Clinical Evaluation of the Prismaflex HF20 Set and Prismaflex® System 7.10 for Acute CRRT in Children
Phase: NA
Conditions: Acute Kidney Injury in Pediatric Patients
Sponsor: Vantive Health LLC



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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ...........................................................................................8 
1. INTRODUCTION........................................................................................................14 
1.1 Background and Rationale ...................................................................................14 
1.2 Benefits and risks for the study population .........................................................14 
2. STUDY OBJECTIVES ................................................................................................15 
2.1 Primary objective ...................................................................................................15 
2.2 Secondary objectives ..............................................................................................15 
2.3 Primary endpoints .................................................................................................15 
2.4 Secondary endpoints ..............................................................................................15 
3. STUDY DESIGN ..........................................................................................................16 
3.1 Study duration........................................................................................................17 
3.2 Study discontinuation rules...................................................................................17 
3.3 Study product and material ..................................................................................17 
3.3.1 Study Product Labeling .................................................................................19 
3.4 Product accountability ..........................................................................................19 
4. SELECTION AND WITHDRAWALS OF PATIENTS ..........................................19 
4.1 Study population ....................................................................................................19 
4.2 Inclusion criteria ....................................................................................................20 
4.3 Exclusion criteria ...................................................................................................20 
4.4 Recruitment ............................................................................................................21 
4.5 Patient withdrawal .................................................................................................21 
4.6 Analysis Population Definitions ............................................................................22 
5. PATIENT TREATMENT ...........................................................................................22 
5.1 Treatment details ...................................................................................................22 
5.2 Procedure to Minimize Fluid Balance Errors .....................................................23 
5.3 Prismaflex System Software Version 7.10 and 7.20 Alarm System for UF 
Errors ......................................................................................................................23 
5.4 Fluid Overload Calculations .................................................................................24 
5.5 Prismaflex Fluid Balance Data .............................................................................25 
5.5.1 Log Files on Technical Data Card .................................................................25 
5.6 Treatment: Prescriptive Guidelines .....................................................................25 
5.6.1 Dialysates .........................................................................................................26 
5.6.2 Replacement Fluids ........................................................................................26 
5.6.3 Anticoagulants .................................................................................................26 

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5.6.3.1 Anticoagulation Considerations .............................................................26 
5.6.4 Hypothermia prevention ................................................................................28 
5.6.5 Priming the Extracorporeal Circuit ..............................................................28 
5.7 Contact and Delivery of Study Material: ............................................................28 
5.8 Data to be Collected ...............................................................................................28 
5.8.1 Patient Information to Be Collected Prior to Initiation of Treatment ......28 
5.8.2 Treatment Data to Be Collected ....................................................................29 
5.8.2.1 Treatment Information ...........................................................................29 
5.8.2.2 Treatment Prescription ...........................................................................29 
5.8.2.3 Dialysate, Pre-blood Pump (PBP) and Replacement Solutions 
Used ...........................................................................................................29 
5.8.2.4 Priming Solution(s) (volume and infusion rate) ....................................30 
5.8.2.5 Anticoagulation Information ..................................................................30 
5.8.2.6 Patient Clotting Parameters ...................................................................30 
5.8.2.7 Treatment Blood & Dialysate Concentration Data ..............................30 
5.8.2.8 Information on Interruptions/Filter Changes and Blood Loss ...........30 
5.8.2.9 Total Fluid Removal, Fluid Overload, Blood & Mean Arterial 
Pressures ...................................................................................................31 
5.8.2.10 Prismaflex Alarms Related to Fluid Balance ......................................31 
5.8.2.11 Treatment and Outcome Data at end of study treatment ..................31 
5.8.2.12 Adverse Events and Unanticipated Adverse Device Effect 
Information ..............................................................................................32 
5.8.2.13 Vital Signs ...............................................................................................32 
5.8.2.14 Concomitant Medications .....................................................................32 
5.9 Sampling Schedule .................................................................................................33 
5.10 Emergency Procedure .........................................................................................36 
6. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND 
UNANTICIPATED ADVERSE DEVICE EFFECTS ..............................................37 
6.1 Anticipated Adverse events (AE)..........................................................................39 
6.2 Unanticipated Adverse Device Effects .................................................................39 
6.3 Other observation ..................................................................................................40 
6.4 Recording of AEs, SAEs and UADEs ...................................................................40 
6.5 Evaluation of AEs, SAEs, and UADEs .................................................................41 
6.5.1 Severity ............................................................................................................41 
6.5.2 Causality ..........................................................................................................41 
6.5.3 Occurrence ......................................................................................................42 
6.5.4 Expectedness ...................................................................................................42 
6.5.5 Seriousness .......................................................................................................43 
7. ETHICS AND REGULATORY ISSUES ..................................................................44 
7.1 Institutional Review Board (IRB) ........................................................................44 
7.2 Food and Drug Administration ............................................................................44 
7.3 Amendments ...........................................................................................................44 

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7.4 Patient data protection ..........................................................................................45 
7.5 Patient’s information and informed consent .......................................................45 
8. INVESTIGATIONAL PROCEDURES .....................................................................45 
8.1 Training ..................................................................................................................45 
8.2 Non-Compliance with the Protocol ......................................................................46 
8.3 Monitoring (verification of compliance with protocol) ......................................46 
8.4 Direct access to source documents .......................................................................47 
8.5 Source data verification .........................................................................................47 
8.6 Audits and inspections ...........................................................................................47 
9. STATISTICAL METHODS .......................................................................................47 
10. DATA MANAGEMENT ...........................................................................................47 
10.1 Web-based Electronic Data Collection ..............................................................47 
10.2 Data entry and storage ........................................................................................48 
10.3 Data management and quality control ...............................................................48 
11. ADMINISTRATIVE PROCEDURES .....................................................................48 
11.1 Study documents and record keeping ................................................................48 
11.2 Archiving of study documentation .....................................................................49 
12. SCHEDULE OF EVENTS ........................................................................................50 
13. REFERENCES ...........................................................................................................54 
14. LIST OF APPENDICES ...........................................................................................57 
Appendix 1 Statistical Plan .........................................................................................58 
List of Tables 
Table 1. Blood Sampling Schedule .................................................................................33 
Table 2. Vital Signs & Fluid Overload Assessment Schedule ......................................36 
 

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LIST OF ABBREVIATIONS 
ACD 
Acid-citrate-dextrose 
ACT 
Activated Clotting Time 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
APTT 
Activated Partial Thromboplastin Time 
ARF 
Acute Renal Failure 
B2M 
Beta -2 microglobulin 
BP 
Blood Pressure (mmHg) 
BUN 
Blood Urea Nitrogen 
Ca/Ca++ 
Calcium 
CFR 
Code of Federal Regulations 
Cl 
Chloride 
CPD 
Continuous Peritoneal Dialysis 
Cr 
Creatinine 
CRF 
Case Report Form 
CRRT 
Continuous Renal Replacement Therapy 
CVVH 
Continuous Veno-Venous Hemofiltration 
CVVHD 
Continuous Veno-Venous Hemodialysis 
CVVHDF 
Continuous Veno-Venous Hemodiafiltration 
ECMO 
Extracorporeal Membrane Oxygenation 
ECV 
Extracorporeal Circuit Volume 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FA 
Full Analysis set 
FDA 
Food and Drug Administration 
FUN 
Fluid urea nitrogen 
g/dl 
grams per deciliter 
GCP 
Good Clinical Practices 
GUI 
Graphical User Interface 
H 
Hour 
Hgb 
Hemoglobin (g/dl) 
ICU 
Intensive Care Unit 
ID 
Identification (number for patient) 

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LIST OF ABBREVIATIONS 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 
IRB 
Institutional Review Board 
K 
Potassium 
Kg 
Kilogram 
L 
Liter 
Lbs 
Pounds 
MAP 
Mean Arterial Pressure (mmHg) 
Min 
Minute 
Ml 
Milliliter 
mmHg 
Millimeters of mercury 
Na 
Sodium 
PO4 3- 
Phosphorous 
PBP 
Pre Blood Pump 
PFR 
Patient Fluid Removal 
PI 
Principal Investigator 
PP 
Per Protocol Analysis Set 
PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SCr 
Serum creatinine 
SCUF 
Slow Continuous Ultrafiltration 
TMP 
Transmembrane pressure (mmHg) 
UADE 
Unanticipated Adverse Device Effect 
UF 
Ultrafiltration 
US 
United States 
510(k)  
Section 510(k)[11] of the Federal Food, Drug, and Cosmetic Act 
Note: For the purpose of this document, “Clinical Study Protocol” is similar to “Clinical Investigation 
Plan” or “Protocol”. 
 
 

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Inclusion criteria 
1. Patients with a hospital admission body weight ≥8 and 
<20 kg (ie, ≥17.6 and <44.09 lbs). 
2. Patients with AKI defined as either 1) AKI by the Kidney 
Disease Improving Global Outcomes (KDIGO) Acute 
Kidney Injury Guideline serum creatinine criteria, which 
is a >50% rise in serum creatinine over baseline or a 0.3 
mg/dL SCr rise in 48 hours OR 2) as AKI by the 
Pediatric modified Risk, Injury, Failure, Loss, End-Stage 
Renal Disease (pRIFLE) criteria which is a 25% 
reduction in estimated creatinine clearance,16 OR 3) a 
serum creatinine >1.2 mg/dL. OR 
Patients with severe fluid overload, defined as a >10% 
fluid accumulation, relative to the ICU admission.  
3. Patients who have received renal replacement therapy 
previously can be included in the study if >24 hours have 
elapsed since previous RRT provision. 
Provide written informed consent from one or both 
parents, as required by the local IRB or legal guardians, 
unless one parent is deceased, unknown, incompetent or 
not reasonably available, or when only one parent has 
legal responsibility for the care and custody of the child 
per 21 CFR Part 50.55(e). 
Exclusion criteria 
1. The following hemoglobin exclusion criteria apply: 
 
Weight 
Starting Hgb (g/dl) 
Exclusion Criteria 
8.0-20.0 kg 
<7.0 
Excluded 
8.0-12.0 kg 
<8.0 
Excluded unless 
blood prime is used 
12.1-20.0 kg 
<7.5 
Excluded unless 
blood prime is used 
2. Children who are wards of the state. 

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Safety (AE, SAE) 
To ensure the safety monitoring of adverse events (AEs), 
Unanticipated Adverse Device Effect (UADEs) and serious adverse 
events (SAEs) will be reported via an emergency reporting process 
as described in the protocol. Also alarms and device deficiencies will 
be reported. 
Statistical analysis 
The planned statistical analysis is described in the Statistical 
Analysis Plan located in Appendix I of the study protocol. 
Regulatory 
The study was submitted as an Investigational Device Exemption 
Application (
) and was approved by the 
FDA on 20Nov2014. The protocol and associated documents will be 
submitted to the Institutional Review Boards (IRBs) at each study 
site. 

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1. INTRODUCTION 
1.1 Background and Rationale 
Renal Replacement Therapies (RRTs) for acute kidney injury (AKI) mainly focus on the 
adult patient population, however children with a vast array of different AKI diagnoses 
also need some form of RRT until renal recovery occurs or a suitable transplant becomes 
available. 
For acute RRT, children either receive treatment through peritoneal dialysis or 
extracorporeal dialysis. While Continuous Peritoneal Dialysis (CPD) is most often 
prescribed for infants with AKI, CRRT has become more commonly used for all children 
in the United States (US) and has been used effectively in infants <10 kg.1,2 
Many aspects of pediatric CRRT need consideration such as vascular access, patient age 
and weight, extracorporeal volume, blood flow rates, ultrafiltration (UF) control,3 the size 
of the dialyzer, the biocompatibility of the dialyzer,4 frequency of treatment,5 duration of 
dialysis6 and center experience. 
This clinical evaluation will focus on using a new high-flux dialyzer, Prismaflex® HF20 
Set (Gambro Industries, France) and related support in the Prismaflex® System Software 
Version 7.10 and 7.20 (Gambro Lundia AB, Sweden) for CRRT in children in centers 
with extensive experience in pediatric dialysis.7,8  Software Version 7.10 and Version 
7.20 of the Prismaflex software have been developed to safely treat children weighing 
down to 8 kg with respect to fluid balance. 
This study is being performed at the request of the US Food and Drug Administration 
(FDA). In a teleconference with the FDA, Gambro was advised that a clinical study with 
the Prismaflex HF20 Set would be required for the clearance of a 510(k) Notification by 
the FDA. This study will be performed under a FDA-approved Investigational Device 
Exemption Application (IDE). 
1.2 Benefits and risks for the study population 
The patient will receive or continue to receive CRRT as part of study participation. 
Additional direct benefits to the patient from the use of the Prismaflex HF20 Set and 
Prismaflex Control Unit with software version 7.10 and version 7.20 are lower 
extracorporeal blood volume and refined fluid management capabilities that are more 
specific to patients with weights between 8 and 20 kg. As such, the patient’s participation 
may help improve the delivery of CRRT to critically ill small children. 

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Foreseeable risks for the patients included in this clinical investigation do not differ from 
those usually observed during this type of treatment. 
No additional risk directly related to the use of the product can be objectively foreseen. 
2. STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of this study is to evaluate the efficacy of the Gambro Prismaflex 
HF20 Set based on testing the hypothesis that it delivers sufficient RRT (>38% reduction 
of BUN from baseline to 24 hours) to effectively treat AKI in pediatric patients weighing 
≥8 and <20 kg (ie, ≥17.6 and <44.09 lbs). This hypothesis will be tested as a percentage 
reduction of blood urea nitrogen (BUN) from baseline until 24 hours after CRRT 
initiation. 
2.2 Secondary objectives 
The efficacy in removing creatinine and normalizing bicarbonate will be tested in a 
similar fashion to BUN, both as secondary objectives. Another secondary objective of 
this study is to evaluate the safety of the Prismaflex System Software Version 7.10 and 
7.20 in pediatric AKI patients weighing ≥8 and <20 kg (ie, ≥17.6 and <44.09 lbs). The 
measurement of the duration of time for which each Prismaflex HF20 Set can be used 
will be evaluated out to a time period of 72 hours from the initiation of CRRT in each 
patient.  
2.3 Primary endpoints 
The primary endpoint is the change from baseline in BUN evaluated at 24 hours 
following initiation of CRRT with the Prismaflex HF20 Set. 
2.4 Secondary endpoints 
The secondary endpoints are: 
• 
The change from baseline in creatinine and bicarbonate measured at 24 hours 
following initiation of CRRT.  
• 
The Prismaflex HF20 Set extracorporeal circuit life assessed by the duration of 
time for which each Prismaflex HF20 Set can be used out to a maximum 72 hour 
period in each patient. 
• 
To demonstrate the safety of the Prismaflex System Software Version 7.10 and 
7.20 in pediatric AKI patients weighing ≥8 and <20 kg (ie, ≥17.6 and <44.09 lbs) 

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by monitoring and recording Prismaflex alarms related to fluid balance as well as 
AEs, SAEs and device deficiencies. 
 
3. STUDY DESIGN 
The clinical study design is a multicentric, open label, single group study in which 
patients meeting all the inclusion criteria and none of the exclusion criteria of this 
protocol, and deemed treatable by their physician with the Gambro Prismaflex HF20 Set 
and Prismaflex System Software Version 7.10 or 7.20, will be enrolled in the study. 
Patients included in the analysis will be treated for a minimum period of 20 of the first 
24 hours and up to 72 hours with each Prismaflex HF20 Set with BUN, creatinine and 
bicarbonate being measured for statistical analysis at 12 hour intervals during CRRT 
treatment. Each patient will provide a sequence of BUN, creatinine, and bicarbonate 
values (measured from baseline onward at 12 hour intervals) and may be treated on each 
Prismaflex HF20 Set for up to 72 hours. 
The duration of time for which each Prismaflex HF20 Set can be used will be evaluated 
out to a time period of 72 hours from the initiation of CRRT in each patient. The end of 
the extracorporeal circuit life will be defined by the occurrence and failure to mitigate 
one or both of the following Prismaflex System alarms, after which CRRT will be 
terminated and the extracorporeal circuit replaced: 
• 
“Warning: Filter Clotted”, and/or 
• 
"Caution: TMP Excessive". 
At 72 hours from the initiation of HF20 study CRRT, if the subject has been on the 
current Prismaflex HF20 set for less than 72 hours, the subject is allowed to continue on 
their current filter set until end of filter life (Refer section 3.2). The site may follow 
applicable institutional practices if additional CRRT is required.  
Alarms from Prismaflex System Software Version 7.10 and 7.20 related to fluid balance 
will be noted and recorded for the following alarms: 
• 
“Caution: Flow Problem”,  
• 
“Caution: Gain Limit Reached”, 
• 
“Caution: Loss Limit Reached”. 
 

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The weight, state of uremia, cardiac status and general physical condition of the patient 
must be carefully evaluated and recorded by the prescribing physician as required and, at 
a minimum, each day during treatment. 
3.1 Study duration 
The study is planned to start in November 2015 (First Visit, First Patient) and to stop in 
December 2018 (Last Patient, Last Visit). It may be terminated earlier if sufficient patient 
numbers (24) reach the primary endpoint of 24 hours of CRRT or later if 24 patients have 
not achieved the endpoint for analysis. 
3.2 Study discontinuation rules 
The Patient is allowed one interruption for a maximum period of less than or equal 
to 4 hours during the first 24 hours of CRRT. A filter set change is considered an 
interruption. A recirculation is also considered an interruption. 
The HF20 Set can be changed only once during the first 24 hours. If the patient’s study 
treatment is interrupted for ≥4 hours within the first 24 hours from CRRT initiation, the 
patient will be withdrawn from the study.  
If the patient’s study treatment is interrupted after the first 24 hours from CRRT 
initiation, the patient will have completed the study observation period. The patient 
cannot restart a new HF20 Set., and instead will return to standard of care.  
If CRRT is no longer required and thus ends prior to 24 hours, then the patient is 
withdrawn from the study. In this case, no additional laboratory sampling is needed to 
support this study.   
For patients who continue HF20 Set CRRT past 24 hours but CRRT ends between the 12 
hour intervals, the last completed l2 hour interval value will be the last set of lab values 
included for analysis. No additional sampling is needed. 
A subject will be discontinued from the study if he/she develops any condition for which 
the investigator believes, according to his/her medical judgment, the patient should 
discontinue from the study. The investigator will try to collect the end of study data if 
possible. 
3.3 Study product and material 
The Prismaflex HF20 Set is indicated for use only with the Prismaflex System equipped 
with software Version 7.10 and Prismaflex System Software Version 7.20 in providing 

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continuous fluid management and RRT. The system is intended for patients who have 
AKI, fluid overload or both, taking into consideration the patient’s access, blood flow, 
body weight and the extracorporeal blood volume. The Prismaflex HF20 Set is intended 
for use in the following veno-venous therapies: CVVH, CVVHD and CVVHDF. The 
Prismaflex HF20 Set should be restricted to patients with a body weight ≥8 kg (17.6 lb.) 
and <20 kg (44.09 lb). 
The Prismaflex HF20 Set incorporates a membrane which is identical to the membrane 
used in the Gambro HF1000 and HF1400 sets, both of which have been previously 
cleared by the FDA for marketing and clinical use in the United States (K042938). The 
Prismaflex HF20 Set dialyzer contains the Polyamix™ membrane, which is 
hemocompatible and able to effectively reject dialysate contaminants. More specifically, 
the membrane contains 0.22 m2 of polyarylethersulfone/polyvinyl-pyrrolidone 
membrane, which is almost identical in composition to the membrane used in other 
Gambro Polyflux hemodialyzers (ie, Polyflux 6H, 140H, 170H, 210H) which have been 
previously cleared by the FDA for marketing and clinical use in the US. Therefore, low 
treatment-induced inflammation is to be expected from the use of the Prismaflex HF20 
Set which utilizes a similar membrane as that studied by Schindler et. al.9 The membrane 
in the Prismaflex HF20 Set has an inner diameter of 215 µm and a wall thickness of 
50 µm and is sterilized by steam, which is the same sterilization method used for the 
previously cleared Gambro Polyflux hemodialyzers. The blood priming volume of the 
extracorporeal circuit for the HF20 set is 60 mL and is lower than previously cleared 
Gambro Polyflux hemodialyzers and CRRT circuits due to its pediatric application. 
Gambro will provide each investigational site with one Prismaflex System equipped with 
software version 7.10 or Prismaflex System Software Version 7.20. The provided 
machine may only be used on patients participating in the clinical study according to the 
FDA IDE regulations. 
The FDA has not given 510(k) clearance for use of either the Prismaflex HF20 Set or the 
Prismaflex System Software Version 7.10 and Prismaflex System Software Version 7.20 
for use in patients weighing <20 kg (44.09 lbs). 
Please refer to the Investigator Brochure in Appendix IV, for a more detailed description 
of the Prismaflex HF20 set and the Prismaflex System version 7.10 and Prismaflex 
System Software Version 7.20. 

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3.3.1 Study Product Labeling 
Each Gambro Prismaflex HF20 Set and Prismaflex System having Software Version 7.10 
or 7.20 will be labeled “CAUTION - Investigational Device. Limited by Federal (or 
United States) law to investigational use." per 21 CFR Part 812.5. 
3.4 Product accountability 
The investigators at each site will be supplied with the investigational products 
(Prismaflex System Software Version 7.10 or Prismaflex System Software version 7.20 
and Prismaflex HF20 Sets) to be used during this clinical study. The accountability 
document must be filled in by the person in charge of receiving the products at site. 
The Prismaflex HF20 Set must be stored in a safe place with restricted access. The 
Prismaflex HF20 Set and Prismaflex System Software Version 7.10 and 7.20 labeled for 
investigational use according to the FDA IDE regulations must only be used to treat 
patients enrolled in the study under the sole supervision of the investigator. 
The Principal Investigator (or delegated person) at each site is solely responsible for 
keeping records of updated documents according to the following requirements: 
• 
Date and number of Prismaflex HF20 Sets received by the investigator at the 
study site 
• 
Dated assignment of Prismaflex HF20 Sets dispensed by the investigator 
• 
Number and code of faulty or destroyed Prismaflex HF20 Sets 
 
At each visit, the Study Monitor must ensure that the investigator has sufficient number 
of Prismaflex HF20 Sets at his/her disposition and that the Prismaflex HF20 Sets are 
being used according to their specifications. 
4. SELECTION AND WITHDRAWALS OF PATIENTS 
4.1 Study population 
The study will include up to 30 pediatric AKI patients with a body weight ≥8 and <20 kg 
(ie, ≥17.6 and <44.09 lbs). These patients must meet all inclusion criteria and none of the 
exclusion criteria defined for this study. Patients will be recruited from a select group of 
pediatric institutions, comprised of investigators from the Prospective Pediatric CRRT 
(ppCRRT) Registry Group – a multi-center collaborative that has published the vast 
majority of pediatric CRRT literature since 2004.2,10-15 

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4.2 Inclusion criteria 
A subject must meet ALL of the following inclusion criteria in order to participate in this 
study: 
1. Patients with a hospital admission body weight ≥8 and <20 kg (ie, ≥17.6 and 
<44.09 lbs). 
2. Patients with AKI defined as either 1)  AKI by the Kidney Disease Improving 
Global Outcomes (KDIGO) Acute Kidney Injury Guideline serum creatinine 
criteria, which is a >50% rise in serum creatinine over baseline or a 0.3 mg/dL 
SCr rise in 48 hours OR 2) as AKI by the Pediatric modified Risk, Injury, 
Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria which is a 25% 
reduction in estimated creatinine clearance,16 OR 3) a serum creatinine 
>1.2 mg/dL.  
OR 
Patients with severe fluid overload, defined as a >10% fluid accumulation 
relative to the ICU admission. 
 
3. Patients who have received RRT previously can be included in the study if >24 
hours have elapsed since their previous RRT treatment. 
4. Provide written informed consent from one or both parents, as required by the 
local IRB or legal guardians, unless one parent is deceased, unknown, 
incompetent or not reasonably available, or when only one parent has legal 
responsibility for the care and custody of the child per 21 CFR Part 50.55(e). 
 
 
4.3 Exclusion criteria 
Exclusion criteria are the following: 
1. The following hemoglobin exclusion criteria apply: 
 
Weight 
Starting Hgb (g/dl) 
Exclusion Criteria 
8.0-20.0 kg 
<7.0 
Excluded 

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8.0-12.0 kg 
<8.0 
Excluded unless blood prime is 
used 
12.1-20.0 kg 
<7.5 
Excluded unless blood prime is 
used 
 
2. Children who are wards of the state. 
 
4.4 Recruitment 
Recruitment for the study will start after FDA approval of the Investigational Device 
Exemption Application (IDE) and the Institutional Review Board (IRB) approvals at 
respective study sites. 
The parent(s) or legal guardian(s) of the patients who meet the inclusion and exclusion 
criteria will be clearly informed on the details of the study, including the potential 
benefits and risks to the patient prior to their enrollment in this study. One or both parents 
(as appropriate and as required by local IRB) must give their permission unless one 
parent is deceased, unknown, incompetent or not reasonably available, or when only one 
parent has legal responsibility for the care and custody of the child per 21 CFR Part 
50.55(e). The parent’s or legal guardian’s consent must be documented via signature and 
date on the Patient Informed Consent form. Patients will be considered enrolled in the 
study after the informed consent has been signed and a copy provided to the 
parents/guardian. 
4.5 Patient withdrawal 
The parent(s) or legal guardian(s) of the patients are free to withdraw their child from the 
study at any time without having to justify their decision. When a patient is withdrawn 
from a study, the parent(s) or legal guardian(s) will be contacted and given the 
opportunity to provide information about the reason(s) of withdrawal and possible 
occurrence of an AE. 
Patients will be withdrawn from the study at any time for the following reasons: 
• 
Patient no longer requires CRRT and ends therapy prior to receiving at least 20 
hours of CRRT treatment,  
• 
Patient requires a non-HF20 filter, 
• 
Interruption of more than 4 hours from CRRT therapy (>4 hr interruption), 
• 
More than one interruption of CRRT on the HF20 set regardless of duration, or 

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• 
Investigator Discretion 
 
Reason for withdrawal will be recorded in the electronic Case Report Form (eCRF). 
If withdrawal is related to the possible occurrence of AEs, the patient will be followed up 
according to the AE procedure. 
4.6 Analysis Population Definitions 
Full Analysis Set (FA): The Full Analysis Set is based on the intent-to-treat principle 
and includes any patient who received CRRT on the Prismaflex HF 20 Set for any period 
of time. 
Per-Protocol Analysis Set (PP): The Per-Protocol Analysis Set defines a subset of the 
FA including patients who: 
• 
fulfilled all inclusion criteria 
• 
did not meet any of the exclusion criteria 
• 
received at least 20 hours of CRRT treatment on the HF20 filter with no more 
than 1 interruption which may have included a filter change  
• 
did not have major protocol deviations that might impact the assessment of the 
primary endpoint 
• 
have available measurements for the primary endpoint (BUN) at baseline (within 
1 hour prior, and 15 min after initiation of CRRT) and at 24 hours (±1 hour) from 
start of CRRT   
 
5. PATIENT TREATMENT 
5.1 Treatment details 
All patients will be followed from the time of obtained informed consent through the time 
they end participation in the study. Patients will be treated for a minimum period of 20 
hours of the first 24 hours. They can be treated up to 72 hours on the same Prismaflex 
HF20 Set. In case of interruption at less than 24 hours, a subject may receive a second 
HF20 set. BUN, creatinine and bicarbonate are to be measured for statistical analysis at 
initiation of CRRT and at 12 hour intervals during CRRT treatment. During study CRRT 
treatment, activated clotting time (ACT), partial thromboplastin time (PTT), and 
activated partial thromboplastin time (APTT) (applicable to heparin use only) will be 

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measured as determined by the standard of care at each site. Patient ionized calcium and 
extracorporeal circuit (post circuit) ionized calcium will be measured per local standard 
of care (applicable to citrate use only). Each patient may be treated on the same 
Prismaflex HF 20 Set for up to 72 hours. 
Treatments will be performed according to this clinical protocol and in accordance with 
the Instructions for Use (IFU) for the Gambro Prismaflex HF20 Set and the Operators 
Manual for the Prismaflex System Software Version 7.10 or 7.20. Treatments will be 
performed in accordance with the IFU and Operations Manual and managed in 
accordance with the local standard of care for pediatric CRRT. 
5.2 Procedure to Minimize Fluid Balance Errors 
All CRRT study clinicians will be trained on the use of Prismaflex System Software 
Version 7.10 and 7.20 and will have previously used Prismaflex in clinical practice. The 
training will also cover specific features in the Prismaflex System Software Version 7.10 
and 7.20 that support safe and effective use of the Prismaflex HF20 Set, including: 
• 
Prismaflex System Software Version 7.10 and 7.20 on-screen support for blood 
priming the Prismaflex HF20 Set 
• 
Setting Prismaflex System Software Version 7.10 and 7.20 UF error limits during 
treatment setup 
• 
Best practice during Prismaflex System Software Version 7.10 and 7.20 fluid bag 
changes and in handling of Prismaflex System Software Version 7.10 and 7.20 
UF alarms 
 
Monitoring for fluid balance errors will be based both on the UF alarms in Prismaflex 
System Software System Version 7.10 and 7.20 as well as through monitoring of the 
Prismaflex System Software Version 7.10 and 7.20. Measurement of fluid bag weights 
will employ an external scale. It is up to the discretion of the responsible physician 
investigator to decide how these will be measured. If performed, local clinical procedures 
are to be followed. 
5.3 Prismaflex System Software Version 7.10 and 7.20 Alarm System for UF Errors 
Prismaflex System Software Version 7.10 and 7.20 alarms will be issued based on 
immediate deviations between delivered and expected fluid weight on each bag of >20 g. 
A treatment shutdown will be issued and alarm given based on the cumulative UF error 
in a 3 hour sliding window. 

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The determination of an acceptable Prismaflex System Software Version 7.10 and 7.20 
UF error limit follows from the UF rate error, which is not to exceed 0.1 mL/kg/min in 
order to avoid complications, up to and including hemodynamic instability. The UF error 
limit default is determined based on the cumulative UF rate error over a sliding 3 hours 
window. The Patient Fluid Removal accuracy (PFR acc) of the Prismaflex System 
Software Version 7.10 and 7.20 is considered in this interval (± 70 mL per 3 hours): 
UF default error limit = 0.1 mL/kg/min × 180 min × BW – PFR acc 
This default UF error limit is calculated based on the patient weight entered during the 
set-up phase of the treatment. As an example, a patient weight of 10 kg would result in a 
default error limit of: 
UF default error limit = 0.1 mL/kg/min × 180 min × 10 kg – 70 mL = 110 mL 
Determination of the actual limit may follow the calculated default value, but is 
ultimately up to the discretion of the prescribing physician investigator. In consideration 
of the patient’s condition, a more stringent limit may apply. 
The prescribed limit is settable down to a limit of 60 mL/3 hours and is entered by the 
device operator. This is a mandatory action in order to be able to proceed to patient 
connection. Once set, the UF error limit is active throughout the treatment. 
Should the preset UF error limit be reached during treatment, the device monitoring 
system will issue an alarm and terminate the treatment. Treatment at this point cannot be 
re-started on the same filter. Occurrence of such events shall prompt a call to the 
investigator and should alert the personnel to reassess the patient before continuation of 
the treatment on a new disposable set. 
5.4 Fluid Overload Calculations 
Fluid overload will be calculated by the methods used by Goldstein and the Prospective 
Pediatric CRRT Registry Group: [Fluid in (L) – Fluid out (L)] /ICU admission 
weight (kg) * 100. The initial fluid overload will be calculated at the time of Study CRRT 
initiation and then at 12 hour intervals from that point until the end of the study. Blood 
pressure data, including mean arterial pressure, will be recorded either non-invasively or 
via an indwelling arterial catheter (present as part of clinical care and not for study 
purposes alone) at Study CRRT initiation and at 1 hour intervals from that point until end 
of study. If CRRT is discontinued before a 6 hours time point for hemodynamic reasons 

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or before a 12 hour time point for reasons related to fluid balance, the last measurements 
available prior to CRRT termination will be recorded as end of treatment. 
5.5 Prismaflex Fluid Balance Data 
There are two ways to track fluid balance data from the Prismaflex System. The first 
consists of recording data from the History Display section of Prismaflex and the second 
one is from the review of the log files on the Prismaflex technical data card. 
5.5.1 Log Files on Technical Data Card 
Prismaflex System Software Version 7.10 and 7.20 automatically saves a log file at the 
end of each CRRT treatment. These log files track all events and alarms occurring during 
Prismaflex CRRT to include pressures, scale weights, pump speed data, etc. 
Logging data are saved on the Prismaflex technical data card after a completed treatment, 
during the unload sequence of the disposable set. The data contained in these files mirror 
the information that was displayed on the GUI of the Prismaflex during treatment, such 
as prescription data, treatment events (alarms, bag changes), as well as treatment data 
including UF volumes. 
Data from the Prismaflex technical data card will be used for the following: 
• 
to allow for the investigation of reported study related events 
• 
as a source of data to allow for the analysis of technical parameters, including 
alarm rates, stability of software, etc. 
 
5.6 Treatment: Prescriptive Guidelines 
The treatment parameters (eg, flow rates, time, etc.), dialysates, replacement fluids and 
anticoagulants will be at the discretion of the physician investigator, but will be recorded 
on the eCRFs and must be consistent with the labeling as follows: 
• 
Minimum combined convective/diffusive prescribed small solute clearance: 
2000 mL/h./1.73m2 patient BSA 
• 
Maximum Blood Flow Rate: 100 mL/min 
• 
Maximum TMP: 450 mmHg/kPa 
 

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5.6.1 Dialysates 
Only prescribed commercially available sterile dialysate solutions with a density similar 
to saline solutions will be used with the Prismaflex System Software Version 7.10 and 
7.20. Sterile dialysate solutions should be standardized and formulated in accordance to 
the patient’s clinical needs. The use of nonsterile dialysates could induce risks of 
bacterial or pyrogenic contamination for the patient. 
5.6.2 Replacement Fluids 
Only prescribed commercially available replacement solutions with a density similar to 
saline solutions and which are labeled for intravenous injections will be used. 
Replacement Fluids should be standardized and formulated in accordance to the patient’s 
clinical needs. 
5.6.3 Anticoagulants 
Anticoagulation plays an important part in extending filter life by retarding plugging and 
clotting. The type of anticoagulants used will be as prescribed by the physician. The IFU 
for the Prismaflex HF20 Set provides the following recommendations for heparinization 
below in Section 5.6.3.1 Anticoagulation Considerations. 
5.6.3.1 Anticoagulation Considerations 
According to the literature, continuous heparinization at a rate of 10 to 20 IU/kg/h 
ensures proper operation of the extracorporeal circuit when performing treatment with 
patients having normal coagulation status. Depending on the patient’s condition, 
however, heparinization can be lowered to < 5 IU/kg/h. Heparinization can be controlled 
by partial thromboplastin time (PTT) measurements: in this case, PTT could be 
maintained at 20 to 30 seconds over baseline.18 Many centers check Activated Clotting 
Times (ACTs) instead of PTT. Each center will follow its own clinical practice for circuit 
heparinization. 
Many US centers, including those involved in this application, use regional citrate 
anticoagulation to prevent clotting of CRRT circuits. The ppCRRT Registry Group has 
shown that such practices lead to comparable filter lifespan with fewer side effects1 and 
regional citrate anticoagulation has been suggested as the preferred method in the recent 
KDIGO AKI guidelines.19 As general guidelines, some sites have altered their regional 
citrate protocol from this original published protocol, but all centers will perform their 
citrate protocol to achieve the following goals per their standard of care:  

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• 
Acid-citrate-dextrose [ACD (Baxter, McGaw Park)] will be the standard citrate 
solution and will be infused either via an external dedicated pump or the 
Prismaflex® Pre-Blood Pump (PBP) at a rate that is per local standard of care. 
• 
A calcium containing solution will be infused at the patient’s return access or via 
a separate central line in composition, concentration and at a rate that is per local 
standard of care. 
• 
Initial citrate rates will be decreased by 50% of standard for patients with 
expected immature/decreased hepatic metabolic function (patients <1 year of age, 
or with acute/chronic hepatic failure). 
• 
Paired (post filter) circuit and patient ionized calcium levels will be obtained per 
local standard of care. 
• 
In addition, paired ionized calcium levels will be drawn one hour after any change 
in citrate or calcium infusion rates. 
• 
The goals of regional citrate anticoagulation will be to achieve a circuit ionized 
Ca level of 0.25 to 0.45 mmol/L and a patient ionized Ca level of 1.0-1.5 mmol/L. 
• 
Twice daily patient total calcium levels will be drawn to assess for total 
hypercalcemia or citrate accumulation. 
• 
Patients with total calcium levels >12.5 mg/dl (hypercalcemia) but with desired 
ionized Ca levels will have the CaCl2 rate decreased per local standard of care. 
• 
Patients with total calcium levels >12.5 mg/dl AND low ionized Ca levels 
< 0.9 mmol/L will be diagnosed with citrate accumulation. The treatment for 
citrate accumulation will be managed by local standard of care but will include 
decreasing the citrate infusion rate or discontinuing it, increasing citrate clearance 
by increasing dialysis and/or replacement fluid rates, or both. Hourly paired 
ionized Ca levels will be obtained until the patient ionized calcium is 
> 1.0 mmol/L. 
 
This protocol, or slight variations to it, has been reported in numerous pediatric 
publications.2,20-22 Given the recent calcium chloride supply shortage in the US, a 
standard conversion will be used to substitute calcium gluconate to provide equimolar 
amounts of calcium to the patient. All of the study sites have over 6 years of experience 
with this citrate anticoagulation protocol. 

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5.6.4 Hypothermia prevention 
When treating infants and children with the Prismaflex HF20 Set, the volume of the 
extracorporeal circuit and the high exchange volume/patient weight ratio may cause 
hypothermia. It is recommended to warm the blood with the Gambro Prismaflow Blood 
and Fluid Warmer or any other standard warming devices used in treatment of patients 
with a weight ≥8 kg and <20 kg. 
5.6.5 Priming the Extracorporeal Circuit 
Circuits will be primed per local standard of care. Since the extracorporeal volume (ECV) 
of the circuit is < 10% of the blood of patients in this study (weight 8-20 kg), priming 
with blood products will not be mandated, but the site may choose to do so based on their 
local standard of care and patient stability. 
5.7 Contact and Delivery of Study Material: 
Investigators that will be participating in this study will be sent a copy of this protocol 
along with any applicable regulatory documents. Once this protocol and regulatory 
documents have been received by a given study site, the study site will be contacted by 
sponsor’s Clinical Study Monitor to encourage the site to complete and return the forms 
in an expeditious manner. 
5.8 Data to be Collected 
5.8.1 Patient Information to Be Collected Prior to Initiation of Treatment 
The following data will be collected and recorded on the Case Report Forms for 
Screening. 
1. Coded Patient I.D. 
2. Inclusion/Exclusion Criteria 
3. Signed Patient Informed Consent 
4. Patient Demographics 
a. Gender 
b. Date of Birth 
c. Hospital Admission Weight, Height, and Body Surface Area 
d. Calculated Intravascular Blood Volume 
5. Patient Medical Information 
a. Cause of Acute Kidney Injury 

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b. Diagnosis 
c. Vital Signs 
d. Medication History for the Last 7 Days 
e. Medical and Surgical History 
 
5.8.2 Treatment Data to Be Collected 
The following data will be collected and recorded on the eCRFs and/or data card for each 
patient treatment using the Gambro Prismaflex HF20 Set and Prismaflex System 
Software Version 7.10 and 7.20. 
5.8.2.1 Treatment Information 
1. Date of Treatment 
2. Sequential Number of Gambro Prismaflex® HF20 Sets used 
3. Date and Time of Treatment Initiation and Discontinuation 
4. Blood access information 
5. Treatment Modality 
a. CVVHD (Hemodialysis) 
b. CVVHDF (Hemofiltration) 
c. CVVH ( Hemofiltration) 
 
5.8.2.2 Treatment Prescription 
1. Patient Fluid Removal Flow Rate (ml/h) 
2. Replacement Flow Rate (ml/h) 
3. Blood Flow Rate (ml/min) 
4. Dialysate Flow Rate (ml/h) 
5. Pre-blood pump (PBP) Flow rate (ml/h) 
 
5.8.2.3 Dialysate, Pre-blood Pump (PBP) and Replacement Solutions Used 
1. Ionic Formulation 
2. Brand Name 
3. Volume used 

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5.8.2.4 Priming Solution(s) (volume and infusion rate) 
1. Blood 
2. Buffered Blood 
3. Saline 
4. Heparinized Saline 
5. Albumin 
 
5.8.2.5 Anticoagulation Information 
1. Type of anticoagulant used 
2. Administration method 
3. Anticoagulant dose 
 
5.8.2.6 Patient Clotting Parameters 
1. ACT, PTT, APTT, or other according to Sampling Schedule in Section 5.9. 
 
5.8.2.7 Treatment Blood & Dialysate Concentration Data 
1. Blood Urea Nitrogen (BUN) – according to the Sampling Schedule in Section 
5.9. 
2. Fluid Urea Nitrogen (FUN) – according to the Sampling Schedule in Section 
5.9.  
3. Creatinine – according to the Sampling Schedule in Section 5.9. 
4. Bicarbonate according to the Sampling Schedule in Section 5.9. 
5. Serum sodium, potassium, chloride, calcium, phosphorous, beta 2 microglobulin 
(B2M) & albumin according to the Sampling Schedule in Section 5.9. 
6. Dialysate fluid urea nitrogen (FUN) according to the Sampling Schedule in 
Section 5.9 
5.8.2.8 Information on Interruptions/Filter Changes and Blood Loss 
1. Reason(s) for filter change 
2. Start time and Stop time of interruption. 
3. Filter duration within treatment before clotting 

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4. Reason for interruption/Filter change 
5. Complications related to filter clotting and associated AE (if applicable) 
a. Transfusion requirements 
b. Estimated blood loss 
 
5.8.2.9 Total Fluid Removal, Fluid Overload, Blood & Mean Arterial Pressures 
1. Amount (cumulative total) of fluid removed 
2. End of study weight 
3. Fluid overload at CRRT initiation and at 12 hour intervals up to end of study or 
72 hours of CRRT according to the schedule in Table 2 
4. Blood pressure including mean arterial pressure at admission to the ICU, at 
CRRT initiation and at hourly intervals up to end of study or 72 hours of CRRT 
according to the schedule in Table 2 
5. Periodic Patient Fluid Removal (PFR) recorded from system GUI display 
hourly and before ending treatment 
6. Unintended Patient Fluid Loss/Gain recorded from system GUI display at least 
every 1 hour and before ending treatment 
 
5.8.2.10 Prismaflex Alarms Related to Fluid Balance 
1. Alarm type (Caution: Flow Problem, Caution: Loss Limit Reached or Caution: 
Gain Limit Reached) 
2. Operator Set Limit for Unintended Patient Fluid Loss/Gain (mL/1h) 
 
5.8.2.11 Treatment and Outcome Data at end of study treatment  
1. Total Prescribed Dose 
2. Total Delivered Dose 
3. Attainment of Dry weight (yes/no) 
4. Attainment of Metabolic control (yes/no) 
5. Continued need for RRT (yes/no) 
6. Death (yes/no) 
a. Time of Death 

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b. Date of Death 
c. Cause of Death 
 
5.8.2.12 Adverse Events and Unanticipated Adverse Device Effect Information 
1. Adverse Event 
2. Start and Stop Date/Time 
3. Causality 
4. Seriousness 
5. Action Taken 
6. Outcome 
5.8.2.13 Vital Signs 
1. Height 
2. Daily Weight 
3. Pulse Rate 
4. Respiratory Rate (Spontaneous or Mechanically Ventilated) 
5. Temperature (location where temperature obtained) 
6. Blood Pressure  
7. Mean Arterial Pressure 
 
5.8.2.14 Concomitant Medications 
1. Medications up to 7 days prior to enrollment (medication name, minimum dose, 
maximum dose, frequency, route, start date and stop dates) 
2. Medications taken during treatment, including any prescribed to treat an AE 
(medication name, minimum dose, maximum dose, frequency, route, start and 
stop dates). 
 

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Monitor, but the Investigator must make, document and report the relationship for every 
AE. All AEs must be documented in source documents and on the eCRFs, no matter how 
common they are for a particular patient and regardless of the causality assigned by the 
Investigator. 
All AEs and SAEs, regardless of relatedness, should be actively solicited and recorded by 
the Investigator or designee at defined visits throughout the course of the study. 
Additionally, any AE voluntarily reported by the patient should be recorded and verified 
by the Investigator or designee on the appropriate source documents and eCRF pages. 
Each SAE will be documented on a separate SAE report form. 
The outcome/resolution of all AEs and SAEs will be determined by the Investigator and 
documented on the AE eCRF and the SAE report form. Investigators will be instructed to 
follow all AEs/SAEs as follows: Unrelated AEs will be followed until resolution or until 
the end of the study, whichever occurs first. Adverse drug/device effects (related AEs) 
and all SAEs (related or not) will be followed until resolution or stable, including 
following the patient after the end of the study if necessary. The outcome categories that 
can be chosen on the eCRF by the Investigator include: Fatal, Not recovered/Not resolved 
(this outcome is reached for AEs which are ongoing when the patient’s end of study is 
due to death related to another AE), Recovering/Resolving (this outcome is reached for 
AEs which are ongoing at the patient’s end of study), Recovered/Resolved with Sequelae 
(if there are some residual effects caused by the event), Recovered/Resolved, and 
Unknown. 
All SAEs regardless of their relationship to the study product will be submitted to sponsor 
by the Investigator or designee within 24 hours of becoming aware of the event. 
An AE can result from the use of the study product in accordance with the protocol, as 
well as from an accidental or intentional misuse of the study product or any other 
treatment error such as unintentional administration or use of another product during the 
course of the study. Each investigator is to inform sponsor as soon as possible of all AEs 
or of any Unanticipated Adverse Device Effects (UADEs) associated with the Prismaflex 
HF20 Set and/or the Prismaflex Control Unit Software Version 7.10 and 7.20 that occurs 
during the course of the study/treatments, by telephone or email. Each investigator is to 
complete the electronic AE form in the EDC and, if applicable, the Serious Adverse 
Event (SAE) Report form and email it to the Prismaflex HF20 study email box. All SAEs 
and UADEs must be reported to the sponsor and the Data Safety Monitor. All UADEs 
must be reported to the  reviewing IRB as soon as possible, but not later than ten working 
days after the investigator first learns of the effect per 21 CFR Part 812.150 (1). 

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Anticipated AEs and UADEs are defined as follows: 
6.1 Anticipated Adverse events (AE) 
The anticipated adverse effects for this study have been identified in the list below. 
• 
Air embolism 
• 
Coagulation of the dialyzer/extracorporeal circuit resulting in blood loss 
• 
Bradycardia 
• 
Cramping 
• 
Disequilibrium syndrome 
• 
Dizziness 
• 
Electrolyte Imbalance 
• 
Excessive weight loss 
• 
Fluid imbalance 
• 
Hemodialyzer blood leak resulting in blood loss 
• 
Hemolysis 
• 
Hypersensitivity or Allergic Reactions “First Use Reaction” 
• 
Hypertension 
• 
Hypervolemia 
• 
Hypotension 
• 
Hypothermia 
• 
Hypovolemia 
• 
Infection 
• 
Nausea 
• 
Pyrogen Reaction 
• 
Tachycardia 
• 
Vomiting 
• 
Bleeding 
 
6.2 Unanticipated Adverse Device Effects 
An UADE is defined as any serious adverse effect on health or safety, any life-
threatening problem or death caused by, or associated with, a device if that effect, 

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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. 
All UADEs are to be recorded on the supplied SAE Initial Report and Follow-up Report 
forms, reported as an SAE and entered into an AE eCRF form in the EDC. 
The sponsor must conduct an investigation of any unanticipated adverse device effect 
according to FDA regulations. If the sponsor determines that the unanticipated adverse 
device effect presents an unreasonable risk to subjects, the sponsor shall terminate all 
investigations or parts of investigations presenting that risk as soon as possible. This 
termination shall occur no later than 5 working days after the sponsor makes the 
determination and no later than 15 working days after the sponsor first received notice of 
the effect. 
6.3 Other observation 
Other observations which do not fall under the definition of AE or SAE concerning 
information related to any Gambro medical device that could indicate a safety risk for the 
patient need to be reported to sponsor. Examples could include deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness or performance of a Gambro 
medical device, such as an error in labeling, packaging, device misuse or spontaneous 
report by a healthcare professional. For medical devices, this also includes technical 
issues such as unusual monitor alarms, damaged devices and/or handling problems. 
6.4 Recording of AEs, SAEs and UADEs 
All AEs and UADEs will be recorded on the AE eCRF form. For UADEs, additional 
information about the UADE will be recorded on the supplied SAE Report form. Initial 
reports and follow up reports will be indicated on the report forms. All AEs, SAEs and 
UADEs will be followed carefully until they resolve. Each AE, SAE or UADE will be 
described by: 
1. Its duration 
2. The severity grade 
3. Its relationship to the study product 
4. The action(s) taken. 
 

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Any patient death occurring during the study shall be considered as a SAE and the cause 
of death form shall be attached to the "SAE Form." 
6.5 Evaluation of AEs, SAEs, and UADEs 
6.5.1 Severity 
The investigator will make an assessment of intensity for each AE, SAE and UADE 
reported during the study. The assessment will be based on the investigator’s clinical 
judgment. The intensity of AE, SAE and UADE recorded in the eCRF should be assigned 
to the following categories: 
• 
Mild: An event that results in transient discomfort, which is easily tolerated by the 
patient and does not interfere in a significant manner with the subject’s normal 
functioning level with everyday activities. The AE resolves spontaneously or may 
require minimal therapeutic intervention. 
• 
Moderate: An event that produces limited impairment of function of normal 
everyday activities and can require therapeutic intervention, but produces no 
sequelae. 
• 
Severe: An event that results in marked impairment of function and can lead to 
temporary inability to resume normal everyday activities. The AE produces 
sequelae requiring prolonged therapeutic intervention. 
 
Comment: The term severity is often used to describe the intensity (severity) of a specific 
event. This is not the same as "seriousness," which is based on patient/event outcome or 
action criteria. 
6.5.2 Causality 
The relationship between the Prismaflex HF20 Set and/or the Prismaflex System 
Software Version 7.10 and 7.20 and the occurrence of each AE/SAE/UADE will be 
assessed and categorized as follows. The investigator will use clinical judgment to 
determine the relationship. Alternative causes, such as natural history of the underlying 
diseases, concomitant therapy, other risk factors etc., will be considered. 
• 
Not related: Temporal relationship of the onset of the event, relative to 
administration of the product, is not reasonable or another cause can by itself 
explain the occurrence of the event 

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• 
Unlikely related: An AE has little or no temporal relationship to the product 
and/or a more likely alternative etiology exists 
• 
Related: An AE follows a strong temporal relationship to the product and another 
etiology is unlikely or significantly less likely 
• 
Possibly related: An AE follows a reasonable temporal relationship to the product 
and an alternative etiology is equally or less likely compared to the potential 
relationship to the device or drug 
Note: All AE/SAE/UADE judged by either the investigator or the Sponsor as having a 
reasonable “suspected” (ie, assessed at least as “Possible”) causal relationship to an 
investigational study product qualify as an Adverse Reaction and may be subject to 
regulatory reporting timeline requirements. 
 
6.5.3 Occurrence 
• 
During treatment: An event arising during the procedure of treatment that 
includes the Prismaflex HF20 Set and/or the Prismaflex System Software Version 
7.10 and 7.20. 
• 
Between treatments: An event arising in between two procedures of treatment that 
includes the Prismaflex HF20 Set and/or the Prismaflex System Software Version 
7.10 and 7.20. 
 
6.5.4 Expectedness 
Following definition should apply to define expectedness of an Adverse Reaction: 
• 
Unexpected: Adverse reactions should be considered as unexpected if the nature, 
seriousness, severity or outcome of the reaction(s) is not consistent with the 
reference information for the Prismaflex HF20 Set and/or the Prismaflex System 
Software Version 7.10 and 7.20. 
• 
Expected: Adverse reactions should be considered as expected if the nature, 
seriousness, severity or outcome of the reaction(s) is consistent with the reference 
information for Prismaflex HF20 Set and/or the Prismaflex Control Unit. The 
expected/anticipated AEs are listed in Section 6.1. 
 

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6.5.5 Seriousness 
An SAE is any untoward medical occurrence or affect that: 
• 
Results in death; an event resulting in death 
• 
Is immediately life-threatening: In the opinion of the investigator, an event that 
would have resulted in immediate death if medical intervention had not been 
undertaken. This does not include an event that would have been fatal if it had 
occurred in a more severe form. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization: An 
event resulting in inpatient admission of the subject to the hospital. (Note: 
Inpatient hospitalization refers to any inpatient admission, regardless of the length 
of stay). Visits to the emergency room or outpatient facility do not constitute 
hospitalization for the purpose of this definition 
• 
Results in persistent, permanent or significant disability or incapacity: An event 
that substantially interferes with the subject’s daily activities of living. This 
category is not intended to include events of relatively minor medical significance 
such as minor trauma, diarrhea, nausea, etc. 
• 
Results in a congenital anomaly or birth defect: An abnormality detected at or 
after birth in the offspring of a study subject. 
• 
Is medically significant as deemed by the investigator: A medically important 
event or reaction that may not be immediately life-threatening or result in death or 
hospitalization, but may jeopardize the subject or requires intervention to prevent 
one of the other outcomes listed above. Examples of such events include intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependence or drug abuse. 
 
Note: 
- 
Medical judgment should be exercised in deciding whether an AE/reaction is 
serious in other situations. Important AEs/ reactions that are not immediately 
life-threatening or do not result in death or hospitalization but may jeopardize 
the subject, or those that may require intervention to prevent one of the other 
outcomes listed in the definition above, should also be considered serious, 

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- 
Any suspected transmission via a medicinal product of an infectious agent is 
also considered a serious adverse effect. 
 
7. ETHICS AND REGULATORY ISSUES 
This study will be performed under a FDA-approved Investigational Device Exemption 
Application (IDE) and will be conducted in accordance with the IDE regulations (21 CFR 
Part 812). 
7.1 Institutional Review Board (IRB) 
The PI at each study site is responsible for Institutional Review Board (IRB) submissions. 
Sponsor will provide investigator with all needed documentation/data needed for IRB 
submission. 
The Study Manager must receive a copy of the IRB approval letter and IRB approved 
Informed Consent Form, prior to the inclusion of patients in the study and before sending 
investigational products to the study site. 
During the study, the investigator must report to the IRB any SAE and/or any amendment 
to the protocol, in accordance with local IRB requirements. All the correspondence with 
the IRB must be filed by the investigator. 
7.2 Food and Drug Administration 
The sponsor is in charge of submissions to the Food and Drug Administration (FDA). 
The Study Manager must receive a copy of the IDE approval document supplied by the 
FDA, prior to the inclusion of patients in the study and before sending investigational 
products to the study sites. 
7.3 Amendments 
No amendment to study procedures shall be made without the mutual agreement of the 
investigators and sponsor. All such modifications must be duly documented and signed 
and are subject to protocol amendments. If any changes are made to the study design, the 
IRBs and FDA shall be informed and, when necessary, shall approve these changes prior 
to the enrollment of new patients except in emergency case for patient’s safety. 
The sponsor Study Manager/Monitor is responsible for the distribution of an amendment 
to the FDA, investigators and other persons that are involved in the study. Investigators 

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are responsible for the distribution of this amendment to the members of their team and to 
their reviewing IRB. 
7.4 Patient data protection 
Each patient must be identified on the eCRF with an identification number indicating 
his/her rank of inclusion into the study. Investigators must keep the list of all the patients, 
including identification numbers, full names and last known addresses. 
The parent(s) or legal guardian(s) of the patients must be informed in writing about the 
possibility of audits by authorized representatives of the company and/or regulatory 
authorities, in which case the relevant parts of study-related hospital records may be 
required. 
The parent(s) or legal guardian(s) of the patients must also be informed that the results 
obtained will be computer-stored and analyzed, that local laws must be applied, that the 
child’s confidentiality must be preserved, and that they are entitled to obtain any 
information concerning the data stored and analyzed by a computerized system. 
7.5 Patient’s information and informed consent 
The parent(s) or legal guardian(s) of the patients who meet the inclusion criteria will be 
clearly informed on the details of the study, including the potential benefits and risks to 
the patient prior to their enrollment in this study. One or both parents (as required by 
local IRB and/or local laws) must give their permission unless one parent is deceased, 
unknown, incompetent, not reasonably available or when only one parent has legal 
responsibility for the care and custody of the child per 21 CFR Part 50.55(e). The 
parent’s or legal guardian’s consent must be documented via signature and date on the 
Patient Informed Consent form. The parent(s) or legal guardian(s) of the patients must 
also be informed that they are free to withdraw their child from the study at any time. 
Patients will be considered enrolled in the study after the informed consent has been 
signed. 
A sample Informed Consent Form can be found in Appendix II. 
8. INVESTIGATIONAL PROCEDURES 
8.1 Training 
Sponsor, the PI and the Co-Investigators must make sure that any other staff participating 
actively in the study have been appropriately trained and received the relevant 
information relating to the performance of this study. 

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The Sponsor Study Monitor(s) will ensure that hospital staff involved in the study 
receives appropriate training for the purpose of the study. 
If needed, a second training could be organized on study site request for clarification 
purposes. 
8.2 Non-Compliance with the Protocol 
In the event of any significant protocol deviation, the PI will notify the sponsor 
immediately by phone and confirm notification to the sponsor in writing as soon as 
possible, but within 5 working days after a deviation to eliminate an apparent immediate 
hazard to the subject. The PI will also notify the IRB of a protocol deviation made to 
eliminate an apparent immediate hazard to the subject. 
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the PI’s participation. The sponsor will notify the 
IRB and applicable regulatory authorities of any investigator termination. 
8.3 Monitoring (verification of compliance with protocol) 
During the course of the study the sponsor monitor(s) will have regular contacts with the 
study sites and will make regular visits. Before the patient enrollment starts and during 
the course of the study, the sponsor monitor(s) will ensure that clinical facilities are 
acceptable, that the study site team complies with the protocol, the GCP, and that the 
study results are properly recorded on eCRFs. 
It is important that investigator and/or another member of the team attend these visits. At 
monitoring visits, the sponsor monitor must ensure that the accountability of the 
investigational product is performed and that source data is checked. The study monitor 
must fill in a monitoring report for each study visit according to the monitoring 
procedure. The monitoring report will include notably information on the following: 
• 
Patient’s informed consent obtained prior to the start of the study 
• 
Number of patients enrolled 
• 
Performance of the treatments in accordance with the protocol 
• 
Verification of source information to the data reported in the eCRF  
• 
Compliance with inclusion and exclusion criteria according to the protocol. 

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8.4 Direct access to source documents 
The investigator must give the Study Monitor direct access to relevant hospital or clinical 
records to confirm their consistency with the eCRF entries. No information in these 
records about the identity of the subjects will leave the study site.  Sponsor monitoring 
standards require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of AEs and the recording of primary efficacy 
and safety variables. Additional checks of the consistency of the source data with the 
eCRFs are performed according to the study-specific monitoring plan. 
8.5 Source data verification 
The investigators agree to allocate their time and the time of their staff to discuss findings 
and any relevant issues linked to source data. 
8.6 Audits and inspections 
The FDA may conduct an inspection during the study or after its completion. 
9. STATISTICAL METHODS 
The preliminary Statistical Plan for the study can be found in Appendix I. Further details 
of the planned statistical methods will be provided in the final statistical analysis plan. 
The purpose of the final statistical analysis plan is to elaborate on all statistical methods 
that will be used to evaluate the study primary and secondary endpoints, safety endpoints, 
and other relevant data (eg, demographics, baseline characteristics, treatment exposure 
and subject disposition) and describes analysis conventions to guide the statistical 
programming work. The statistical analysis plan will be finalized in accordance with 
sponsor’s standard operating procedures. 
10. DATA MANAGEMENT 
10.1 Web-based Electronic Data Collection 
Web-based electronic data entry must be completed for all patients enrolled in the study. 
Electronic Investigator signatures will be used to attest to the accuracy of data entered 
into the electronic data collection system. Modifications made by the investigator or their 
delegated assistants will be tracked in the EDC system. Any data corrections as a result of 
data monitoring will be documented using an electronic generated query, as needed, and 
re-verified. 
In collaboration with the investigators, the Study Monitor must ensure that data entered 
into the electronic data collection system are correct. Data editing for correction or 

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clarification purposes must be done before the case report forms have been transmitted 
for data processing and analysis. Subsequent corrections must be checked in writing and 
validated in signing by the investigators. 
The eCRF data are the property of the sponsor. The investigators must ensure that the 
original source data are accessible to the Study Monitor, the Study Manager or any 
authorized people at any time during the course of the study. 
10.2 Data entry and storage 
The electronic data entry will be the responsibility of the investigator, along with the 
collection of Prismaflex data card. 
The database and the data card will be maintained by sponsor. Data cards will be 
archived at the end of study. 
10.3 Data management and quality control 
Data management will be carried out by sponsor. 
Sponsor is responsible of the creation of the study eCRF and the associated electronic 
database (EDC). Queries (ie, Data Clarification Forms) will be generated electronically in 
order to solve questions regarding missing data, unreadable text and coherence. 
11. ADMINISTRATIVE PROCEDURES 
11.1 Study documents and record keeping 
Individual investigators are responsible for completing the eCRFs and the Study Monitor 
is responsible for reviewing them and clarifying and resolving any data queries. The 
completed and corrected electronic eCRFs for completed visits will be initially reviewed 
and approved by the Study Monitor initially and then sent for data processing. A copy of 
the eCRFs in PDF or electronic file will be provided by sponsor and is retained by the 
investigator, who must ensure that it is stored with other study documents such as the 
protocol, investigator’s brochure and any protocol amendments in a secure place with 
restricted access. 
Data on subjects collected on eCRFs during the study will be documented in an 
anonymous fashion and the subject will only be identified by the subject number. If, as an 
exception, it is necessary for safety or regulatory reasons to identify the subject, the Study 
Monitor and the investigator are bound to keep this information confidential. 

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The investigator must maintain source documents for each subject in the study. All 
information on eCRFs must be traceable to these source documents, which are generally 
maintained in the subject's medical file. The source documents should contain all 
demographic and medical information, including laboratory data, as well as a copy of the 
signed informed consent, which should indicate the study number and title of the study. 
11.2 Archiving of study documentation 
The investigators must keep all original raw data together with the patient's identification 
list and signed informed consents for at least 30 years (the Sponsor reserves the right to 
require a longer archiving period related to the product lifespan). 
Prior to destroying study-related documentation, the investigator shall contact the 
sponsor. 
The investigator agrees to adhere to the document-retention procedures by signing the 
protocol. 
 

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13. REFERENCES 
1. 
Symons JM, Brophy PD, Gregory MJ, et al. Continuous renal replacement 
therapy in children up to 10 kg. Am J Kidney Dis. 2003;41(5):984-989. 
2. 
Symons JM, Chua AN, Somers MJ, et al. 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. 
3. 
Goldstein SL. Hemodialysis in the pediatric patient: state of the art. Adv Ren 
Replace Ther. 2001;8(3):173-179. 
4. 
Musial K, Zwolińska D, Szprynger K, Szczepańska M. sL-selectin/sVCAM-1 
ratio as a marker of biocompatibility in children and young adults on chronic 
hemodialysis (HD). W:XLI Congress of the European Renal Association European 
Dialysis and Transplant Association. Lisbon, Portugal; 2004:SP336. 
5. 
Fischbach M, Terzic J, Laugel V, et al. Daily on-line haemodiafiltration: a pilot 
trial in children. Nephrol Dial Transplant. 2004;19(9):2360-2367. 
6. 
Bell L, Espinosa P. Intensive in-center hemodialysis for children: a case for 
longer dialysis duration. Hemodial Int. 2003;7(4):290-295. 
7. 
Donckerwolcke RA, Bunchman TE. Hemodialysis in infants and small children. 
Pediatr Nephrol. 1994;8(1):103-106. 
8. 
Warady B, Jabs K, Goldstein S. Acute Dialysis in Children. Principles and 
Practice of Dialysis: Lippincott Williams & Wilkins; 2004. 
9. 
Schindler R, Boenisch O, Fischer C, Frei U. Effect of the hemodialysis membrane 
on the inflammatory reaction in vivo. Clin Nephrol. 2000;53(6):452-459. 
10. 
Zappitelli M, Goldstein SL, Symons JM, et al. Protein and calorie prescription for 
children and young adults receiving continuous renal replacement therapy: a report from 
the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group. Crit 
Care Med. 2008;36(12):3239-3245. 

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11. 
Goldstein SL, Somers MJ, Brophy PD, et al. The Prospective Pediatric 
Continuous Renal Replacement Therapy (ppCRRT) Registry: design, development and 
data assessed. Int J Artif Organs. 2004;27(1):9-14. 
12. 
Goldstein SL, Somers MJ, Baum MA, et al. Pediatric patients with multi-organ 
dysfunction syndrome receiving continuous renal replacement therapy. Kidney Int. 
2005;67(2):653-658. 
13. 
Flores FX, Brophy PD, Symons JM, et al. Continuous renal replacement therapy 
(CRRT) after stem cell transplantation. A report from the prospective pediatric CRRT 
Registry Group. Pediatr Nephrol. 2008;23(4):625-630. 
14. 
Hackbarth R, Bunchman TE, Chua AN, et al. The effect of vascular access 
location and size on circuit survival in pediatric continuous renal replacement therapy: a 
report from the PPCRRT registry. Int J Artif Organs. 2007;30(12):1116-1121. 
15. 
Sutherland SM, Zappitelli M, Alexander SR, et al. Fluid overload and mortality in 
children receiving continuous renal replacement therapy: the prospective pediatric 
continuous renal replacement therapy registry. Am J Kidney Dis. 2010;55(2):316-325. 
16. 
Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein 
SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int. 
2007;71(10):1028-1035. 
17. 
Zappitelli M, Parikh CR, Akcan-Arikan A, Washburn KK, Moffett BS, Goldstein 
SL. Ascertainment and epidemiology of acute kidney injury varies with definition 
interpretation. Clin J Am Soc Nephrol. 2008;3(4):948-954. 
18. 
Zobel G, Rödl S, Urlesberger B, Kuttnig-Haim M, Ring E. Continuous renal 
replacement therapy in critically ill patients. Kidney Int Suppl. 1998;66:S169-173. 
19. 
Group KDIGOKAKIW. KDIGO Clinical Practice Guideline for Acute Kidney 
Injury. Kidney International Supplements. 2012;3(1). 
20. 
Brophy PD, Somers MJ, Baum MA, et al. Multi-centre evaluation of 
anticoagulation in patients receiving continuous renal replacement therapy (CRRT). 
Nephrol Dial Transplant. 2005;20(7):1416-1421. 

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21. 
Bunchman TE, Maxvold NJ, Brophy PD. Pediatric convective hemofiltration: 
Normocarb replacement fluid and citrate anticoagulation. Am J Kidney Dis. 
2003;42(6):1248-1252. 
22. 
Bunchman TE, Maxvold NJ, Barnett J, Hutchings A, Benfield MR. Pediatric 
hemofiltration: Normocarb dialysate solution with citrate anticoagulation. Pediatr 
Nephrol. 2002;17(3):150-154. 
 
 

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14. LIST OF APPENDICES 
 
 
 
APPENDIX I 
Statistical Plan 

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Appendix 1 Statistical Plan 
 
Objective 
The primary objective of the trial is to verify that the Prismaflex HF20 Set is able to 
deliver effective treatment in small patients. Its efficacy will be measured by the 
reduction in blood urea nitrogen (BUN). This will be measured every 12 hours at the start 
of, and during, treatment. Creatinine reduction and the TCO2 profile will be assessed as 
secondary endpoints along with survival time of the Prismaflex HF20 Set out to 72 hours. 
 
. A repeated measures ANOVA will be used to test 
TCO2. No formal statistical analysis of the safety endpoint will be carried out; rather 
these events will be assessed for severity and device-relatedness, and reported in 
narrative form. 
Primary Endpoint 
The primary endpoint of analysis will be to demonstrate that a mean reduction of greater 
than 38% in BUN is seen at 24 hours from initiation of CRRT. This percentage reduction 
is motivated by the target of getting patients with an initial BUN of 80 mg/dL below 
50 mg/dL after 24 hours of treatment. 
The null hypothesis to be tested is 
 
H0: µ ≤ 38,   vs 
 
Ha: µ >38 
Where µ stands for the mean percentage reduction in BUN from baseline to 24 hours. 
Secondary Endpoints 
A secondary endpoint will consist of testing whether there is a significant change in 
creatinine and TCO2 from baseline to 24 hours. This will be done by turning the 
creatinine and TCO2 readings into percent change from baseline and testing whether the 
percent change is significantly different from zero for each parameter.  Another 
secondary endpoint is the survival time of the Prismaflex HF20 Set.  The failure time of 
the Prismaflex HF20 Set, defined as when one of the following two alarms continues to 

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be triggered despite mitigation steps, “Warning: Filter Clotted”, and/ or "Caution: TMP 
Excessive", will be recorded and analyzed to determine the survival function of the filter 
set. Safety will also be investigated by reporting: AEs, SAEs, device deficiencies and 
alarms. 
 
In addition, the mean concentrations of BUN, creatinine and TCO2 will be computed, 
along with 95% confidence intervals, at baseline and at each subsequent 12-hour 
sampling time. 
 
 
Other Measures 
Other patient and treatment measures will be captured during each patient’s treatment. 
Summary numbers for these measures (mean, standard deviation, minimum and 
maximum) will be reported for each time point at which the measure is made. 
Statistical Analysis Plan 
Analysis of Primary Endpoint  
The primary endpoint for the reduction in BUN will be assessed using a one-sample t 
test. 
The actual mean percentage reduction in BUN will be quantified using 95% confidence 
intervals.  
As a supportive analysis, an analysis of variance (ANOVA) will be implemented to 
investigate the mean change from baseline among the different sites. 
The Analysis of the primary endpoint will be carried out on both the FA and PP. 
Analysis of Secondary Endpoints 
The change from baseline in creatinine and TCO2 will be analyzed as described above for 
the primary endpoint.   
The survival time of the Prismaflex HF20 Set will be analyzed using a Kaplan Meier 
survival curve to generate the survival function of the filter set. 

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• did not meet any of the exclusion criteria 
• received at least 20 hours of CRRT treatment on the Prismaflex HF20 Set with no 
more than 1 interruption which may have included a filter change.    
• did not have major protocol deviations that might impact the assessment of the 
primary endpoint 
• have available measurements for the primary endpoint (BUN) at baseline (within 
1 hour prior, and 15 min after initiation of CRRT) and at 24 hours (±1 hour) from 
start of CRRT   
Dropout 
The primary endpoint is assessed at 24 hours, with a baseline reading within one hour 
prior to CRRT initiation and within 15 minutes after start of CRRT, patients are allowed 
one interruption which may include a filter change lasting up to 4 hours. Patients with an 
interruption lasting more than 4 hours or with a second Prismaflex HF20 Set change will 
be excluded from the PP.  
Sample Size 
The sample size calculation is based on the primary objective of 24-hour BUN reduction. 
It is anticipated that the true mean reduction at 24 hours will be some 62%, as would be 
obtained from a patient with initial BUN of 80 mg/dL and reaching 30 mg/dL after 
24 hours of treatment. Data from the earlier M-10 study suggest that the standard 
deviation in the BUN reduction is about 45%. 
Under these assumptions, the sample size needed to obtain 80% power is 24, as reported 
by SAS PROC POWER. 
A target sample size of up to 30 patients is therefore proposed to allow for a possible 
20% loss of data between the baseline and 24 hour marks.