidelines and CytoPherx, Inc. Clinical Monitoring Plan to ensure the 
following: 
 
• The facilities continue to be acceptable. 
• The protocol is appropriately followed. 
• Any agreed upon changes to the protocol have been approved by the IRB and 
approval has been received in writing by CytoPherx, Inc. 
• 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 CytoPherx, Inc. 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 CytoPherx, Inc. 
• The Principal Investigator continues to assume primary responsibility for the 
study. 
 
The Investigator or designee must, upon request, provide to the Clinical Research 
Associate (CRA), Quality Assurance Auditor, 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 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 
 
 

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13. 
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 CytoPherx, Inc and to the IRB, as 
required by the protocol and IRB regulations. 
• Assure access by study monitors to original source documents. 
• Cooperate fully with any study-related GCP audit as performed by CytoPherx, 
Inc, their designee, 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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14. 
REFERENCES 
 
1. 
Kjellstrand CM, Gornick C, Davin T. Recovery from acute renal failure. Clin Exp Dialys 
Apher 1981;5(1&2):143–161. 
 
2. 
Hall JW, Johnson WJ, Maher FT, Hunt JA, Immediate and Long-Term Prognosis in Acute 
Renal Failure. Ann Intern Med 1970;73: 515–521. 
 
3. 
Wald R, McArthur E, Neill KJ, Adhikari, Bagshaw SM et.al, Changing Incidence and 
Outcomes Following Dialysis-Requiring Acute Kidney Injury Among Critically Ill Adults: 
A Population-Based Cohort Study. American Journal of Kidney Diseases 2015;65(6):870-
877. 
 
4. 
Van Den Noortgate D, Mouton V, Lamot C, Van Nooten G, Chondt A, Vanholder R, 
Afschrift A, Lameire N. Outcome in a post-cardiac surgery population with acute renal 
failure requiring dialysis: Does age make a difference? Nephrol Dial Transplant 2003; 
18:732–736. 
 
5. 
Liaño F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure in the 
intensive care unit compared with that seen in other settings. Kidney Int Suppl 1998;53 
Supplement 66:S16-S24. 
 
6. 
Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a 
multinational, multicenter study. JAMA 2005;294: 813-818. 
 
7. 
Metnitz PG, Krenn CG, Steltzer H, et al. Effect of acute renal failure requiring renal 
replacement therapy on outcome in critically ill patients. Crit Care Med 2002; 30:2051-
2058. 
 
8. 
McCarthy JT. Prognosis of patients with acute renal failure in the intensive care unit: a tale 
of two eras. Mayo Clin Proc 1996;71: 117-126. 
 
9. 
Star RA. Treatment of acute renal failure. Kidney Int 1998;54: 1817-1831. 
 
10. 
Symons JM, Chua AN, Somers MJ, Baum MA, Bunchman TE, Benfield MR, Brophy PD, 
Blowey D, Fortenberry JD, Chand D, Flores FX, Hackbarth R, Alexander SR, Mahan J, 
McBryde KD, Goldstein SL. Demographic characteristics of pediatric continuous renal 
replacement therapy: a report of the prospective pediatric continuous renal replacement 
therapy registry. Clin J Am Soc Nephrol. 2007;2(4):732-738. PMID: 17699489. 
 
11. 
Modem V, Thompson M, Gollhofer D, Dhar AV, Quigley R. Timing of Continuous Renal 
Replacement Therapy and Mortality in Critically Ill Children. Crit Care Med. 2013. PMID: 
24231758. 
 
12. 
Goldstein SL, Somers MJ, Baum MA, Symons JM, Brophy PD, Blowey D, Bunchman TE, 
Baker C, Mottes T, McAfee N, Barnett J, Morrison G, Rogers K, Fortenberry JD. Pediatric 
patients with multi-organ dysfunction syndrome receiving continuous renal replacement 
therapy. Kidney Int. 2005;67(2):653-658. PMID: 15673313 
 
13. 
Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, 
Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA, et al. Plasma cytokine levels predict 
mortality in patients with acute renal failure. Kidney Int 2004; 65:1357–1365. 
 

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14. 
Mutunga M, Fulton B, Bullock R, Batchelor A, Gascoigne A, Gillespie JI, Baudouin SV. 
Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 
2001; 163:195–200. 
 
15. 
Himmelfarb J, McMonagle E, Freedman S, Klenzak J, McMenamin E, Le P, Pupim LB, 
Ikizler TA, et al. Oxidative stress is increased in critically ill patients with acute renal 
failure. J Am Soc Nephrol 2004; 15:2449–2456. 
 
16. 
Kaneider NC, Leger AJ, Kuliopulos A. Therapeutic targeting of molecules involved in 
leukocyte-endothelial cell interactions. FEBS J 2006;273: 4416–4424. 
 
17. 
Maroszynska I, Fiedor P. Leukocytes and endothelium interaction as rate limiting step in 
the inflammatory response and a key factor in the ischemia-reperfusion injury. Ann 
Transplant 2000;5(4):5–11. 
 
18. 
Ware, LB, Matthay, MA. The acute respiratory distress syndrome. N Engl J Med, 342(18), 
1334-49, 2000 
 
19. 
Ding F, Song JH, Jung JY, Lou L, Wang M et.al, A Biomimetic Membrane Device That 
Modulates the Excessive Inflammatory Response to Sepsis. PLOS one 2011:6(4) e18584 
 
20. 
Humes HD, Sobota J, Ding F, Song JH. A Selective Cytopheretic Inhibitory Device to 
Treat the Immunological Dysregulation of Acute and Chronic Renal Failure. Blood 
Purification, 2011;29:183-190 
 
21. 
Ding F, Yevzlin AS, et al: The effects of a novel therapeutic device on acute kidney injury 
outcomes in the intensive care unit: a pilot study. ASAIO J 2011:57(5):426–432 
 
22. 
Tumlin JA, Chawla L, Tolwani AJ, Mehta R, Dillon J, Finkel K, DaSilva JR, Astor BC, 
Yevzlin AS, Humes HD: The effect of the selective cytopheretic device on acute kidney 
injury outcomes in the intensive care unit: a multi-center pilot study. Seminars in Dialysis 
2012;25(6) PMID:23106607 
 
23. 
Tumlin JA, Galphin CM, Tolwani AJ, Chan MR, Vijayan A, Finkel K, Szamosfalvi B, Dev 
D, DaSilva JR, Astor BC, Yevzlin AS, Humes HD., A Multi-Center, Randomized, 
Controlled, Pivotal Study To Assess the Safety and Efficacy of a Selective Cytopheretic 
Device In Patients with Acute Kidney Injury. PLos ONE 2015:10(8) e0132482 
 
24. 
Bridges BC, Askenazi DJ, Smith J, Goldstein SL. Pediatric renal replacement therapy in the 
intensive care unit. Blood Purif 2012;34:138-48 
 
25. 
Kaddourah A, Goldstein SL. Renal replacement therapy in neonates. Clinics in perinatology 
2014;41:517-27 
 
26. 
Hackbarth RM, Eding D, Smith CG, Koch A, et.al Zero balance ultrafiltration (Z-BUF) in 
blood-primed CRRT circuits achieves electrolyte and acid-base homeostasis prior to patient 
connection. Pediatr Nephrol 2005:(20) 1328-1333 
 
27. 
Kanter RK, Edge WE, et al – Pediatric Mortality Probability Estimated From Pre-ICU 
Severity of Illness. PEDIATRICS 1997;(99) 59-63  
 
28. 
Goldstein B, Giroir B Randolph A, et al. International pediatric sepsis consenus conference: 
Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005 6(1) 
2-8 
 
. 
 

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15. 
APPENDICES 
APPENDIX A – PEDIATRIC RISK OF MORTALITY (PRISM II) SCORE [27] 
 
ORGAN SYSTEM 
MEASURE 
Respiration 
PaO2 to FiO2 Ratio, PaCO2, Resp. Rate 
Coagulation 
Protime, PTT 
Liver 
Serum Total Bilirubin 
Cardiovascular 
Systolic BP, Diastolic BP, Heart rate 
Central nervous system 
Glasgow Coma Score, Pupillary Reflexes 
Metabolic 
Serum potassium, calcium, glucose, 
bicarbonate glucose 
 
ORGAN 
SYSTEM 
MEASURE 
FINDING 
POINTS 
Respiration 
PaO2 to FiO2 Ratio 
(please see Pulmonary 
System Conversion Table for 
Non-ventilated Pts) 
200 – 300 mmHg 
2 
<200 mmHg 
3 
PaCO2 
51-65 mmHg 
1 
>65 
5 
Respiratory Rate (breath/min) 51-70 
1 
>70 or Apnea 
5 
Coagulation 
Protime or Partial 
Thromboplastin Time 
1.5 x control 
2 
Liver 
Serum Total Bilirubin 
>3.5 mg/dL 
6 
Cardiovascular 
Systolic Blood Pressure 
(mmHg) 
150-200 or 65-75 
2 
>200 or 50-64 
6 
Diastolic Blood Pressure 
(mmHg) 
>110 
6 
Heart Rate (beat/min) 
>150 or <80 
4 
Central 
Nervous 
System 
Glasgow Coma Score 
<8 
6 
Pupillary Reactions 
Unequal or dilated 
4 
Fixed and dilated 
10 
Metabolic 
Potassium (mEq/L) 
3.0 – 3.5 or 6.5 – 7.5 
1 
<3.0 or >7.5 
5 
Calcium (mg/dL) 
7.0 – 8.0 
2 
12.0 – 15.0 or <7.0 
6 
Glucose (mg/dL) 
40-60 or 250 – 400 
8 
<40 or >400 
8 
Bicarbonate (mEq/L) 
<16 or >32 
3 
Conventions used for the above table include: 
• 
PaO2 is in mmHg and FiO2 in percent from 0.21 to 1.00. 
 

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APPENDIX A (Continued) 
PEDIATRIC RISK OF MORTALITY (PRISM II) SCORE [27] 
 
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 [27] 
 
 
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 – DEFINITIONS OF ACUTE KIDNEY INJURY 
 
Acute Kidney Injury 
 
Acute Kidney Injury (AKI) is sudden loss of the ability of the kidneys to excrete wastes, 
concentrate urine, and conserve electrolytes.  AKI is due to a variety of etiologies.  These 
conditions are found in circumstances of acute injury and conform to one of the following 
criteria: 
 
• 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 7days or:  
• Urine volume <0.5ml/kg/h for 6 hours 
(Note: pre-renal, vascular, , and obstructive etiologies are excluded on 
clinical or other diagnostic grounds.) 
 
AKI develops predominantly due to the injury and necrosis of HPTC (Human Proximal 
Tubular Cells).  AKI is caused by ischemia of the kidneys or by exposure to nephrotoxic 
agents. Risks for AKI include injury or trauma with resulting damage to the muscles, 
recent major surgery, blood transfusion reaction, septic shock or other forms of shock, 
and severe hypotension longer than 30 minutes.   
 
Any condition that causes a reduction in the amount of blood being pumped by the heart 
may cause AKI.  Liver disease and damage caused by diabetes mellitus (diabetic 
nephropathy) may predispose a person to the condition.  AKI can also be caused by 
exposure to nephrotoxic agents (e.g., aminoglycoside antibiotics), antifungal agents (e.g., 
amphotericin), medications to prevent rejection of transplanted organs (e.g., 
cyclosporine), dye used for radiographic studies, and other toxins.  In SCD studies, 
patients with AKI due to a variety of etiologies are eligible for study participation.  As 
noted above, pre-renal, vascular, and obstructive etiologies are excluded on clinical or 
other diagnostic grounds. 
 
 
 
 
 

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APPENDIX C – DEFINITIONS OF ORGAN FAILURE AND SEPSIS [28] 
 
A. 
SEPSIS 
 
Sepsis is defined in this protocol as the presence (probable or documented) of infection 
together with two or more of the following systemic manifestations of infection: 
 
Age 
2-5 years 
6-12 years 
13-18 years 
19-22 years 
Tachypnea 1 
(breaths / min) 
>22 
>18 
>14 
>14 
Tachycardia 
(beats / min) 
>140 
>130 
>110 
>90 
Hyper/Hypothermia 
(all ages) 
>38.5⁰C or <36⁰C 
WBC 
(x103 /mm) 
>15.5 or <6 
>13.5 or <4.5 
>11 or <4.5 
>12 or <4.0 
1. Patient meets this criteria if mechanically ventilated, not related to underlying neuromuscular disease or 
the receipt of general anesthesia. 
 
 
B. 
NON-RENAL ORGAN FAILURE 
 
 
At least one non-renal organ failure (defined as receiving mechanical ventilation [12] or 
at least one vasoactive medication to treat hypotension) OR presence (proven or 
suspected) of sepsis. 
 
 

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APPENDIX D – ENDPOINT DEFINITIONS 
 
ALL-CAUSE MORTALITY: 
All cause mortality is defined as in-hospital, 28-day and 60-day all cause mortality. 
 
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 SCD-F40 INTEGRITY AND PERMORMANCE: 
The SCD-F40 will be evaluated for the presence of clotting, leaking or any other 
malfunction.   
 
 

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APPENDIX E – CRRT MANAGEMENT 
 
 
Continuous Renal Replacement will be provided to all patients enrolled in the SCD-PED-
01 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 Only 
Anticoagulation Prescription:  
Prescribed by Investigator Team – Treating Team 
CRRT Device 
Gambro PrismaFlex, B. Braun Diapact 
Hemofilter:* 
Gambro Prismaflex HF 1000, Renaflow HF 400, 
Renaflow HF 700, Renaflow HF 1200 
CRRT System Change: 
 
Per participating center protocol 
SCD-F40 Change: 
 
 
Every 24 hours and as needed due to clotting 
SCD Blood Tubing Set Change 
With each SCD change 
CRRT+SCD Interruption: 
Up to twelve (12) hours per 24 hour period (or up to 
24 hours if interruption was needed to initiate 
ECMO in the middle of the SCD course) 
 
*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 F – SCD-PED-01 Study Schedule of Events  
 
 
Baseline 
Hr 
0-24 
Hr 
25-48 
Hr 
49-72 
Hr 
73-96 
Hr 
97-120 
Hr 
121-144 
Hr 
145-
168 
Therapy 
End 
Vital Signs/Physical Assessment  
  Temperature , Body Weight (baseline only) 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Blood Pressure (if no bp, MAP acceptable), Heart Rate 
X 
X 
X 
X 
X 
X 
X 
X 
  PRISM II Score 
X 
 
 
 
 
 
 
 
  Physical Exam 
X 
 
 
 
 
 
 
 
  Urine Output  (previous 24 hours) 
X 
X 
X 
X 
X 
X 
X 
X 
  Net Fluid Balance (previous 24 hours) 
 
X 
X 
X 
X 
X 
X 
X 
 
Sepsis 
X 
 
 
 
 
 
 
 
 
ICU Percent Fluid Overload at CRRT Initiation 
X 
 
 
 
 
 
 
 
 
Clinical Laboratory Testing 
  CBC with differential 
X 
q12h 
q12h 
q12h 
q12h 
q12h 
q12h 
q12h 
 
  BUN/Creatinine 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Na, K, Cl, HCO3, Ca, Mg, PO4, Ionized Calcium 
X 
X 
X 
X 
X 
X 
X 
X 
 
ALT, AST, Bilirubin, ALP, TP, Albumin, Glucose 
X 
X 
X 
X 
X 
X 
X 
X 
 
PT, PTT, INR 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Urinalysis (if urine is available) 
X 
 
 
 
 
 
 
 
 
Respiratory 
  Arterial Blood Gas (pH, PaO2, PaCO2) (if on vent)* 
X 
X 
X 
X 
X 
X 
X 
X 
 
  Ventilator Settings ( FiO2,)  
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood For Research 
  Blood for Biomarkers 
X 
 
X(hr/48) 
 
X(hr/96) 
 
X(hr/144) 
 
X 
Extracorporeal Device Parameters 
  CRRT (Settings- Event Driven) 
X (hour 0) 
X 
X 
X 
X 
X 
X 
X 
 
  Post Filter Ionized Calcium 
X (hour 0) 
q1h until 
<0.40mmol/L; 
then q6h 
q6h 
q6h 
q6h 
q6h 
q6h 
q6h 
 
  CRRT Device and SCD-F40 Performance (Event Driven) 
 
X 
X 
X 
X 
X 
X 
X 
 
  SCD 24hr. Daily Change 
 
X 
X 
X 
X 
X 
X 
X 
 
Other (Event-Driven) 
  Adverse Events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Critical Medications, Blood products (yes/no) per Appendix J 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Diagnosis/Therapeutic Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  Microbiology/culture data 
X 
X 
X 
X 
X 
X 
X 
X 
 
*Required only if the presence of an A-line; see Section 6.3 and Section 6.4 for details

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APPENDIX G – SCD-PED-01 Study Schedule of Events: Follow-up Period 
 
Day 1 - 5 or until ICU discharge (whichever occurs first unless otherwise specified) 
 
Measurement 
Hour  
0 - 24 
Hours  
25 – 1201 
Vital Signs/Physical Assessment 
 
Blood pressure, temperature, and heart rate 
X 
X 
Physical Exam 
X 
 
Urine Output (from previous 24 hours)  
X 
X 
Net Fluid Balance – (from previous 24 hours)  
X 
X 
Clinical Laboratory Tests  
 
CBC with differential  
X 
 
BUN/Creatinine  
X 
 
Na, K, Cl, HCO3, Ca, Mg, PO4, Ionized Calcium 
X 
 
Respiratory:   
 
Arterial Blood Gas (pH, PaO2, PaCO2) 
X 
X 
Ventilator Settings (FiO2) 
X 
X 
Other(event driven) 
 
Renal Replacement Therapy status 
X 
X 
Microbiology/Culture Data  
X 
X 
Adverse Events 
X 
X 
Serious Adverse Event 
X 
X 
Antibacterial Medications (yes/no) 
X 
X 
 
       
1Events listed in this column are to be performed once per 24 hour time period. 
 
 
 
 

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APPENDIX H – SCD-PED-01 Study Schedule of Events: Day 28 and Day 60 
 
Measurement 
Day 281 
Day 602 
Presence of mechanical ventilation (since last visit) 
X 
X 
Presence of renal replacement therapy (since last visit) 
X 
X 
Hospital and ICU Discharge information  
X 
X 
Serious Adverse events (since last visit) 
X 
X 
Serum Creatinine (if office visit takes place) 
X 
X 
 
1 This visit may be done via telephone call or office visit.  Please record the above information on 
day 28 (+7 days) following enrollment. 
 
2 This visit may be done via telephone call or office visit.  Please record the above information on 
day 60 (+7 days) following enrollment. 
 
 
 

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APPENDIX I – INFORMED CONSENT TEMPLATE 
CHILD 
 
 
 
A Multi-Center, Pilot Study To Assess the Safety and Efficacy 
of A Selective Cytopheretic Device (SCD) In Pediatric Patients 
with Acute Kidney Injury 
(SCD-PED-01) 
INTRODUCTION 
 
We are asking for your permission for your child to be in a research study so that we can 
learn new information that may help others.  If you decide not to give your permission for 
your child to be in this study, we will still take good care of him/her.  If you decide to 
allow your child to be in this study, you may change your mind at any time during the 
study and your child can stop being in the study.  Take all the time you need to make 
your choice.  Ask us any questions you have.  It is also okay to ask more questions after 
you decide to allow your child to be in the study.  You can ask questions at any time.   
 
WHY ARE WE DOING THIS RESEARCH? 
 
In this research study, we want to learn more about the effects of a new device which is 
similar to a dialysis filter used in the treatment of Acute Kidney Injury (AKI).  Because 
of your child’s kidney injury, continuous renal replacement therapy (CRRT) is being 
used to help your child’s kidneys recover.  This research involves using an investigational 
device or filter on the CRRT machine which is called a selective cytopheretic device 
(SCD).  The SCD works by allowing cells that cause kidney injury to be desensitized, 
inactivated, or stopped from causing more harm. 
 
We are asking your child and other children with AKI and requiring CRRT to be in the 
research, to understand the safety and effectiveness of the dialysis filter, selective 
cytopheretic device (SCD). 
 
We are asking 30 children to participate in this research. 
 
WHO IS IN CHARGE OF THE RESEARCH?  
 
__________________ is the researcher at __________________ that is in charge of this 
study.   
 
______________is being paid by the National Institutes of Health to do this study. 

SCD-PED-01 Investigational Protocol 
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CytoPherx, Inc. 
Confidential 
Page 57 of 79 
WHO SHOULD NOT BE IN THE STUDY 
Your child cannot be in this study if he/she has any of the following: 
• Older than 22 years old 
• Not receiving care in an intensive care unit 
• Pregnant or lactating 
• Heart support devices like, LVAD, RVAD, BiVAD 
• History of previous dialysis treatments during this admission 
• History of End Stage Kidney Disease 
• Severe chronic liver failure  
• Cancer 
• Chronic immunosuppression 
• HIV or AIDS. 
• Weight of less than 15kg (33 lbs.) 
• Concurrent enrollment in another interventional clinical trial. Patients enrolled in 
clinical trials where only measurements and/or samples are taken are allowed to 
participate. 
• Use of any other Investigational drug or device within the previous 30 days. 
 
WHAT WILL HAPPEN IN THE STUDY? 
 
The research staff will explain each visit to you.  You will be able to ask questions to 
make sure you understand what will happen to your child. 
 
These are the things that will happen to your child while in the study: 
• CRRTas prescribed by your child’s doctor with the addition of the SCD filter for 
up to 7 days 
• SCD will be changed once every 24 hours (See below the description of SCD) 
• Daily blood work for safety monitoring 
• In addition to daily blood work, a blood sample for Complete Blood Count will be 
done daily in the evening from an existing catheter for safety monitoring (extra 1 
mL/day)  
• Every other day blood samples for biomarkers (for this and future research) drawn 
from an existing catheter (total amount 4 mL/during the study period) 
• Data collection from your child’s medical record for every day the SCD is used, 
and up to 60 days or discharge from the hospital.  
• If your child still needs dialysis after 7 days, your child will be treated r per 
standard of care without the SCD filter as prescribed by your child’s doctor.  
 
The SCD is a synthetic membrane similar to filters used for hemodialysis to filter 
unwanted substances from the blood. The SCD will be connected to an existing CRRT 
circuit. Blood from the CRRT machine is flowed through the SCD, then returned back to 
the CRRT machine, and then returned back to the patient.  
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 58 of 79 
To keep the blood from forming clots in the circuit, a solution of citrate is put in the 
CRRT and SCD.  Citrate is a medication that keeps blood from forming clots when the 
blood is outside the body.  Citrate is used with CRRT as part of normal care at this 
hospital.  
 
Future Research: 
Researchers in this study are dedicated to researching biomarkers of kidney disease 
related to AKI.  The data and blood samples collected during this study are important to 
this study and to future AKI research.  With your additional consent, blood collected 
during this study will be kept in an outside laboratory for an indefinite period of time 
with samples from other children who have enrolled in this study.  All identifying 
information will be removed from the samples.  They will be identified only by a unique 
study number.  
 
These samples may be used in the future in ongoing research related to biomarkers 
involved in AKI and other kidney conditions.  They will only be studying kidney disease, 
which your child has already been diagnosed as having.  They will not be researching 
non-kidney related disease.  
 
These samples will be sent to an outside laboratory chosen by the sponsor, CytoPherx, 
Inc, but we will not give them any information that would personally identify your child.  
We will not put the results of any tests conducted on these samples in your child’s 
medical record.  Your child may still participate in this study even if you do not agree to 
participate in the sample repository. 
 
WHAT ARE THE GOOD THINGS THAT CAN HAPPEN FROM THIS 
RESEARCH? 
 
Being in this study may have potential benefit of improved outcome in terms of survival, 
improved blood pressure stability and a shorter ICU course; however, this cannot be 
guaranteed.  Being in this study may not help your child right now.   
 
When we finish the study, we hope that we will know more about the effects of the new 
dialysis filter on patients with AKI.  The results from this study may help other children 
with AKI later on.   
 
 
 
 
 
 
 
 
 
 
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 59 of 79 
WHAT ARE THE BAD THINGS THAT CAN HAPPEN FROM THIS 
RESEARCH? 
 
 
 
Life 
Threatening 
Serious 
Mild 
Common 
 
 
General aching 
Skin rash 
Nausea 
Vomiting 
Low blood pressure 
Low white blood 
counts 
Uncommon Irregular heart 
rate 
Infections 
Electrolyte disorders 
Temperature 
Pain 
Confusion 
Rare 
 
Pneumonia 
Bleeding from low platelet 
count 
Low or high calcium levels 
 
There may be other risks that we do not know about yet. 
WHAT OTHER CHOICES ARE THERE? 
 
Instead of being in this study, you can choose not to have your child be in it.  If you 
choose not to participate, your child will receive CRRT as standard of care. 
 
HOW WILL INFORMATION ABOUT YOUR CHILD BE KEPT PRIVATE? 
  
Making sure that information about your child remains private is important to us.  To 
protect your child’s privacy in this research study we will:  
 
• Identifiable data will have limited access, only the appropriate study staff will 
have access. 
• Store all study information in a locked cabinet or password protected file 
• Enter de-identified data into a secure password protected system  
• Ensure only appropriate study staff will have access to patient information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify your 
child. At most, the website will include a summary of the study results. You can search 
this website at any time. 
 
The Food and Drug Administration (FDA) may choose to inspect your child’s records 
since your child is a subject in this investigation of an unapproved drug/device. 
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
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WHAT IF WE LEARN NEW INFORMATION DURING THE RESEARCH?  
 
You will be told of any new information that might affect your child’s health, welfare, or 
willingness to allow your child to continue to take part in this study. 
 
WILL IT COST YOU ANYTHING EXTRA FOR YOUR CHILD TO BE IN THE 
RESEARCH STUDY?  
 
There will be no extra costs to you because your child is participating in this study.  You 
or your child’s health plan will pay for all the things you would have paid for even if you 
were not in the study, including the ICU stay, CRRT, and other hospital related health 
costs.  The SCD study device will be provided at no cost to you or your health insurance 
provider.   
 
WILL YOU/YOUR CHILD BE PAID TO BE IN THIS RESEARCH STUDY?  
 
Your child will not be paid for participating in the study.  
 
WHAT HAPPENS IF YOUR CHILD IS INJURED FROM BEING IN THIS 
STUDY?  
 
If you believe that your child has been injured as a result of this research you should 
contact the Principal Investigator as soon as possible to discuss the concerns.  Treatment 
for injuries is available at the study institution.  If your child goes to the Emergency 
Room or to another hospital or doctor it is important that you tell them that your child is 
in a research study.  If possible, you should give them a copy of this parental permission 
form. 
 
The study institution follows a policy of making all decisions about compensation for the 
medical treatment of physical injuries that happened during or were caused by research 
on an individual basis. 
 
WHO DO YOU CALL IF YOU HAVE QUESTIONS OR PROBLEMS?  
 
For questions, concerns, or complaints about this research study you can contact the 
study person listed on page 1 of this document.  
 
If you would like to talk to someone that is not part of the research staff or if you have 
general questions about your research study rights or questions, concerns, or complaints 
about the research, you can call the institution’s Institutional Review Board at   
_______________.  
 
AUTHORIZATION FOR USE/DISCLOSURE OF HEALTH INFORMATION 
FOR RESEARCH 
 
To be in this research study you must also give your permission (or authorization) to use 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 61 of 79 
and disclose (or share) your child’s “protected health information” (called PHI for short).  
 
What protected health information will be used and shared during this study? 
The study institution will need to use and share your child’s PHI as part of this study.  
This PHI will come from: 
 Your child’s study institution medical records 
 Your child’s research records 
 The types of information that will be used and shared from these records include: 
 Laboratory test results, diagnosis, and medications 
 Reports and notes from clinical and research observations 
 Imaging (like CT scans, MRI scans, x-rays, etc.) studies and reports 
 If applicable, information concerning HIV testing or the treatment of AIDS or AIDS-
related conditions, drug or alcohol abuse, drug-related conditions, alcoholism, and/or 
psychiatric/psychological conditions (but not psychotherapy notes). 
 
Who will share, receive and/or use your child’s protected health information in this 
study? 
 Staff at all the research study sites (including this study institution) 
 Personnel who provide services to your child as part of this study 
 Other individuals and organizations that need to use your child’s PHI in connection 
with the research, including people at the sponsor and organizations that the sponsor 
may use to oversee or conduct the study. 
 The members of the study institution’s Institutional Review Board and staff of the 
Office of Research Compliance and Regulatory Affairs. 
 
How will you know that your child’s PHI is not misused? 
People that receive your child’s PHI as part of the research are generally limited in how 
they can use your child’s PHI.  In addition, most people who receive your child’s PHI are 
also required by federal privacy laws to protect your child’s PHI.  However, some people 
that may receive your child’s PHI may not be required to protect it and may share the 
information with others without your permission, if permitted by the laws that apply to 
them.   
 
Can you change your mind? 
You may choose to withdraw your permission at any time.  A withdrawal of your 
permission to use and share your child’s PHI would also include a withdrawal from 
participation in the research study.  If you wish to withdraw your permission to use and 
share your child’s PHI you need to notify the study doctor, listed on the first page of this 
document, in writing.  Your request will be effective immediately and no new PHI about 
your child will be used or shared.  The only exceptions are (1) any use or sharing of PHI 
that has already occurred or was in process prior to you withdrawing your permission and 
(2) any use or sharing that is needed to maintain the integrity of the research. 
 
Will this permission expire? 
Your permission will expire at the end of the study.  If the study involves the creation or 
maintenance of a research database repository, this authorization will not expire.  

SCD-PED-01 Investigational Protocol 
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Will your child’s other medical care be impacted? 
By signing this document you agree for your child to participate in this research study 
and give permission to this study institution to use and share your child’s PHI for the 
purpose of this research study.  If you refuse to sign this document your child will not be 
able to participate in the study.  However, your child’s rights concerning treatment not 
related to this study, payment for services, enrollment in a health plan or eligibility of 
benefits will not be affected. 
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
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Confidential 
Page 63 of 79 
 
 
SIGNATURES 
 
[    ] _____________ (check box and initial) I AGREE to allow my blood samples to be 
saved for future biomarker studies.  
 
 
The research team has discussed this study with you and answered all of your questions.  
Like any research, the researchers cannot predict exactly what will happen.  Once you 
have had enough time to consider whether your child should participate in this research 
you will document your permission by signature below.   
 
You will receive a copy of this signed document for your records.  
 
_____________________________________ 
Printed Name of Research Participant 
 
 
____________________________________             
_________________ 
Signature of Parent or Legally Authorized 
             
 
Date 
Representative*  
 
 
______________________________________ 
* If signed by a legally authorized representative,  
a description of such representative’s authority must be provided 
 
 
_____________________________________    
 
________________ 
Signature of Individual Obtaining Consent  
 
 
Date 

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ADULT 
 
 
 
A Multi-Center, Pilot Study To Assess the Safety and Efficacy 
of A Selective Cytopheretic Device (SCD) In Pediatric Patients 
with Acute Kidney Injury 
(SCD-PED-01) 
INTRODUCTION 
 
We are asking for your permission to be in a research study so that we can learn new 
information that may help others. If you decide not to give your permission to be in this 
study, we will still take good care of you.  If you decide to be in this study, you may 
change your mind at any time during the study and you can stop being in the study.  Take 
all the time you need to make your choice.  Ask us any questions you have.  It is also 
okay to ask more questions after you decide to be in the study.  You can ask questions at 
any time.   
 
WHY ARE WE DOING THIS RESEARCH? 
 
In this research study, we want to learn more about the effects of a new device which is 
similar to a dialysis filter used in the treatment of Acute Kidney Injury (AKI).  Because 
of your kidney injury, continuous renal replacement therapy (CRRT) is being used to 
help your kidneys recover.  This research involves using an investigational device or 
filter on the CRRT machine which is called a selective cytopheretic device (SCD).  The 
SCD works by allowing cells that cause kidney injury to be desensitized, inactivated, or 
stopped from causing more harm. 
 
We are asking you and other people with AKI and requiring CRRT to be in the research, 
to understand the safety and effectiveness of the dialysis filter, the selective cytopheretic 
device (SCD). 
 
We are asking 30 people to participate in this research. 
 
WHO IS IN CHARGE OF THE RESEARCH?  
 
__________________ is the researcher at __________________ that is in charge of this 
study.   
 
______________is being paid by the National Institutes of Health to do this study. 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 65 of 79 
WHO SHOULD NOT BE IN THE STUDY 
You cannot be in this study if you have any of the following: 
• Older than 22 years old 
• Not receiving care in an intensive care unit 
• Pregnant or lactating 
• Heart support devices like LVAD, RVAD, BiVAD 
• History of previous dialysis treatments during this admission 
• History of End Stage Kidney Disease 
• Severe chronic liver failure  
• Cancer 
• Chronic immunosuppression 
• HIV or AIDS. 
• Weight of less than 15kg (33 lbs.) 
• Concurrent enrollment in another interventional clinical trial. Patients enrolled in 
clinical trials where only measurements and/or samples are taken are allowed to 
participate. 
• Use of any other Investigational drug or device within the previous 30 days. 
WHAT WILL HAPPEN IN THE STUDY? 
 
The research staff will explain each visit to you.  You will be able to ask questions to 
make sure you understand what will happen to you. 
 
These are the things that will happen to you while in the study: 
• CRRT as prescribed by your doctor with the addition of the SCD filter for up to 7 
days 
• SCD will be changed once every 24 hours (See below the description of SCD) 
• Daily blood work for safety monitoring  
• In addition to daily blood work, a blood sample for Complete Blood Count will be 
done daily in the evening from an existing catheter for safety monitoring (extra 1 
mL/day)  
• Every other day blood samples for biomarkers (for this and future research) drawn 
from an existing catheter (total amount 4 mL/during the study period) 
• Data collection from your medical record for every day the SCD is used and up to 
60 days or discharge from the hospital.  
• If you still need dialysis after 7 days, you will be treated per standard of care 
without the SCD filter as prescribed by your doctor.  
 
The SCD is a synthetic membrane similar to filters used for hemodialysis to filter 
unwanted substances from the blood. The SCD will be connected to an existing CRRT 
circuit. Blood from the CRRT machine is flowed through the SCD, then returned back to 
the CRRT machine, and then returned back to the patient.  
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 66 of 79 
To keep the blood from forming clots in the circuit, a solution of citrate is put in the 
CRRT and SCD. Citrate is a medication that keeps blood from forming clots when the 
blood is outside the body. Citrate is used with CRRT as part of normal care at this 
hospital.  
 
Future Research: 
Researchers in this study are dedicated to researching biomarkers of kidney disease 
related to AKI. The data and blood samples collected during this study are important to 
this study and to future AKI research. With your additional consent, blood collected 
during this study will be kept in an outside laboratory for an indefinite period of time 
with samples from other patients who have enrolled in this study. All identifying 
information will be removed from the samples. They will be identified only by a unique 
study number.  
 
These samples may be used in the future in ongoing research related to biomarkers 
involved in AKI and other kidney conditions. They will only be studying kidney disease, 
which you have already been diagnosed as having. They will not be researching non-
kidney related disease.  
 
These samples will be sent to an outside laboratory chosen by the sponsor, CytoPherx, 
Inc, but we will not give them any information that would personally identify you. We 
will not put the results of any tests conducted on these samples in your medical record. 
You may still participate in this study even if you do not agree to participate in the 
sample repository. 
 
WHAT ARE THE GOOD THINGS THAT CAN HAPPEN FROM THIS 
RESEARCH? 
 
Being in this study may have potential benefit of improved outcome in terms of survival, 
improved blood pressure stability and a shorter ICU course; however, this cannot be 
guaranteed.  Being in this study may not help you right now.   
 
When we finish the study, we hope that we will know more about the effects of the new 
dialysis filter on patients with AKI.  The results from this study may help other people 
with AKI later on.   
 
 
 
 
 
 
 
 
 
 
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 67 of 79 
WHAT ARE THE BAD THINGS THAT CAN HAPPEN FROM THIS 
RESEARCH? 
 
 
 
Life 
Threatening 
Serious 
Mild 
Common 
 
 
General aching 
Skin rash 
Nausea 
Vomiting 
Low blood pressure 
Low white blood 
counts 
Uncommon Irregular heart 
rate 
Infections 
Electrolyte disorders 
Temperature 
Pain 
Confusion 
Rare 
 
Pneumonia 
Bleeding from low platelet 
count 
Low or high calcium levels 
 
There may be other risks that we do not know about yet. 
WHAT OTHER CHOICES ARE THERE? 
 
Instead of being in this study, you can choose not to participate in it.  If you choose not to 
participate, you will receive CRRT as standard of care. 
 
HOW WILL INFORMATION ABOUT YOU BE KEPT PRIVATE? 
  
Making sure that information about you remains private is important to us.  To protect 
your privacy in this research study we will:  
 
• Identifiable data will have limited access, only the appropriate study staff will 
have access. 
• Store all study information in a locked cabinet or password protected file 
• Enter the-identified data into a secure password protected system  
• Ensure only appropriate study staff will have access to patient information 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you.  At 
most, the website will include a summary of the study results. You can search this 
website at any time. 
 
The Food and Drug Administration (FDA) may choose to inspect your records since you 
are a subject in this investigation of an unapproved drug/device. 
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 68 of 79 
WHAT IF WE LEARN NEW INFORMATION DURING THE RESEARCH?  
 
 You will be told of any new information that might affect your health, welfare, or 
willingness to continue to take part in this study. 
WILL IT COST YOU ANYTHING EXTRA TO BE IN THE RESEARCH STUDY?  
 
There will be no extra costs to you to participate in this study. Your health plan will pay 
for all the things you would have paid for even if you were not in the study, including the 
ICU stay, CRRT, and other hospital related health costs.  The SCD study device will be 
provided at no cost to you or your health insurance provider.   
 
WILL YOU BE PAID TO BE IN THIS RESEARCH STUDY?  
 
You will not be paid for participating in the study.  
 
WHAT HAPPENS IF YOU ARE INJURED FROM BEING IN THIS STUDY?  
 
If you believe that you have been injured as a result of this research you should contact 
the Principal Investigator as soon as possible to discuss the concerns.  Treatment for 
injuries is available at the study institution.  If you go to the Emergency Room or to 
another hospital or doctor it is important that you tell them that you are in a research 
study.  If possible, you should give them a copy of this permission form. 
 
The study institution follows a policy of making all decisions about compensation for the 
medical treatment of physical injuries that happened during or were caused by research 
on an individual basis. 
 
WHO DO YOU CALL IF YOU HAVE QUESTIONS OR PROBLEMS?  
 
For questions, concerns, or complaints about this research study you can contact the 
study person listed on page 1 of this document.  
 
If you would like to talk to someone that is not part of the research staff, or if you have 
general questions about your research study rights or questions, concerns or complaints 
about the research, you can call the institution’s Institutional Review Board at 
_______________.  
 
AUTHORIZATION FOR USE/DISCLOSURE OF HEALTH INFORMATION 
FOR RESEARCH 
 
To be in this research study you must also give your permission (or authorization) to use 
and disclose (or share) your “protected health information” (called PHI for short).  
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 69 of 79 
What protected health information will be used and shared during this study? 
The study institution will need to use and share your PHI as part of this study.  This PHI 
will come from: 
 Your study institution medical records 
 Your research records 
 The types of information that will be used and shared from these records include: 
 Laboratory test results, diagnosis, and medications 
 Reports and notes from clinical and research observations 
 Imaging (like CT scans, MRI scans, x-rays, etc.) studies and reports 
 If applicable, information concerning HIV testing or the treatment of AIDS or AIDS-
related conditions, drug or alcohol abuse, drug-related conditions, alcoholism, and/or 
psychiatric/psychological conditions (but not psychotherapy notes). 
 
Who will share, receive and/or use your protected health information in this study? 
 Staff at all the research study sites (including this study institution) 
 Personnel who provide services to you as part of this study 
 Other individuals and organizations that need to use your PHI in connection with the 
research, including people at the sponsor and organizations that the sponsor may use 
to oversee or conduct the study. 
 The members of the study institution’s Institutional Review Board and staff of the 
Office of Research Compliance and Regulatory Affairs. 
 
How will you know that your PHI is not misused? 
People that receive your PHI as part of the research are generally limited in how they can 
use your PHI.  In addition, most people who receive your PHI are also required by federal 
privacy laws to protect your PHI.  However, some people that may receive your PHI may 
not be required to protect it and may share the information with others without your 
permission, if permitted by the laws that apply to them.   
 
Can you change your mind? 
You may choose to withdraw your permission at any time.  A withdrawal of your 
permission to use and share your PHI would also include a withdrawal from participation 
in the research study.  If you wish to withdraw your permission to use and share your PHI 
you need to notify the study doctor, listed on the first page of this document, in writing.  
Your request will be effective immediately and no new PHI about you will be used or 
shared.  The only exceptions are (1) any use or sharing of PHI that has already occurred 
or was in process prior to you withdrawing your permission and (2) any use or sharing 
that is needed to maintain the integrity of the research. 
 
 
Will this permission expire? 
Your permission will expire at the end of the study.  If the study involves the creation or 
maintenance of a research database repository, this authorization will not expire.  
 
Will your other medical care be impacted? 
By signing this document you agree to participate in this research study and give 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 70 of 79 
 
 
 
permission to this study institution to use and share your PHI for the purpose of this 
research study.  If you refuse to sign this document you will not be able to participate in 
the study.  However, your rights concerning treatment not related to this study, payment 
for services, enrollment in a health plan or eligibility of benefits will not be affected. 
 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
CytoPherx, Inc. 
Confidential 
Page 71 of 79 
 
 
 
 
 
SIGNATURES 
 
[    ] _____________ (check box and initial) I AGREE to allow my blood samples to be 
saved for future biomarker studies.  
 
 
The research team has discussed this study with you and answered all of your questions.  
Like any research, the researchers cannot predict exactly what will happen.  Once you 
have had enough time to consider whether you should participate in this research you will 
document your permission by signature below.   
 
You will receive a copy of this signed document for your records.  
 
_____________________________________ 
Printed Name of Research Participant 
 
 
____________________________________             
_________________ 
Signature of Research Participant                                                         Date 
or Legally Authorized  Representative*   
 
 
______________________________________ 
* If signed by a legally authorized representative,  
a description of such representative’s authority must be provided 
 
 
_____________________________________    
 
________________ 
Signature of Individual Obtaining Consent  
 
 
Date 

SCD-PED-01 Investigational Protocol 
Version 1.6 
 
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Confidential 
Page 72 of 79 
APPENDIX J – CRITICAL MEDICATION LIST 
 
The following is a list of medication categories (with examples) to be acknowledged 
(yes/no) in the Case Report Forms if administered to the patient during the SCD-PED-01 
Clinical Trial (starting at 24 hours prior to Observation until 168 hours of treatment or 
ICU discharge, whichever comes first.  Only antibacterial use is captured during follow-
up period. 
 
ANTIBACTERIALS FOR SYSTEMIC USE 
Ampicillin 
Ceftazidime 
Moxifloxacin 
Azithromycin 
Ciprofloxacin 
Nafcillin 
Aztreonam 
Ciprofloxacin hydrochloride 
Piperacillin 
Bactrim (Sulfamethoxazole,  
   Trimethoprim) 
Clindamycin 
Piperacillin w/tazobactam 
Daptomycin 
(Piperacillin, Tazobactam) 
Cefadroxil 
Doripenem 
Synercid  
Cefalexin 
Erythromycin 
(Dalfopristin,Quinupristin) 
Cefazolin 
Gentamicin 
Tigecycline 
Cefazolin sodium 
Levofloxacin 
Tobramycin 
Cefepime 
Linezolid 
Vancomycin 
Cefepime hydrochloride 
Meropenem 
 
Cefoxitin 
Metronidazole 
 
 
 
 
ANTIMYCOTICS FOR SYSTEMIC USE 
Amphotericin b, liposome 
Fluconazole 
 
Caspofungin 
Micafungin 
 
 
 
 
ANTITHROMBOTIC AGENTS 
 
Acetylsalicylic acid 
Clopidogrel 
Enoxaparin sodium 
Argatroban 
Drotrecogin alfa 
Heparin 
Bivalirudin 
Enoxaparin 
Warfarin sodium 
 
 
 
BLOOD SUBSTITUTES 
 
 
Albumin 
Albumin human 
Blood, whole 
Cryoprecipitate 
Red blood cells 
 
Plasma 
Red blood cells, leucocyte depleted 
 
Platelets 
 
 
 
 
 
 
VASOPRESSORS 
 
 
Dobutamine 
Norepinephrine 
Phenylephrine hydrochloride 
Dopamine 
Norepinephrine bitartrate 
Vasopressin 
Epinephrine 
Milrinone 
Phenylephrine 
 
 
 
 
 
 

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Page 73 of 79 
APPENDIX K – CRRT PRESCRIPTION GUIDELINE and REGIONAL 
CITRATE ANTICOAGULATION (RCA) PROTOCOL EXAMPLE 
 
1. Purpose: The purpose of the guidelines is to standardize, to the extent possible, 
the provision of CRRT 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. Modality: CRRT will be prescribed as continuous veno-venous hemodiafiltration 
(CVVHDF).  A total minimum small solute clearance of 2000 ml/min/1.73m2 will 
be prescribed. The clearance will be divided equally between dialysis and 
hemofiltration as follows: 
a. 50% as dialysis fluid using Prismasate™ via the dialysis pump 
b. 50% as replacement fluid divided between pre-replacement and post-
replacement as follows: 
i. 50 ml/hour as post-filter replacement fluid via the replacement 
fluid pump using (Prismasol™).  This is necessary to prevent 
clotting of the deaeration chamber (50 ml/hour is the lowest 
allowable rate) 
ii. The remaining fluid rate (total replacement fluid rate – 50 ml/hour) 
pre-filter replacement fluid via the pre-blood pump (PBP) using 
Prismasol™. 
c. The composition of Prismasate™ and Prismasol™ should be equivalent.  
Any additives (e.g. potassium chloride) should be added in equivalent 
concentrations to both dialysis and replacement solutions. 
 
 

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3. 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 2 hours after 
CRRT settings at prescribed rates. 
4. Check patient and system ionized calcium every 8 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 
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% 

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3. For patient ion Ca 1.3-1.5, decrease CaCl2 10% 
4. For patient ion Ca> 1.5, decrease CaCl2 20% 
 
4. Access Size: (per clinical investigator decision) 
 
5. Blood pump flow rate: The minimum blood pump flow rate should be 50 
ml/minute to prevent circuit clotting unless not clinically tolerated: 
a. Neonate/Infants – 8 to12 ml/kg/minute 
b. Toddlers – 6 to 8 ml/kg/minute 
c. Older children  and adolescents– 3-6 ml/kg/minute 
 
6. 3-hour Fluid Balance Safety Limit: Limits set to prevent < 5% of blood 
volume error over 3 hours for smaller patients and <10% over three hours 
for larger patients 
a. Patients < 30 kg – 150 ml 
b. Patients 30-50 kg – 200 ml 
c. Patients > 50 kg – 300 ml 
 
7. Scheduled circuit changes: Circuits should be changed no later than every 72 
hours, as this is the maximum interval at which the machine has been tested 
by the manufacturer for accuracy.  Any diversion from this recommendation 
must have rationale documented in the medical record. The following 
situations serve as examples: 
a. The patient has a do not resuscitate or do not escalate care order that was 
placed on the chart while the patient is receiving CRRT. 
b. The patient is so clinically unstable that the patient will likely not tolerate 
stopping and restarting CRRT. 
 
8. Blood priming at CRRT initiation and blood return at CRRT termination 
a. Blood priming of the CRRT circuit should be done if the extracorporeal 
volume of the circuit is > 10% of the patient’s blood volume. 
b. Blood should not be returned to the patient at CRRT termination when 
circuits are blood primed unless specifically requested by the physician in 
a separate order. 
 
 

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APPENDIX L – SCD/CRRT BLOOD PRIMING PROTOCOL 
 
Prismaflex HF1000 
 
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.  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) [24]. 
As such, there are three patient weight ranges that will dictate the need, or lack 
thereof for blood priming: 
 
Patient weight (kg) 
Total Blood Volume 
Blood Prime Need: HF1000 
>40 kg 
>2800 ml 
None (a) 
24-40 kg 
1680-2800 ml 
HF1000 alone (b) 
15-24 kg 
1050-1680 ml 
HF1000+SCD (c) 
 
This additional circuit blood volume for the standard SCD in 24-40 kg patients 
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. [25] 
 
Renaflo HF 400, HF 700, and HF 1200 
 
The following tables display the same breakdown of blood prime need by weight 
for the extracorporeal blood volume of the Renaflo HF 400, HF 700, and HF 
1200.  
 
Renaflow HF 400 
 
Renaflo HF 400 ECV 28ml + Braun Tubing ECV 156ml + SCD ECV 120ml = 
304ml Total ECV 
 
Patient Weight (kg) 
Total Blood Volume 
Blood Prime Need: HF 400 
>43 kg 
>3010 ml 
None (a) 
26 – 43 kg 
1820 – 3010 ml 
HF400 alone (b) 
15 – 26 kg 
1050 – 1820 ml 
HF400 + SCD (c) 
 
 
 

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Renaflow HF 700 
 
Renaflo HF 700 ECV 53ml + Braun Tubing ECV 156ml + SCD ECV 120ml = 
329ml Total ECV 
 
Patient Weight (kg) 
Total Blood Volume 
Blood Prime Need: HF 700 
>47 kg 
>3290 ml 
None (a) 
30 – 50 kg 
2100 – 3290 ml 
HF700 alone (b) 
15 – 30 kg 
1050 – 2100 ml 
HF700 + SCD (c) 
 
Renaflow HF 1200 
 
Renaflo HF1200 ECV 83ml + Braun Tubing ECV 156ml + SCD ECV 120ml = 
359ml Total ECV 
 
Patient Weight (kg) 
Total Blood Volume 
Blood Prime Need: HF 1200 
>51 kg 
>3570 ml 
None (a) 
34 – 51 kg 
2380 – 3570 ml 
HF1200 alone (b) 
15 – 34 kg 
1050 – 2380 ml 
HF1200 + SCD (c) 
 
Investigators should use the reference letters in the third column (i.e. a, b, or c) to 
determine the blood prime protocol in the text below. 
 
a) For patients >40 kg: The blood volume for this patient population is >2800 
ml, so the HF1000 plus the SCD represents <10% of the patient blood 
volume. Thus, for patients >40 kg: 
 
i. 
The initial and all new CRRT circuits will be not primed with blood 
but with crystalloid or other fluid that is the local standard of care. 
ii. 
For daily SCD filter changes (not associated with a CRRT circuit 
change), a new crystalloid primed SCD will be placed in line with the 
CRRT circuit without need for blood priming. 
iii. 
The investigator can prime with blood or other colloid if they believe it 
is clinically indicated. 
 
b) For patients >24-40 kg: The blood volume for this patient population is 
>1680-2800 ml, thus the SCD alone represents <10% of the patient blood 
volume, but the ECV of the SCD and any CRRT circuit will comprise >10% 
of the total patient blood volume.  Thus, for patients >24 kg: 
 
i. 
The initial and all new CRRT circuits will be primed with blood per 
the local standard of care protocol.   
ii. 
For initial and daily SCD filter changes (not associated with a CRRT 
circuit change), a new crystalloid primed SCD will be placed in line 
with the CRRT circuit without need for blood priming. 

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iii. 
The investigator can prime the SCD with blood or other colloid if they 
believe it is clinically indicated. 
 
c) For patients 15-24 kg: The blood volume for this population is <1680 ml, thus 
the HF1000 + SCD ECV represents >10% for the entire range of patient 
weight from 15-24 kg.  Thus, for patients with a weight of 15-24 kg: 
 
i. 
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 
group, the following patient lab parameters should be achieved prior to 
initiating CRRT/SCD therapy to prevent severe acidosis or 
hypocalcemia 
a. Patient pH of at least 7.20 
b.Patient ionized calcium of at least 1.1 mmol/L 
ii. 
Patient should be given calcium gluconate IV (at least 300 mg) at the 
start of CRRT/SCD therapy. 
a. An equivalent about of IV calcium can be given in a different 
formulation (ex. 100 mg of IV calcium chloride). 
iii. 
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. 
iv. 
For the daily SCD circuit change, one of two options will be available: 
a. A completely new CRRT circuit can be used with the SCD 
circuit with a repeat of the procedure in the paragraph above 
b. 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 
 
 

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APPENDIX M – PLACEMENT OF SCD IN CRRT / ECMO CIRCUIT