Clinical trial NCT02860130
Conditions: Regional Citrate Anticoagulation (RCA) Continuous Renal Replacement Therapy (CRRT) Acute Kidney Injury
Keywords: Regional Citrate Anticoagulation (RCA) Continuous Renal Replacement Therapy (CRRT) Acute Kidney Injury
Sponsor: Vantive Health LLC
Start date: 2016-09-27; Completion date: 2018-05-12
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research is to determine if an investigational new drug solution called Prismocitrate 18 lengthens extracorporeal circuit life in patients treated with continuous renal replacement therapy (CRRT). Patients who receive CRRT treatment with Prismocitrate 18 as the anticoagulant will be compared to patients who receive CRRT treatment with no anticoagulation.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Prismocitrate 18 intervention 2: No Anticoagulation
Intervention descriptions: intervention 1: Modality of CVVHDF intervention 2: Modality of CVVHDF

Protocol documents:
Prot_000.pdf: 


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Table of Contents 
SYNOPSIS ..........................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................10 
1. INTRODUCTION........................................................................................................13 
1.1 Background and Rationale ...................................................................................13 
1.2 Benefits and Risks for the Study Population .......................................................14 
1.3 Study Sponsor ........................................................................................................14 
2. STUDY OBJECTIVES ................................................................................................14 
2.1 Primary Objective(s) .............................................................................................14 
2.2 Secondary Objective(s) ..........................................................................................14 
3. INVESTIGATIONAL PLAN .....................................................................................15 
3.1 Overall Study Design and Plan .............................................................................15 
3.2 Rationale for Study Design and Control Group .................................................16 
3.3 Selection of Study Sites ..........................................................................................16 
3.4 Study Duration .......................................................................................................16 
3.5 Study Product and Material .................................................................................16 
3.6 Commercial Product Provided by Sponsor .........................................................18 
4. STUDY POPULATION SELECTION ......................................................................18 
4.1 Study Population ....................................................................................................18 
4.2 Inclusion Criteria ...................................................................................................18 
4.3 Exclusion Criteria ..................................................................................................19 
4.4 Removal of Patient from Therapy, Assessment, or Study .................................20 
4.5 Recruitment ............................................................................................................21 
5. STUDY TREATMENT(S) ..........................................................................................21 
5.1 Enrollment ..............................................................................................................21 
5.2 Treatment Administered .......................................................................................21 
5.2.1 Cross-Over Patients ........................................................................................24 
5.2.2 Study Arm Protocols ......................................................................................25 
5.2.2.1 Initial Prescription Orders for Control Arm ........................................25 
5.2.2.2 Initial Prescription Orders for the Prismocitrate 18 Arm ...................25 
5.2.2.3 Continuous Renal Replacement Therapy Dialysate .............................29 
5.2.2.4 Continuous Renal Replacement Therapy Replacement 
Fluids/Solutions ........................................................................................29 
5.2.2.5 Anticoagulants and Dosing/Administration of Prismocitrate 18 ........29 


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5.2.3 Monitoring of Therapy ...................................................................................29 
5.3 Selection and Timing of Dose for Each Patient ...................................................30 
5.4 Method of Assigning Patients to Treatment Groups ..........................................31 
5.5 Blinding ...................................................................................................................31 
5.6 Packaging and Labeling ........................................................................................31 
5.7 Storage and Accountability ...................................................................................31 
5.8 Investigational Product Destruction ....................................................................32 
6. STUDY PROCEDURES .............................................................................................33 
6.1 Informed Consent ..................................................................................................33 
6.2 Medical History ......................................................................................................33 
6.3 Physical Examination ............................................................................................33 
6.4 Vital Signs ...............................................................................................................34 
6.5 Clinical Laboratory Tests .....................................................................................34 
6.5.1 Laboratory Parameters ..................................................................................34 
6.5.2 Sample Collection, Storage, and Shipping ...................................................34 
6.6 Dispensing Study Drug ..........................................................................................34 
6.7 Efficacy Variables ..................................................................................................34 
6.7.1 Primary Efficacy Endpoint ............................................................................34 
6.7.2 Secondary Efficacy Endpoints .......................................................................35 
6.8 Safety Assessments .................................................................................................35 
6.9 Analysis of Training on Administration of Prismocitrate 18 ............................36 
6.10 Adverse Events Assessments ...............................................................................37 
6.10.1 Definitions of Adverse Event Terms ...........................................................38 
6.10.2 Serious Adverse Event (SAE) ......................................................................40 
6.10.3 Adverse Drug Reaction ................................................................................40 
6.10.4 Unexpected Adverse Drug Reaction ...........................................................40 
6.10.5 Suspected Unexpected Serious Adverse Reaction .....................................40 
6.10.6 Adverse Events Related to Anticoagulation or CRRT ..............................41 
6.11 Site Reporting Requirements ..............................................................................42 
6.11.1 Sponsor to FDA/
 and Investigator to IRB/Ethics 
Committee .......................................................................................................44 
6.12 Concomitant Therapy ..........................................................................................44 
6.13 Restrictions ...........................................................................................................44 
6.14 Treatment Compliance ........................................................................................44 
7. STUDY ACTIVITIES .................................................................................................44 
7.1 Training on the Administration of Prismocitrate 18 ..........................................44 
7.2 Consenting and Screening Period ........................................................................45 
7.3 Patient Information to be Collected Prior to Initiation of Treatment ..............45 
7.4 Treatment Period ...................................................................................................46 
7.4.1 Treatment Information ..................................................................................46 
7.4.2 Treatment Prescription – initial and all changes during Treatment 
Period ...............................................................................................................46 


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7.4.3 Dialysate Used .................................................................................................47 
7.4.4 Replacement Solutions Used ..........................................................................47 
7.4.5 Priming Solution .............................................................................................47 
7.4.6 Calcium Gluconate or Calcium Chloride .....................................................47 
7.4.7 Extracorporeal Circuit (Prismaflex M150 Set) Information ......................47 
7.4.8 Anticoagulation Information .........................................................................48 
7.4.9 Patient Clotting Parameters ..........................................................................48 
7.4.10 Treatment Blood Concentration Data – According to the Sampling 
Schedule in Appendix 1 ..................................................................................48 
7.4.11 Fluid Balance and Hemodynamic Parameters ...........................................49 
7.5 End of Treatment or Early Termination Procedures .........................................49 
7.6 End of Study Procedures .......................................................................................50 
8. PLANNED STATISTICAL METHODS ...................................................................50 
8.1 General Considerations .........................................................................................50 
8.2 Determination of Sample Size ...............................................................................50 
8.3 Analysis Populations ..............................................................................................51 
8.4 Demographics and Baseline Characteristics .......................................................51 
8.5 Efficacy Endpoints .................................................................................................52 
8.5.1 Primary Efficacy Endpoint ............................................................................52 
8.5.2 Secondary Efficacy Endpoints .......................................................................53 
8.6 Safety Endpoints ....................................................................................................54 
8.7 Analysis of Training on Administration of Prismocitrate 18 ............................55 
8.8 Interim Analysis .....................................................................................................55 
9. ADMINISTRATIVE CONSIDERATIONS ..............................................................56 
9.1 Investigators and Study Administrative Structure .............................................56 
9.2 Institutional Review Board or Research Ethics Board Approval .....................56 
9.3 Ethical Conduct of the Study ................................................................................57 
9.4 Compliance with Protocol and Protocol Amendments ......................................57 
9.5 Patient Confidentiality ..........................................................................................57 
9.5.1 HIPAA Authorization Procedures – US Sites Only .....................................57 
9.5.2 Personal Health Information – Canadian Sites Only ..................................58 
9.6 Study Monitoring ...................................................................................................58 
9.7 Electronic Case Report Forms and Study Records ............................................59 
9.8 Data Monitoring Committee .................................................................................59 
9.9 Primary Endpoint Adjudication ...........................................................................59 
9.10 Protocol Violations/Deviations ............................................................................60 
9.11 Access to Source Documentation ........................................................................60 
9.12 Data Generation and Analysis ............................................................................60 
9.13 Retention of Data .................................................................................................61 
9.14 Audits and Inspections ........................................................................................61 
9.15 Financial Disclosure .............................................................................................61 
9.16 Publication and Disclosure Policy ......................................................................62 


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10. REFERENCE LIST ...................................................................................................64 
 
List of In-Text Tables 
Table 1. Prismocitrate 18 ................................................................................................17 
 
List of In-Text Figures 
Figure 1. University of Alabama at Birmingham Continuous Venovenous 
Hemodiafiltration Protocol .....................................................................................28 
 
List of Appendices 
Appendix 1 Blood Sampling Schedule ...........................................................................66 
Appendix 2 Schedule of Events .......................................................................................69 
Appendix 3 Investigator’s Signature ..............................................................................72 
 


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SYNOPSIS 
Sponsor: 
Baxter Healthcare Corporation 
Name of Finished Product: 
Prismocitrate 18  
Name of Active Ingredient: 
Prismocitrate containing 18 mmol/L trisodium citrate 
Study Title: 
Clinical Evaluation of Use of Prismocitrate 18 in Patients Undergoing Acute Continuous Renal 
Replacement Therapy (CRRT) 
Study Number: 
1407-004 
Study Phase: III 
Primary Objective(s):  
The primary objective of this study is to evaluate the efficacy of Prismocitrate 18 in prolonging 
extracorporeal circuit life in patients treated with continuous renal replacement therapy (CRRT). The 
Control Group will be patients receiving CRRT with no anticoagulation. 
Secondary Objectives: 
The secondary objectives of this study are to: 
• 
evaluate the efficacy of using Prismocitrate 18 in achieving appropriate anticoagulation through 
assessments of systemic and post-filter blood ionized calcium (iCa) concentrations, 
• 
evaluate the efficacy of using Prismocitrate 18 in delivering the prescribed CRRT dose, with 
delivered dose based on total (daily) effluent volume and expressed as mL/kg/hour, 
• 
evaluate the safety profile of Prismocitrate 18 through assessments of metabolic parameters 
(including serum bicarbonate, iCa, total calcium, total calcium/iCa ratio, magnesium, chloride, 
and other relevant serum electrolytes); anion gap, pH, base excess, bleeding events (number, 
location, duration); and the number and type of blood transfusions along with the number of units 
infused, and 
• 
complete training on administration of Prismocitrate 18 and demonstrate the understanding of the 
user groups on how to use the solution by passing an assessment at the end of training. 
Study Design: 
This study is a multi-center, prospective, non-blinded, one to one randomized study. A total of 160 adult 
patients, 80 in each study arm, will be enrolled at up to 15 investigational sites in the United States and 
Canada. Patients meeting all of the inclusion criteria and none of the exclusion criteria of this protocol 
and deemed treatable by either CRRT with Prismocitrate 18 solution or CRRT with no systemic 
anticoagulation are eligible for enrollment in the study.  If a patient is receiving standard-of-care CRRT, 
they must be randomized within 24 hours of initiation of their standard-of-care CRRT. All patients will 
be treated with continuous venovenous hemodiafiltration (CVVHDF) as the study CRRT modality. 
Patients enrolled in the study will receive either Prismocitrate 18 anticoagulation or no systemic 
anticoagulation during their CRRT, and the extracorporeal circuit life will be monitored for up to 
120 hours of study CRRT (Treatment Period). During the Treatment Period, the adequacy of 
anticoagulation in the Prismocitrate 18 patients will be assessed by monitoring extracorporeal circuit 
pressures and by assessment of systemic and post-filter blood iCa concentrations. Patients will be 
monitored for acid-base parameters and serum electrolytes at baseline (prior to any CRRT), initiation 
(after randomization but before the initiation of study CRRT), at initiation of study CRRT and at pre-
determined intervals during treatment. Information on bleeding events (number, location, duration) and 
the number and type of blood transfusions along with the number of units infused will also be collected. 


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Study Population:  
One hundred sixty (160) adult patients with AKI or other serious conditions who require CRRT are 
planned. 
Inclusion/Exclusion Criteria: 
Each patient must meet the following inclusion criteria to be enrolled in this study. 
1. Patient or legally-authorized representative has signed a written informed consent form (ICF). 
2. Patient must be receiving medical care in an intensive care unit (ICU) (eg, medical ICU, surgical 
ICU, cardiothoracic ICU, Trauma ICU, Mixed ICU, other). 
3. Patient age ≥ 18 years. 
4. Adult patients with AKI or other serious conditions who require treatment with CRRT. 
5. Patients are expected to remain in the ICU and on CRRT for at least 72 hours after randomization. 
6. Patients already receiving standard-of-care CRRT must be randomized within 24 hours of 
initiation of their standard-of-care CRRT. 
 
Patients who meet any of the following exclusion criteria will not be enrolled in the study. 
1. Patients requiring systemic anticoagulation with antithrombotic agents for reasons other than 
CRRT. The exception is patients receiving subcutaneous heparin for deep vein thrombosis 
prophylaxis according to institutional practice or patients on aspirin may be enrolled. 
2. Patients in whom citrate anticoagulation is contraindicated such as patients with a known allergy 
to citrate or who have experienced adverse events associated with citrate products including 
patients with a prior history of citrate toxicity or patients with uncorrected severe hypocalcemia 
(whether in the context of current citrate administration or due to the underlying disease state). 
3. Patients who are not candidates for CRRT. 
4. Patients who are receiving extracorporeal membrane oxygenation (ECMO) therapy. 
5. Patients with severe coagulopathy [ie, platelets < 30,000/mm3, international normalized ratio 
(INR) > 2, partial thromboplastin time (PTT) > 50 seconds] including severe thrombocytopenia 
(platelets < 30,000/mm3), HIT (heparin induced thrombocytopenia), ITP (idiopathic 
thrombocytopenia purpura), and TTP (thrombotic thrombocytopenia purpura) should not be 
enrolled in the trial. 
6. Patients with fulminant acute liver failure or acute on chronic liver failure as documented by a 
Child-Pugh Liver Failure Score > 10. 
7. Patients with refractory shock associated with persistent, worsening lactic acidosis (lactate 
> 4 mmol/L). However, patients with improving subsequent serum lactate levels may be enrolled.  
8. Patients unlikely to survive at least 72 hours. 
9. Female patients who are pregnant, lactating, or planning to become pregnant during the study 
period. Note: A female patient of childbearing potential, defined as a woman less than 55 years 
old who has not had partial or full hysterectomy or oophorectomy, must have a negative serum 
beta human chorionic gonadotropin (β-hCG) pregnancy test during the screening period (after 
consent and prior to randomization) and before CRRT treatment begins. A female patient of 
childbearing potential must use medically acceptable means of contraception during their 
participation in the study. 
10. Patients who are currently participating in another interventional clinical study. 
11. Patients with a medical condition that may interfere with the study objectives. 
Test Product, Dose, and Mode of Administration:  
Prismocitrate 18 (the investigational drug) is intended to be used as a replacement solution for regional 
anticoagulation of the extracorporeal circuit in patients undergoing continuous renal replacement therapy 
(CRRT). The renal replacement solution for regional anticoagulation containing 18 mmol/L citrate is 


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designed for pre-dilution infusion into the extracorporeal circuit before the blood pump (target blood 
citrate concentration of 3 to 5 mmol/L of blood). 
Study Duration:  
The anticipated duration of the clinical trial is approximately 4 years from the first patient enrolled to the 
last patient complete. 
Individual patients will participate in the study for up to 35 days with a study treatment period of up to 
120 hours of study CRRT post-randomization. At the conclusion of study treatment, patient adverse 
events and serious adverse events will be collected for a period of 30-days. 
Efficacy Assessments: 
Primary Efficacy Endpoint: 
The Prismaflex M150 Set extracorporeal circuit life will be assessed over a maximum of 120 hours by 
the duration of time for which each Prismaflex M150 Set can be used continuously over a maximum 
72 hour timeperiod in each patient. The Prismaflex M150 Set will be replaced any time study CRRT is 
stopped during the Treatment Period (regardless of duration) or any time a circuit is used for 
72 continuous hours (ie, "Advisory Time to Change Set"). The end of the extracorporeal circuit life will 
be defined by the occurrence of one or both of the following Prismaflex® System alarms/conditions if 
the alarms cannot be mitigated. At this point, study CRRT will be terminated and the extracorporeal 
circuit replaced because mitigation of the following alarms is not possible: 
• 
“Warning: Filter Clotted” , and/or 
• 
“Advisory TMP Too High” 
Secondary Efficacy Endpoints: 
Systemic and post-filter blood iCa concentrations will be assessed at baseline (systemic only), initiation 
(systemic only), 1 hour and every 6 hours during the 120 hour Treatment Period and at 120 hours or end 
of the Treatment Period from the initiation of study CRRT in each patient as indications of both the 
extent of calcium chelation prior to the CRRT filter and calcium restoration after the CRRT filter. Post-
filter iCa will only be measured in the Prismocitrate 18 arm. 
Delivery of the prescribed CRRT dose will be based on the patient’s weight and daily recordings of the 
effluent volume (in mL). These data will be used to calculate delivered dose (mL/kg/hour). 
Safety Assessments: 
Safety endpoints include: 
1. Serum bicarbonate and pH, will be measured at baseline, at initiation of study CRRT and every 
6 hours from the initiation of study CRRT during the 120 hour Treatment Period and at 120 hours 
or end of the Treatment Period. 
2. Blood total calcium concentrations will be measured at baseline, at initiation of study CRRT 
1 hour and every 6 hours from the initiation of study CRRT during the 120 hour Treatment Period 
and at 120 hours or end of the Treatment Period from the initiation of study CRRT.  
3. Serum electrolytes (sodium, potassium, chloride, phosphate, and magnesium) will be measured at 
baseline, at initiation of study CRRT and every 6 hours from the initiation of study CRRT during 
the 120 hour Treatment Period and at 120 hours or end of Treatment Period. 
4. As indicators of citrate accumulation (along with pH), the total calcium/iCa ratio (both 
measurements in mmol/L) will be measured at baseline, at initiation of study CRRT, 1 hour and 
every 6 hours from the initiation of study CRRT during the 120 hour Treatment Period and at 
120 hours or end of Treatment Period. Anion gap and base excess will be measured at baseline, at 
initiation of study CRRT and every 6 hours from the initiation of study CRRT during the 120 hour 
Treatment Period and at 120 hours or end of Treatment Period. 
5. The number, location and duration of bleeding events during the 120 hour Treatment Period will 
be collected. If a blood transfusion is needed during the 120 hour Treatment Period, the number 
and type of transfusions along with the number of units infused will be collected. 


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6. Change from baseline to final measurement in laboratory and vital signs measurements will be 
collected. 
7. The incidence of adverse events and serious adverse events from the time the patient signs the 
informed consent form (ICF) until 30-days post study CRRT treatment (end of study) will be 
collected. 
Analysis of Training on Administration of Prismocitrate 18 
The site level user groups will be trained on the use of Prismocitrate 18 in CRRT and their understanding 
assessed prior to use in the clinical trial setting. The user groups will be comprised of physicians, nurses, 
and other clinicians who may be part of prescribing, initiating, or modifying treatment during the 
120 hour Treatment Period. A descriptive summary of training results on administration of 
Prismocitrate 18 will be provided in the Clinical Study Report following completion of the study. 
Statistical Methods:  
The Statistical Plan for the study can be found in Section 8. 
Date of Original Approved Protocol: 2016 FEB 08 
Date of Approved Amendment 1: 2016 MAY 20 
Date of Approved Amendment 2: 2017 JAN 05 
Date of Approved Amendment 3: 2018 FEB 08 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION 
DEFINITION 
ABG 
arterial blood gases 
ADR 
adverse drug reaction 
AE 
adverse event 
AKI 
acute kidney injury 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANCOVA 
analysis of covariance 
APACHE II 
Acute Physiology and Chronic Health Evaluation II classification system 
AST 
aspartate transaminase 
β-hCG 
serum beta human chorionic gonadotropin 
BFR 
blood flow rate 
BUN 
blood urea nitrogen 
Ca2+ 
calcium  
CFR 
Code of Federal Regulations 
CRRT 
continuous renal replacement therapy 
CT 
computerized tomography 
CTA 
Clinical Trial Application 
CVVHDF 
continuous venovenous hemodiafiltration 
DMC 
data monitoring committee 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FA 
full analysis set 
FDA 
Food and Drug Administration 
g/dL 
grams per deciliter 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GPS 
Global Patient Safety 
 
 
HD 
hemodialysis 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
iCa or iCa2+ 
ionized calcium 


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ABBREVIATION 
DEFINITION 
ICU 
intensive care unit 
ICH 
International Conference on Harmonization 
IFU 
Instructions For Use 
IND 
Investigational New Drug  
INR 
international normalized ratio 
IP 
investigational product 
IRB 
institutional review board 
IV 
intravenous 
kg 
kilogram 
L 
Liter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mEq 
milliequivalent 
mg 
milligram 
mL 
milliliter 
mmHg 
millimeter of mercury 
mmol 
millimole 
MMRM 
mixed-effects model repeated measures 
mOsm 
milliosmol 
PBP 
pre-blood pump 
PI 
principal investigator 
PP 
per protocol set 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QB 
blood flow rate (real blood flow pumped out of the patient) 
QD 
dialysate rate 
QE 
effluent rate 
QFR 
fluid removal rate 
QPBP 
pre-blood pump infusion rate 
QR 
replacement fluid rate 
RCA 
regional citrate anticoagulation 
REB 
research ethics board 
RRT 
renal replacement therapy 
SAE 
serious adverse event 


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ABBREVIATION 
DEFINITION 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis Software 
SOC 
system organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMP 
transmembrane pressure (mmHg) 
US 
United States 
VBG 
venous blood gases 
 


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1. INTRODUCTION 
1.1 Background and Rationale 
Prismocitrate 18 Solution is an investigational new drug intended to be used as a 
replacement solution for regional anticoagulation of the extracorporeal circuit in patients 
undergoing continuous renal replacement therapy (CRRT). Prismocitrate 18 is a CRRT 
solution developed by Gambro AB (now part of Baxter Healthcare Corporation) for use 
as both a replacement solution and an anticoagulant to prevent clotting of the 
extracorporeal circuit. Regional citrate anticoagulation (RCA) has been in use for renal 
replacement therapy (RRT) since 1961 for conventional hemodialysis (HD) and for 
CRRT since 1990.[1,2] Multiple publications in the literature document the use of RCA 
in RRT and CRRT.[1-8] Recent meta-analyses of randomized controlled trials 
demonstrate benefits for RCA over standard heparin anticoagulation with respect to 
bleeding and circuit longevity in AKI patients treated with CRRT.[9-11] 
The mechanism underlying the efficacy of citrate as an extracorporeal anticoagulant is 
chelation of calcium, an integral physiologic component of the clotting cascade. During 
CRRT with RCA, delivery of citrate to the “arterial” blood prior to the CRRT filter 
results in chelation of calcium, rendering blood passing through the filter effectively 
anticoagulated. After blood leaves the filter in the “venous” bloodline, the anticoagulant 
effect is reversed when the citrate containing blood is returned to the patient. The ionized 
calcium levels in the patient are maintained within normal levels by a calcium infusion.  
Due to the pivotal role played by calcium, frequent monitoring of both systemic (patient) 
and post-filter blood ionized calcium (iCa) concentrations is typically performed during 
RCA. Post-filter blood iCa concentration is considered an appropriate surrogate for 
assessing the level of anticoagulation achieved. 
Continuous renal replacement therapy comprises several different therapies used 
primarily for the management of AKI patients. These therapies differ with respect to the 
primary mechanism for solute removal (ie, diffusion and/or convection). The modality to 
be applied in this trial will be continuous venovenous hemodiafiltration (CVVHDF) in 
which solute clearance occurs by both diffusion and convection, achieved by the use of 
dialysate and replacement fluid, respectively. Prismocitrate 18 will serve as a 
replacement and anticoagulation solution containing citrate as both an anticoagulant and 
buffer source, the latter being necessary for the treatment of metabolic acidosis that 
routinely accompanies AKI or other serious conditions.[12] In CVVHDF, use of a 
cleared bicarbonate-containing dialysate not only provides additional solute clearance but 
also specifically affords the capability to modulate acid-base balance with changes in 
dialysate flow rate or composition. 


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1.2 Benefits and Risks for the Study Population 
Since RCA has been demonstrated in controlled trials to decrease the risk of bleeding in 
comparison to heparin, participating patients may benefit in this respect.[9,10] Moreover, 
the patient’s participation may demonstrate clinical benefits associated with RCA’s 
ability to increase delivery of the prescribed CRRT dose (relative to no anticoagulation). 
Foreseeable risks for the patients receiving Prismocitrate 18 mainly pertain to the changes 
that may occur in electrolyte and acid-base balance in association with RCA. However, 
specific aspects of the protocol are designed to mitigate these risks. The main risk to the 
Control Group in which no anticoagulation will be used is shortened filter life due to 
filter and extracorporeal circuit clotting, potentially resulting in patient blood loss and a 
lower delivery of the prescribed dose of CRRT due to more frequent treatment 
interruptions. 
Foreseeable risks related to the use of the Prismaflex® System for Prismocitrate 18 
treatment include operational errors related to patient preparation, line or bag 
connections, machine settings, bag handling, and bag contents. These risks have been 
addressed within the study protocol, investigator brochure, operator manuals, and 
training. Additionally, these risks will be minimized with the inclusion of the training 
assessment secondary endpoint by which user groups will be trained on the use of 
Prismocitrate 18 in CRRT and their understanding will be assessed prior to their use of 
the Prismaflex® System for Prismocitrate 18 treatment in the clinical trial setting. These 
risks will undergo monitoring and mitigation activities throughout the duration of the 
study. 
1.3 Study Sponsor 
Gambro AB, the manufacturer of Prismocitrate 18, was acquired by Baxter Healthcare 
Corporation in 2013. Baxter Healthcare Corporation is the sponsor of this study. 
2. STUDY OBJECTIVES 
2.1 Primary Objective(s) 
The primary objective of this study is to evaluate the efficacy of Prismocitrate 18 in 
prolonging extracorporeal circuit life in patients treated with CRRT. The Control Group 
will be patients receiving CRRT with no anticoagulation. 
2.2 Secondary Objective(s) 
The secondary objectives of this study are to evaluate the efficacy of Prismocitrate 18 in 
achieving appropriate anticoagulation through assessments of systemic and post-filter 


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blood iCa concentrations, and to evaluate the efficacy of using Prismocitrate 18 in 
delivering the prescribed CRRT dose, with delivered dose based on total (daily) effluent 
volume and expressed as mL/kg/hour. Additionally, the safety profile will be evaluated 
through assessments of metabolic parameters, including serum bicarbonate, pH, base 
excess, iCa, total calcium, magnesium, chloride, and other relevant serum electrolytes 
along with anion gap. The potential for the development of citrate accumulation will be 
evaluated specifically through assessments of the total calcium/iCa ratio (both 
measurements in mmol/L), anion gap and base excess (along with pH).[13] Finally, the 
potential for bleeding events (number, location, duration), and the number and type of 
blood transfusions along with the number of units infused will also be assessed. 
From the functional perspective, another secondary objective is to complete training on 
administration of Prismocitrate 18 and demonstrate the understanding of the user groups 
on how to use the solution by passing an assessment at the end of training. The user 
groups who need to be assessed prior to use of Prismocitrate 18 in the clinical trial setting 
will be comprised of physicians, nurses, and other clinicians who may be part of 
prescribing, initiating, or modifying treatment during the 120 hour Treatment Period. 
3. INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan 
This study is a multi-center, prospective, non-blinded, one to one randomized study. A 
total of 160 adult patients, 80 in each study arm, will be enrolled at up to 
15 investigational sites in the United States (US) and Canada. Patients meeting all of the 
inclusion criteria and none of the exclusion criteria of this protocol, and deemed treatable 
by either CRRT with Prismocitrate 18 solution or CRRT with no systemic 
anticoagulation, are eligible for enrollment in the study. If a patient is already receiving 
standard-of-care CRRT, they must be randomized within 24 hours of initiation of their 
standard-of-care CRRT. All patients will be treated with predilution CVVHDF as the 
study CRRT modality. Patients enrolled in the study will receive either Prismocitrate 18 
anticoagulation or no systemic anticoagulation during their study CRRT, and 
extracorporeal circuit life will be monitored for up to 120 hours of study CRRT 
(Treatment Period). During the Treatment Period, the adequacy of anticoagulation in the 
Prismocitrate 18 patients will be assessed by monitoring extracorporeal circuit pressures 
and by assessment of systemic and post-filter blood iCa concentrations. Patients will be 
monitored for acid-base parameters and serum electrolytes at baseline prior to any 
CRRT), initiation (after randomization but before the initiation of study CRRT) and at 
pre-determined intervals during treatment. Information on bleeding events (number, 
location, duration) and the number and type of blood transfusions along with the number 


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of units infused will also be collected. During the Treatment Period, the patient will be 
monitored at baseline and as detailed in Section 7.  
See Appendix 1, Blood Sampling Schedule and Appendix 2, Schedule of Events Table. 
3.2 Rationale for Study Design and Control Group 
During meetings with the US Food and Drug Administration (FDA) and with 
 
 both regulatory authorities determined the existing literature data are 
insufficient to support a New Drug Application/Submission and advised that a 
prospective clinical study was needed to demonstrate the effectiveness and safety of 
Prismocitrate 18. In the meetings with the FDA, an endpoint for an eventual clinical trial 
was clarified and it was agreed that extracorporeal circuit life would be considered an 
acceptable efficacy endpoint. Moreover, it was determined that the Control Group in the 
randomized controlled trial would receive no anticoagulation during CRRT. The decision 
to avoid systemic heparinization in the Control Group was based largely on recent 
controlled studies showing an increased bleeding risk with heparin anticoagulation (vs 
citrate) in CRRT patients.[3,4,6-8,14] This study will be performed under a FDA-
authorized Investigational New Drug Application (IND). 
This study will also be conducted at a study site(s) in Canada. For the Canadian site(s), 
this study will be performed under a 
 
3.3 Selection of Study Sites 
This clinical trial will be conducted at up to 15 clinical trial sites in the US and Canada. 
The participating physicians, nurses and clinicians at these sites must have experience 
using citrate anticoagulation for CRRT with the Prismaflex device.  
3.4 Study Duration 
The anticipated duration of the clinical trial is approximately 4 years from the first patient 
enrolled to the last patient complete. 
Individual patients will participate in the study for up to 35 days with a study treatment 
period of up to 120 hours of study CRRT post-randomization. At the conclusion of study 
treatment, patient adverse events and serious adverse events will be collected for a period 
of 30-days. 
3.5 Study Product and Material 
Prismocitrate 18 is an investigational CRRT solution developed by the Sponsor and 
provided to the participating sites for use as a replacement solution containing an 


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anticoagulant to prevent clotting of the extracorporeal circuit. All other solutions used for 
standard-of-care CRRT are to be provided by the investigational site. 
Prismocitrate 18 Solution contains standard electrolytes (sodium and chloride) and 
citrate. 
Table 1 shows Composition of Prismocitrate 18. 
Table 1. Prismocitrate 18 
Name of the Substance 
Quantity for Prismocitrate 18 (g/L) 
Sodium chloride 
5.03 
Sodium citrate 
5.29 
Composition 
Prismocitrate 18 (mmol/L) 
Citrate 
18 
Sodium 
140 
Chloride 
86 
Water for injections to 1,000 mL. 
Hydrochloric acid for pH adjustment. 
Theoretical Osmolarity=244 mOsm/L and pH≈7.4. 
 
Prismocitrate 18 acts as both an anticoagulant for the extracorporeal circuit and a 
replacement solution to compensate for water and electrolytes removed in the filter 
effluent and achieve solute clearance through convection. Therefore, this solution would 
be indicated for continuous venovenous hemodiafiltration (CVVHDF). The pre-filter 
infusion rate of Prismocitrate 18 (based on its citrate concentration) is indexed to the 
blood flow rate (BFR) to achieve a target blood citrate concentration of 3 - 5 mmol/L of 
blood, manifested as a post-filter blood iCa concentration of < 0.4 mmol/L. Moreover, 
the rate of calcium reinfusion is guided by a target systemic blood iCa of 0.9 -
1.3 mmol/L. In the protocol, specific instructions regarding prescription adaptations to 
achieve these targets will be provided in Section 5.2.1. 
In addition to its role as a replacement solution and anticoagulant, Prismocitrate 18 also is 
a buffer source through the metabolism of citrate to bicarbonate by the patient. Therefore, 
the prescription of Prismocitrate 18 is made according to the patient’s fluid removal 
requirements, additional fluid inputs and outputs, and the desired acid-base and 
electrolyte balances. Moreover, Prismocitrate 18 is prescribed relative to the flow rates of 
the other therapeutic fluids used during CRRT (replacement fluid and/or dialysate). A 


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dedicated anticoagulation pump and infusion line, incorporated into the CRRT system 
and extracorporeal circuit, respectively, are required for the administration of 
Prismocitrate 18. 
3.6 Commercial Product Provided by Sponsor 
The Sponsor will loan each investigational site at least one Prismaflex System Control 
Unit with Version 7.xx Software. This loaner machine will be used with study patients 
only. An investigational site has the option to decline the loaner machine and use their 
institution’s Prismaflex System Control Unit(s) with Version 7.xx Software. In addition, 
the Sponsor will provide each investigational site with commercially available 
Prismaflex M150 Sets for delivery of CRRT for all patients in the study (Prismocitrate 
Group and Control Group). 
4. STUDY POPULATION SELECTION 
4.1 Study Population 
The study will include 160 adult patients with AKI or other serious conditions who 
require CRRT. These patients are critically ill and may require a legally-authorized 
representative to make medical decisions and provide informed consent on their behalf. 
Patients must meet all the inclusion criteria and not meet any of the exclusion criteria 
defined for this study. 
4.2 Inclusion Criteria 
Each patient must meet the following inclusion criteria to be enrolled in this study. 
1. Patient, or legally-authorized representative, has signed a written informed 
consent form (ICF). 
2. Patient must be receiving medical care in an intensive care unit (ICU) [eg, 
medical ICU, surgical ICU, cardiothoracic ICU, Trauma ICU, Mixed ICU, other]. 
3. Patient age ≥ 18 years. 
4. Adult patients with AKI or other serious conditions who require treatment with 
CRRT. 
5. Patients are expected to remain in the ICU and on CRRT for at least 72 hours 
after randomization. 
6. Patients already receiving standard-of-care CRRT must be randomized within 
24 hours of initiation of their standard-of-care CRRT. 
 


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4.3 Exclusion Criteria 
Patients who meet any of the following exclusion criteria will be excluded from the 
study. 
1. Patients requiring systemic anticoagulation with antithrombotic agents for reasons 
other than CRRT. The exception is patients receiving subcutaneous heparin for 
deep vein thrombosis prophylaxis according to institutional practice or patients on 
aspirin may be enrolled. 
2. Patients in whom citrate anticoagulation is contraindicated such as patients with a 
known allergy to citrate or who have experienced adverse events associated with 
citrate products including patients with a prior history of citrate toxicity or 
patients with uncorrected severe hypocalcemia (whether in the context of current 
citrate administration or due to the underlying disease state). 
3. Patients who are not candidates for CRRT. 
4. Patients who are receiving extracorporeal membrane oxygenation (ECMO) 
therapy.  
5. Patients with severe coagulopathy [ie, platelets < 30,000/mm3, international 
normalized ratio (INR) > 2, partial thromboplastin time (PTT) > 50 seconds]; 
including severe thrombocytopenia (platelets < 30,000/mm3), HIT (heparin 
induced thrombocytopenia), ITP (idiopathic thrombocytopenia purpura), and TTP 
(thrombotic thrombocytopenia purpura) should not be enrolled in the trial. 
6. Patients with fulminant acute liver failure or acute on chronic liver failure as 
documented by a Child-Pugh Liver Failure Score > 10. 
7. Patients with refractory shock associated with persistent, worsening lactic acidosis 
(lactate > 4 mmol/L).  However, patients with improving subsequent serum 
lactate levels may be enrolled.   
8. Patients unlikely to survive at least 72 hours. 
9. Female patients who are pregnant, lactating, or planning to become pregnant 
during the study period. Note: A female patient of childbearing potential, defined 
as a woman less than 55 years old who has not had partial or full hysterectomy or 
oophorectomy, must have a negative serum beta human chorionic gonadotropin 
(β-hCG) pregnancy test during the screening period (after consent and prior to 
randomization) and before CRRT treatment begins. A female patient of 


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childbearing potential must use medically acceptable means of contraception 
during their participation in the study. 
10. Patients who are currently participating in another interventional clinical study. 
11. Patients with a medical condition that may interfere with the study objectives. 
 
4.4 Removal of Patient from Therapy, Assessment, or Study 
Patients are considered withdrawn/prematurely discontinued from the study if their 
participation is discontinued before completion of the required evaluations as specified in 
the protocol Section 6.5. However, only the patient’s individual treatment will be 
interrupted and the study will continue. Patients may be withdrawn/prematurely 
discontinued from the study for any of the following reasons: 
1. Adverse event (AE) or serious adverse event (SAE). 
2. Protocol violation/deviation (ie, the patient failed to meet protocol entry criteria or 
did not adhere to the protocol requirements). 
3. Pregnancy. 
4. Voluntary withdrawal (ie, patient’s request). 
5. Termination of the study. 
6. Investigator’s discretion. 
7. Death. 
8. Other [with reason noted on the electronic case report form (eCRF)]. 
 
The Investigator may terminate a patient’s study participation at any time during the 
study if he/she judges it to be in the patient’s best interest. If a patient is withdrawn from 
the study, the Study Monitor must be informed in the shortest possible time, regardless of 
the reason for withdrawal. In addition, a patient may discontinue his or her participation 
at any time during the study. If a patient’s participation is discontinued, the reason(s) 
must be recorded in the source documents and on the eCRFs. If a patient discontinues for 
any reason, every effort should be made to perform all of the procedures that are 
scheduled for the End of Treatment visit. Patients who are withdrawn from the study will 
not be replaced. In addition, all SAEs, related or not, will be followed post-study 
treatment period for 30 days and until stabilized, resolved, or returned to baseline. 
The patient’s individual treatment will be interrupted but the study will continue if an 
event occurs that is considered by the investigators and/or the Sponsor as possibly 


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leading to a deficiency in the patient's treatment and is related to the use of 
Prismocitrate 18. 
4.5 Recruitment 
Country level recruitment for the study will start in the US after FDA authorization of the 
IND and the Institutional Review Board (IRB) approvals at respective study sites and in 
Canada after 
 authorization of the CTA and the Research Ethics Board (REB) 
approvals at respective study sites. 
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. The patient’s consent must be documented via signature and date on the 
Patient ICF. Patients will be considered in screening for the study after the ICF has been 
signed. For patients who are unable to provide informed consent themselves, a legally-
authorized representative consent is appropriate. 
5. STUDY TREATMENT(S) 
5.1 Enrollment 
All patients who sign an ICF will be assigned a Subject ID number. Those patients who 
are confirmed to meet the inclusion/exclusion criteria will be considered enrolled 
patients. Enrolled patients will be randomized to one of two treatment arms 
(Prismocitrate Group or Control Group) in a 1:1 manner using a site-stratified central 
randomization scheme. 
5.2 Treatment Administered 
All patients in this study will be treated with the Prismaflex System Control Unit with 
Version 7.xx Software and the disposable Prismaflex M150 Set. The patients will be 
followed post-randomization for up to 120 hours from the initiation of study CRRT. This 
120 hour post-randomization period will be referred to as the Treatment Period. At the 
time of randomization, if a patient is currently receiving CRRT, the standard-of-care 
CRRT extracorporeal circuit will be replaced with a new Prismaflex M150 Set. During 
the Treatment Period, patients will be treated up to 120 hours of study CRRT with either 
Prismocitrate 18 or no systemic anticoagulation. “Baseline” during the Treatment Period 
is defined as prior to any CRRT therapy, “Initiation” is defined as after randomization but 
before the initiation of study CRRT. Initiation may occur at the same time point as 
baseline, should enrollment and randomization occur prior to any CRRT therapy. 
Following data points will be collected during study CRRT for the duration of the 
Treatment Period: 


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• Extracorporeal circuit pressures will be measured and recorded by the Prismaflex 
System device in real time. The end of the extracorporeal circuit life will be 
defined by the occurrence of one or both of the following Prismaflex System 
alarms/conditions, if the alarms cannot be mitigated. At this point study CRRT 
will be terminated and the extracorporeal circuit replaced, because  mitigation of 
the following alarms is not possible: 
- 
“Warning: Filter Clotted” , and/or 
- 
"Advisory TMP Too High" 
Note: The nurse at the clinical site will document the alarm and rationale to stop 
treatment on the eCRF. In addition, the Prismaflex logging information from the 
data cards (one card per patient) will be collected on an ongoing basis and 
anonymized data will be sent to Baxter for technical analysis. An Independent 
Adjudicator will make the final determination of the alarm cause (see Section 9.9 
Primary Endpoint Adjudication). 
• Serum bicarbonate and pH will be measured at baseline, initiation of study CRRT, 
at 6 hour intervals and at 120 hours or end of the Treatment Period (see Appendix 
1). 
• For measurement of delivered dose, daily effluent volume (in mL) will be 
recorded from the Prismaflex System history screen. In the Prismaflex software, 
the starting time for the charting interval will be set (eg, at 8:00 am) and the 
volumes and doses will be stored for each day starting at that time. The effluent 
volume together with the patient's weight will be used to calculate delivered dose 
(mL/kg/hour). Note that daily weight will need to be obtained and 
recorded/entered each morning (eg, at 8:00 am) in the “System Tools” screen for 
determination of both prescribed and delivered dose as part of standard clinical 
practice for each patient receiving CRRT. 
• For both study arms - Systemic ionized blood calcium concentrations will be 
measured at baseline and initiation, 1 hour after initiation of CRRT 
(post-randomization) and then at 6 hour intervals up to 120 hours of CRRT (see 
Appendix 1).  
• For the Prismocitrate 18 Arm, the systemic ionized calcium must be measured 
1 hour prior to the initiation of study CRRT. If initiation ionized calcium is 
less than 0.9 mmol/L, the investigator must correct the serum level to greater 


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than 0.9 mmol/L in order to begin CRRT. This corrected systemic ionized 
calcium will be considered the patient’s initiation value (see Appendix 1). 
• For Prismocitrate 18 Arm Only - Post-filter blood iCa will be measured 1 hour 
after initiation of CRRT (post-randomization) and then at 6 hour intervals up to 
120 hours of CRRT (see Appendix 1). 
• Blood total calcium concentrations will be measured at baseline, initiation, 1 hour 
and every 6 hours during the 120 hour Treatment Period and at 120 hours or end 
of the Treatment Period from the initiation of study CRRT in each. In conjunction 
with simultaneous systemic iCa concentrations, the total calcium/iCa ratio (both 
measurements in mmol/L) will be determined (see Appendix 1). 
• Serum electrolytes (sodium, potassium, chloride, phosphate, and magnesium, 
anion gap) and base excess will be measured at baseline, initiation and at 6 hour 
intervals of study CRRT (post-randomization) up to 120 hours (see Appendix 1). 
• Blood urea nitrogen (BUN) and serum creatinine measurements will be measured 
at baseline, initiation and twice daily (post-randomization) up to 120 hours of 
study CRRT (see Appendix 1). 
• Partial thromboplastin time (PTT), prothrombin time [(PT); PT/INR], 
hemoglobin/hematocrit and platelet count will be measured at baseline, initiation 
and at least once daily (post-randomization) up to 120 hours of study CRRT (see 
Appendix 1). 
• Liver function tests are to be measured at baseline, initiation and then as 
determined by local standard-of-care (see Appendix 1). 
 
During the Treatment Period, if a Prismaflex M150 Set clots or reaches an unacceptable 
circuit pressure as indicated by machine alarms/conditions, it will be replaced. The 
Prismaflex M150 Set will also be replaced after 72 hours of continuous use 
(ie, "Advisory Time to Change Set") or any time the patient (prior to 72 hours of use) 
must temporarily stop CRRT (eg, CT scan, etc.). In these cases, the filter set will be 
replaced before continuing CRRT. 
Treatments will be performed according to this clinical protocol and in conjunction with 
the Operator's Manual for the Prismaflex System (Version 7.xx Software) and the 
Instructions for Use (IFU) for the Prismaflex M150 Set, respectively. Study sites, 
especially those who do not currently use the Prismaflex M150 Set, should carefully 
review the Prismaflex M150 Set IFU “Warnings” section #3 and “Hypersensitivity 


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Reactions” section as special attention must be paid to patients receiving ACE inhibitors 
and/or having already shown similar hypersensitivity reactions. The Principal 
Investigator (PI) or a trained healthcare professional must be present at all times during 
CRRT to immediately address and manage any clinical concerns or other issues. All 
recommendations and warnings mentioned in the Operator's Manual and IFU shall be 
strictly followed. 
Recommendations for the initial flow rates in the experimental arm of Prismocitrate 18, 
post-dilution replacement solution, and dialysate are provided to the investigator (refer to 
Section 5.2.2.2). However, according to the clinical manifestations and needs of the 
patient, the local standard-of-care for CRRT may be instituted based upon the 
investigator’s medical judgement. For the control arm, investigators are advised to use 
standard-of-care practices per their local institution. However, all such prescription data 
must be recorded on the eCRFs and adhere to the following general guidelines in both 
arms of the trial: 
• Modality must be CVVHDF 
• Minimum prescribed CVVHDF dose (based on total effluent 
volume) - 25 mL/kg/hour. 
• Minimum BFR – 100 mL/minute. 
• Experimental Arm - Maximum BFR – 200 mL/minute. 
• Control Arm - Maximum BFR – 400 mL/minute. This maximum BFR allows 
centers to follow their local standard-of-care procedures related to higher BFR use 
in non-anticoagulated circuits 
• Minimum post-filter replacement fluid rate of 200 mL/hour for de-aeration 
chamber 
• Minimum pre-blood pump infusion of 1000 mL/hour (either citrate or 
replacement fluid depending on the study arm) 
 
5.2.1 Cross-Over Patients 
During the course of this clinical trial the assigned arms (Prismocitrate Group or Control 
Group) must be maintained for the duration of the study CRRT treatment if at all 
possible. Based on the controlled design of this study, the cross-over of patients is not 
allowed.  


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5.2.2 Study Arm Protocols 
Participating investigator sites will use the following general guidelines for CRRT: 
• Modality must be CVVHDF 
• Minimum prescribed CVVHDF dose (based on total effluent 
volume) - 25 mL/kg/hour. 
• Minimum BFR – 100 mL/minute. 
• Experimental Arm - Maximum BFR – 200 mL/minute. 
• Control Arm - Maximum BFR – 400 mL/minute. This maximum BFR allows 
centers to follow their local standard-of-care procedures related to higher BFR use 
in non-anticoagulated circuits 
• Minimum post-filter replacement fluid rate of 200 mL/hour for de-aeration 
chamber 
• Minimum pre-blood pump infusion of 1000 mL/hour (either citrate or 
replacement fluid depending on the study arm) 
5.2.2.1 Initial Prescription Orders for Control Arm 
For the control arm, investigators are advised to use the general guidelines listed in 
Section 5.2.2 in combination with the standard-of-care practices per their local institution. 
5.2.2.2 Initial Prescription Orders for the Prismocitrate 18 Arm 
This initial prescription only applies to patients randomized to the Prismocitrate 18 Arm. 
• Blood Flow Rate (QB): 100 to 200 mL/minute. 
• The anticoagulant/replacement solution to be used is Prismocitrate 18, which at 
final concentration will provide: 140 mmol/L sodium, 86 mmol/L chloride, 
18 mmol/L citrate. 
• Minimal Initial Flow rate (mL/hour) of Prismocitrate 18 (delivered from the 
Prismaflex System PBP scale by the PBP pump): 1000 mL/hour. 
- 
The flow rate can be titrated by 100 mL/hour increments to maintain post-
filter blood iCa levels < 0.4 mmol/L. 
 
Rinse and prime the Prismaflex M150 Set according to the IFU. No heparin containing 
solutions should be used for priming. 


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After the initial citrate protocol prescription, the general guidelines outlined in Section 
5.2.2 should be followed. 
5.2.2.2.1 Effluent Rate 
Total effluent rate (QE) (mL/hour) = Pre-blood pump (PBP) infusion rate (QPBP) + Post-
dilution replacement fluid rate (QR) + Dialysate rate (QD) + patient fluid removal rate 
(QFR). 
• QPBP corresponds to the infusion rate of Prismocitrate 18. 
• As specified in the Prismaflex M150 Set IFU, post-filter replacement fluid should 
be prescribed according to institutional practice for proper functioning of the de-
aeration chamber. The use of a calcium-containing post-dilution solution is not 
recommended. 
• To calculate the hourly effluent rate to be prescribed, assume the effluent rate is a 
surrogate for the daily CRRT dose and the minimum prescribed dose is 
25 mL/kg/hour with a minimum target delivered dose of 20 mL/kg/hour per 
24 hours dose of treatment for both groups. 
• The required effluent rate (mL/hour) can then be calculated by multiplying the 
patient weight (in kg) at the time of CRRT initiation by the target prescribed dose. 
• For example, a 90 kg patient would require a total effluent rate of 2,250 mL/hour 
(90 kg x 25 mL/kg per hour). While adjustments in the infusion rates of 
Prismocitrate 18, post-dilution replacement solution, and dialysate can be titrated 
to meet the desired metabolic and anticoagulation requirements for the patient, the 
total effluent rate should not appreciably change, with maintenance of a minimum 
prescribed dose of 25 mL/kg/hour. 
 
5.2.2.2.2 Blood Flow Adjustments 
Based on the anticoagulation and metabolic requirements of the patient, a change in BFR 
should prompt consideration of the need for concomitant changes in the citrate infusion, 
post-dilution replacement fluid, and dialysate rates (as described in Section 5.2.2.2.1). 
5.2.2.2.3 Dialysate Fluid Orders 
• Ensure the dialysate contains no calcium. 


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5.2.2.2.4 Calcium Fluid Orders 
5.2.2.2.4.1 Calcium Gluconate Fluid Orders 
Calcium gluconate, 38.75 mmol/L (1 amp: 4.65 mEq or 93 mg elemental calcium) in 
500 mL of normal saline 0.9%; IV Infusion, 60 mL/hour. The actual calcium calculations 
applied will be based on current standard-of-care for patients receiving CRRT. 
REQUIRED: 
• Maintain systemic blood iCa levels between 0.9 and 1.3 mmol/L. 
• Monitor blood iCa level 1 hour after initiation and then every 6 hours, and adjust 
as needed to maintain post-filter blood iCa < 0.4 mmol/L. 
• Post-filter blood iCa levels can be measured from the post-filter blood sample port 
(blue in color) located on the return line of the Prismaflex M150 Set; this level 
can be used to guide the Prismocitrate infusion rate. 
• Potassium, phosphorus, and magnesium should be replaced separately, as needed. 
 
**Calcium infusion should stop if CRRT is stopped. 
5.2.2.2.4.2 Calcium Chloride Fluid Orders 
Calcium chloride 108.8 mEq in 1 L of normal saline 0.9% (note-total bag volume is 
1080 mL); IV Infusion, 60 mL/hour. The actual calcium calculations applied will be 
based on current standard-of-care for patients receiving CRRT. 
REQUIRED: 
• Maintain systemic blood iCa levels between 0.9 and 1.3 mmol/L. 
• Monitor blood iCa level from patient 1 hour after initiation and then every 
6 hours, and adjust as needed to maintain post-filter blood iCa < 0.4 mmol/L. 
• Post-filter blood iCa levels can be measured from the post-filter blood sample port 
(blue in color) located on the return line of the Prismaflex M150 Set; this level 
can be used to guide the Prismocitrate infusion rate. 
• Potassium, phosphorus, and magnesium should be replaced separately, as needed. 
 
**Calcium infusion should stop if CRRT is stopped. 


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5.2.2.3 Continuous Renal Replacement Therapy Dialysate 
Sites will be instructed to use only commercially available standard CRRT sterile 
dialysate solutions having a density similar to saline solutions (close to 1) with the 
Prismaflex System. Dialysate formulation and flow rate are prescribed in accordance with 
the patient’s clinical needs and each institution’s standard clinical practice for CRRT.  
For the Prismocitrate 18 Arm, the dialysate should have a bicarbonate concentration that 
accounts for the significant buffer load provided by Prismocitrate. Study sites will also 
ensure that the dialysate contains no calcium in the Prismocitrate 18 Arm. 
5.2.2.4 Continuous Renal Replacement Therapy Replacement Fluids/Solutions 
In the Prismocitrate 18 Arm, both Prismocitrate 18 and an intravenous-quality solution 
infused post-dilution will serve as the replacement fluids/solutions. Prismocitrate 18 will 
be delivered to the extracorporeal circuit by the Prismaflex System PBP via the PBP 
infusion line. The use of a calcium-containing post-dilution solution is not recommended 
in the Prismocitrate 18 Arm.  
For the Control Group, replacement fluids (including one infused post-dilution) should be 
prescribed according to institutional practice at the investigative site. 
5.2.2.5 Anticoagulants and Dosing/Administration of Prismocitrate 18 
Either Prismocitrate 18 or no systemic anticoagulant will be used in this study. 
Prismocitrate 18 will be infused at a minimal initial rate of 1000 mL/hour. The rate will 
be titrated to maintain post-filter blood iCa levels < 0.4 mmol/L. 
5.2.3 Monitoring of Therapy 
Systemic iCa levels will be measured at baseline, initiation, and systemic and post-filter 
blood iCa levels will be measure 1 hour after initiation of study CRRT 
(post-randomization) and then every 6 hours thereafter and at 120 hours or end of 
Treatment Period. The pH and bicarbonate should be measured at baseline, initiation, and 
every 6 hours during the 120 hour Treatment Period and at 120 hours or end of Treatment 
Period. Health care professionals managing the patient should be instructed to notify the 
clinician immediately if the serum pH is < 7.20 or > 7.45, serum bicarbonate is < 15 or 
> 35 mmol/L, and/or the systemic blood iCa is < 0.9 or > 1.3 mmol/L. 
Citrate metabolism may be impaired in patients with moderate to severe liver failure. The 
additional steps outlined below are needed to monitor specifically for the potential 
development of citrate accumulation, not only in these patients but in the entire study 


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population. Blood total calcium concentrations will be measured at baseline, initiation, 
1 hour and every 6 hours during the 120 hour Treatment Period and at 120 hours or end 
of the Treatment Period from the initiation of study CRRT. In conjunction with 
simultaneous systemic iCa concentrations, the total calcium/iCa ratio (both measurements 
in mmol/L) will be determined as an indicator of citrate accumulation and health care 
professionals managing the patient should be instructed to notify the clinician for any 
value above 2. 1. Moreover, based on the clinical judgement of the managing physician, 
this threshold value should also prompt an immediate CRRT prescription change 
designed to correct the metabolic disturbance. One of the following prescription changes 
should occur: 
• Decrease in the Prismocitrate infusion rate; or 
• Increase in the BFR; or 
• Increase in the dialysate flow rate 
 
The effect of one of these changes should be assessed with ongoing monitoring of 
relevant clinical and laboratory parameters - if improvement does not occur within two 
(2) hours, the Prismocitrate infusion should be stopped. 
When a total calcium/iCa ratio of more than 2.1 is reported, any one of the following 
abnormalities reported concurrently should heighten the clinical suspicion of citrate 
accumulation and reinforce the need to undertake the steps outlined above: 
• Decrease in iCa concentration to less than 1.1 mmol/L (despite adequate calcium 
compensation).Decrease in pH to value less than 7.20 or decrease in base excess 
(threshold value: -5 mmol/L). 
• Increase in anion gap to more than 11 mmol/ L 
 
Serum electrolytes (sodium, potassium, chloride, bicarbonate, phosphate, magnesium and 
anion gap) and base excess should be recorded at baseline, initiation, every 6 hours 
during the 120 hour Treatment Period and at 120 hours or end of Treatment Period. 
Coagulation parameters, hemoglobin, and hematocrit will be recorded at least once daily. 
5.3 Selection and Timing of Dose for Each Patient 
The timing and dose of the Prismocitrate infusion for the Prismocitrate Group will be 
prescribed and adjusted for each patient during the 120 hour Treatment Period per 
Section 5.2 


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5.4 Method of Assigning Patients to Treatment Groups 
All enrolled subjects will be randomized to one of two treatment arms (Prismocitrate 
Group or Control Group) in a 1:1 manner using a site-stratified central randomization 
scheme. 
5.5 Blinding 
This is an open-label study that will not utilize blinding of the investigational drug. The 
study site team will be made aware of the treatment assignment at randomization. The 
study site team will be instructed to document the randomization assignment in source 
documents and follow their local procedure(s) to ensure their study patients receive their 
appropriate treatment. 
5.6 Packaging and Labeling 
For this clinical trial, investigational Prismocitrate 18 will be provided by the sponsor and 
will come packed in 5 L bags. All other solutions used in the management and care of 
patients in the trial will be provided by the local institution. Each bag will be labeled with 
a production lot number for product accountability.  
Each Prismocitrate 18 product will be labeled according to local regulations. The US 
product will be labeled per Title 21 of the Code of Federal Regulations (CFR) Part 312.6 
and Part 201. The Canadian product will be labeled per Part C, Division 5 of the 
Canadian Regulations. 
All labels in the US will include the investigational statement: 
"Caution: New Drug--Limited by Federal (or United States) law to investigational use."  
All labels in Canada will include the investigational statement: 
“CAUTION: New Drug – Limited by Federal Law to investigational use. To be used by 
qualified investigator only. Mise en garde: Nouveau medicament – Utilisation limitée à 
des fins de recherche par la loi fédérale. Doit être administer uniquement par des 
investigateurs qualifies.” 
5.7 Storage and Accountability 
All investigational drug and clinical supplies will be manufactured, handled, stored, and 
provided to patients in accordance with Good Manufacturing Practice (GMP) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice 
(GCP). 


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The investigators at each site will be supplied with the investigational product (IP), 
Prismocitrate 18, to be investigated during this clinical study. Prismocitrate 18 will be 
stored according to product label specifications, or other specific directions provided by 
the Sponsor. 
Prismocitrate 18 must be stored in a locked area with restricted access. Prismocitrate 18 
must only be used to treat patients enrolled in the study and randomized to the 
Prismocitrate Group under the sole supervision of the investigator. 
The PI (or delegated person) at each site is solely responsible for keeping records of 
documents according to the following requirements: 
• Date, quantity and lot numbers of Prismocitrate 18 units received by the 
investigator at the study site. 
• Date, lot numbers and patient assignment of Prismocitrate 18 dispensed by the 
investigator. 
• Lot numbers of damaged or destroyed Prismocitrate 18. 
 
At each visit, the Study Monitor must ensure that the investigator has sufficient number 
of Prismocitrate 18 units at his/her disposition and that the Prismocitrate 18 is being used 
according to site requirements. 
5.8 Investigational Product Destruction 
If the IP, Prismocitrate 18, is determined to be unacceptable for initial or continued use, it 
shall be destroyed on site in accordance with the site’s SOPs and replaced. The clinic 
coordinator will notify the Sponsor or its designee to arrange  for delivery of replacement 
IP.  
All IP will be reconciled and accounted for throughout the study. The study monitor will 
verify that all unused  IP has been destroyed during the site close out visit. Additionally, 
at the conclusion of the study, records of all IPs delivery, inventory, dispensation, return, 
destruction, and disposition will be collected from the investigational site. If the 
investigational site procedures do not allow for IP destruction on site, the study monitor 
will arrange for the return of all unused IP.  


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6. STUDY PROCEDURES 
6.1 Informed Consent 
Patients or their legally-authorized representative will sign an ICF for the clinical study. 
As part of the consenting process, each ICF will be reviewed with the prospective study 
participants or their legal representatives, and an investigator will be available to answer 
questions regarding procedures, risks, and alternatives. The PI or his/her entitled designee 
will obtain a signed ICF from each patient or from the patient’s legally-authorized 
representative or designee as defined by local law. Informed Consent Forms will be 
obtained before any protocol-specific procedures are performed. 
The PI should allow the time necessary for the patient or the patient's legally-authorized 
representative to inquire about the details of the study after which the ICF must be signed 
and personally dated by the patient or by the patient's legally-authorized representative 
and by the person who conducted the informed consent discussion. The patient or a 
legally-authorized representative should receive a copy of the signed ICF and any other 
written information provided to the study patient. Only patients with the initial intention 
to complete the study should be considered for entry into the study. 
The Sponsor will provide a template ICF which includes all GCP required elements. 
Preparation of the ICFs is the responsibility of the PI and must include all elements 
required by GCP and applicable regulatory requirements and must adhere to GCPs and to 
the ethical principles that have their origin in the Declaration of Helsinki. The language 
must be nontechnical and easily understood. All ICFs will be approved and reviewed by 
the Sponsor prior to IRB/REB review. The PI must furnish the Sponsor or its designee 
with a copy of each IRB/REB-approved ICF to be used in this study prior to the 
commencement of the study. 
6.2 Medical History 
Medical history relevant to the ICU admission for each patient will be obtained during 
Screening. Past and present conditions, as well as surgical procedures, will be recorded 
for the main body systems. Medication history will include all medications taken and/or 
prescribed during the 7-day window prior to informed consent and those relevant to ICU 
admission.. 
6.3 Physical Examination 
Physical examinations will be obtained at the Screening and End of Treatment. Any new 
condition or worsening of a pre-existing condition from Screening will be noted and 
recorded on the AE eCRF page. 


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An attempt should be made to perform a final physical examination on patients who 
complete Screening and enroll, but who discontinue from the study early, particularly if 
the patient is discontinuing from the study because of an AE. 
6.4 Vital Signs 
Vital signs will include measurements of blood pressure, respiratory rate, temperature, 
and pulse rate. These vital signs will be obtained at Screening and at End of Treatment, 
with the exception of blood pressure which is collected at baseline (after randomization 
but before the initiation of study CRRT) and at 6 hour intervals during the Treatment 
Period, as well as at End of Treatment. 
6.5 Clinical Laboratory Tests 
6.5.1 Laboratory Parameters 
Clinical laboratory tests are shown in Appendix 1. 
6.5.2 Sample Collection, Storage, and Shipping 
Sample collection is detailed in Appendix 1. All laboratory samples will be collected, 
stored, shipped and processed by local laboratories according to each site's procedures. 
6.6 Dispensing Study Drug 
Prismocitrate 18 must only be used to treat patients enrolled in the study and randomized 
to the Prismocitrate Group under the sole supervision of the PI. Study drug will be 
dispensed, recorded on source documents, and entered into eCRFs by site personnel as 
authorized by the PI. 
6.7 Efficacy Variables 
6.7.1 Primary Efficacy Endpoint 
The Prismaflex M150 Set extracorporeal circuit life will be assessed as a time-to-event 
endpoint over a maximum 120 hours by the duration of time for which each 
Prismaflex M150 Set can be used continuously over a maximum 72 hour period in each 
patient. The Prismaflex M150 Set will be replaced any time CRRT is stopped during the 
Treatment Period (regardless of duration) or any time a circuit is used for 72 continuous 
hours (ie, "Advisory Time to Change Set"). The end of the extracorporeal circuit life will 
be defined by the occurrence of one or both of the following Prismaflex System 
alarms/conditions if the alarm cannot be mitigated. At this point, study CRRT will be 
terminated and the extracorporeal circuit replaced because mitigation of the following 
alarms is not possible: 


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• “Warning: Filter Clotted”, and/or 
• "Advisory TMP Too High" 
Note: The nurse at the clinical site will document the alarm and rationale to stop 
treatment on the eCRF. In addition, the Prismaflex logging information from the 
data cards (one card per patient) will be collected on an ongoing basis and 
anonymized data will be sent to Baxter for technical analysis. An Independent 
Adjudicator will make the final determination of the alarm cause by examining 
the applicable historical electronic data available surrounding the alarm events 
(see Section 9.9 Primary Endpoint Adjudication). 
 
The extracorporeal circuit life will be censored for cases where the Prismaflex M150 Set 
has been replaced for reasons other than reaching the end of the extracorporeal circuit 
life. Only filters for which the end of the extracorporeal circuit life was reached (ie, one 
or both Prismaflex System alarms/conditions occurred as defined above and alarm causes 
have been confirmed by an Independent Adjudicator) will be considered ‘events’ in terms 
of the statistical analysis. 
6.7.2 Secondary Efficacy Endpoints 
Systemic and post-filter blood iCa concentrations will be assessed at baseline (systemic 
only), initiation (systemic only), 1 hour and every 6 hours during the 120 hour Treatment 
Period and at 120 hours or end of the Treatment Period from the initiation of study CRRT 
in each patient as indications of both the extent of calcium chelation prior to the CRRT 
filter and calcium restoration after the CRRT filter. Post-filter iCa will only be measured 
in the Prismocitrate 18 arm. 
Delivery of the prescribed CRRT dose will be based on the patient’s weight and daily 
recordings of the effluent volume (in mL). These data will be used to calculate delivered 
dose (mL/kg/hour). 
6.8 Safety Assessments 
Safety endpoints include: 
1. Serum bicarbonate and pH will be measured at baseline, initiation and every 
6 hours during the 120 hour Treatment Period and at 120 hours or end of the 
Treatment Period. 


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2. Blood total calcium concentrations will be measured at baseline, initiation, 1 hour 
and every 6 hours during the 120 hour Treatment Period and at 120 hours or end 
of the Treatment Period from the initiation of study CRRT.  
3. Serum electrolytes (sodium, potassium, chloride, phosphate, magnesium, and 
anion gap) and base excess will be measured at baseline, initiation and every 
6 hours during the 120 hour Treatment Period and at 120 hours or end of 
Treatment Period. 
4. As indicators of citrate accumulation (along with pH), the total calcium/iCa ratio 
(both measurements in mmol/L) will be measured at baseline, initiation, 1 hour 
and every 6 hours during the 120 hour Treatment Period and at 120 hours or end 
of Treatment Period, anion gap and base excess will be measured at baseline, 
initiation and every 6 hours during the 120 hour Treatment Period and at 
120 hours or end of Treatment Period. 
5. The number, location and duration of bleeding events during the 120 hour 
Treatment Period will be collected. If a blood transfusion is needed during the 
120 hour Treatment Period, the number and type of transfusions along with the 
number of units infused will be collected. 
6. Change from baseline to final measurement in laboratory and vital signs 
measurements will be collected. 
7. The incidence of adverse events and serious adverse events from the time the 
patient signs the informed consent form (ICF) until the end of the study will be 
collected. 
 
6.9 Analysis of Training on Administration of Prismocitrate 18 
The end users who need to be assessed prior to use of Prismocitrate 18 in the clinical trial 
setting (as delegated by an investigator) will be comprised of physicians, nurses, and 
other clinicians who may be part of prescribing, initiating, or modifying treatment during 
the 120 hour Treatment Period. The assessment materials, 
1407-004 Protocol Training Assessment 2015May26, are provided separate from the 
protocol through a secure access internet site. Additional assessment materials for 
specific end user groups may be provided as needed or as determined by an investigator. 
A descriptive summary of training results on administration of Prismocitrate 18 will be 
provided in the Clinical Study Report following completion of the study. 


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6.10 Adverse Events Assessments 
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a study product, and that does not necessarily have a causal relationship 
with the treatment or drug. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory function), symptom (eg, rash, pain, discomfort, fever, 
dizziness, etc.), organ dysfunction (eg, cardiovascular failure, pancreatitis, etc.), systemic 
illness (eg, sepsis), or outcome of death temporally associated with the use of the study 
product, whether or not the event is considered associated with the study product. 
• Laboratory and vital sign abnormalities qualify as AEs if medical intervention is 
required to treat or address the abnormality, if the patient must be discontinued 
from the study due to the abnormality, or if the value exceeds specific limits 
defined by the standard-of-care as qualifying it as an AE. 
• An elective procedure/surgery that occurs during the course of a study, but is 
being performed for a documented pre-existing condition and was pre-planned 
prior to study entry will not qualify as an AE. If, however, the pre-existing 
condition unexpectedly deteriorates during the study requiring the 
procedure/surgery to be performed earlier than planned, the condition for which 
the procedure/surgery is being performed will qualify as an AE. 
 
Adverse events will be collected starting from the time the patient signs the ICF until 30-
days post study treatment period (end of the study). During the course of the study, the 
Investigator or designee shall monitor each patient for the occurrence of any AE. If an 
AE occurs, a full description of the event should be recorded including the date of onset, 
severity, time course, description, actions taken, and causal relationship of the AE to the 
study product(s). Investigators should review and reference the Causality definitions 
located in Section 6.10.1 when determining the relationship of the AE to the study 
product. The investigators may also discuss the event(s) with the Baxter Medical 
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 throughout the course of the study. Additionally, any AE 
voluntarily reported by the patient should be recorded and verified by the Investigator or 


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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 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 Baxter 
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. 
6.10.1 Definitions of Adverse Event Terms 
Study Product: 
Depending on the protocol, the term “study product” can mean the IP, the 
comparator product, or the blinded product. 
Date of Onset: 
The date that the signs and symptoms of the AE began. 
Signs & Symptoms vs 
Diagnosis: 
If a definitive diagnosis has been medically established by the physician 
caring for the patient or by the Investigator, this diagnosis should then be 
recorded as the AE. If a definitive diagnosis has not been medically 
established, the signs and symptoms should then be recorded as the AEs. 
Diagnosis vs 
Complications 
If a patient experiences not only a diagnosis, but additionally a complication 
of the diagnosis (ie, myocardial infarction with congestive heart failure), 
both the diagnosis and the medical complication should be collected and 
recorded as separate AEs on separate eCRFs. 
Severity: 
Severity will be assessed for each AE and defined using the following 
criteria:  
Mild – Is a transient discomfort and does not interfere in a significant 
manner with the patient’s normal functioning level. The AE resolves 
spontaneously or may require minimal therapeutic intervention. 
Moderate – Produces limited impairment of function and can require 
therapeutic intervention, but produces no sequelae. 


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Severe – Results in a marked impairment of function and can lead to 
temporary inability to resume usual life pattern. The AE produces sequelae 
requiring (prolonged) therapeutic intervention. 
Causality: 
Causality Assessment – A determination is made by the Investigator and 
sponsor as to whether there is a reasonable possibility that the device or drug 
is etiologically related to/associated with the AE. Causality assessment 
includes, for example, assessment of temporal relationships, association (or 
lack of association) with underlying disease, treatment association (or lack of 
association), presence (or absence) of a more likely cause, and physiologic 
plausibility. Categories for causality assessment are “probably associated,” 
“possibly associated,” “unlikely associated” and “not associated.” 
Probably Associated: An AE follows a strong temporal relationship to the 
device or drug, and another etiology is unlikely or significantly less likely. 
Possibly Associated: An AE follows a reasonable temporal relationship to 
the device or drug, and an alternative etiology is equally or less likely 
compared to the potential relationship to the device or drug. 
Unlikely Associated: An AE has little or no temporal relationship to the 
device or drug and/or a more likely alternative etiology exists. 
Not Associated: An AE that is due to underlying or concurrent illness, 
complications, concurrent treatments or effect of another concurrent 
drug/therapy and is not associated to the device or drug (ie, does not follow a 
reasonable temporal relationship to the use of the device or drug nor has a 
much more likely alternative etiology). 
 


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6.10.2 Serious Adverse Event (SAE) 
The following criteria qualify an AE as an SAE: 
Death: 
An event resulting in death (including a fetal death). 
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. 
Hospitalization: 
During this investigation, all patients will be hospitalized. 
Prolongation of 
Hospitalization: 
An event that prolongs the patient’s stay in the hospital. By definition, this is 
a different event from the event that resulted in the hospitalization. 
Congenital 
Abnormality: 
An abnormality detected at or after birth in the offspring of a study patient. 
Persistent or Significant 
Disability/Incapacity: 
An event that substantially interferes with the patient’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. 
Important Medical 
Event: 
A medically important event or reaction that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the 
patient 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. 
Abortion: 
The spontaneous or induced termination of pregnancy (includes elective, 
induced, spontaneous and missed abortion, as well as miscarriage). 
 
6.10.3 Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product that are related to any dose 
should be considered adverse drug reactions (ADR). The phrase “responses to a 
medicinal product” means that a causal relationship between a medicinal product and an 
AE is at least a reasonable possibility (ie, the relationship cannot be ruled out). 
6.10.4 Unexpected Adverse Drug Reaction 
An unexpected ADR is an adverse reaction for which the nature or severity is not 
consistent with the applicable product information. 
6.10.5 Suspected Unexpected Serious Adverse Reaction 
An AE suspected to have a causal relationship to an investigational or marketed drug and 
meeting criteria for seriousness and unexpectedness. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) are also reportable for active comparator products, 
placebo, or the clinical study protocol itself (ie, events due to study procedures). 


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6.10.6 Adverse Events Related to Anticoagulation or CRRT 
The anticipated adverse effects for this study have been identified in the list below. 
• Air embolism 
• Anemia 
• Bleeding episodes 
• Blood loss 
• Bradycardia 
• Cardiopulmonary arrest 
• Coagulation of the dialyzer/extracorporeal circuit resulting in blood loss 
• Cramping 
• Disequilibrium syndrome 
• Dizziness 
• Electrolyte Imbalance 
- 
Hypercalcemia 
- 
Hypocalcemia 
- 
Hyperkalemia 
- 
Hypokalemia 
- 
Hypermagnesemia 
- 
Hypomagnesemia 
- 
Hypernatremia 
- 
Hyponatremia 
- 
Hyperphosphatemia 
- 
Hypophosphatemia 
• Excessive weight loss or gain 
• Filter or tubing set blood leak resulting in blood loss 
• Fluid imbalance 
• Hemolysis 
• Hypersensitivity or Allergic Reactions “First Use Reaction” 
• Hypertension 


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• Hypotension 
• Hypothermia 
• Hypervolemia 
• Hypovolemia 
• Infection 
• Metabolic acidosis 
• Metabolic alkalosis 
• Nausea 
• Pyrogenic Reaction 
• Tachycardia 
• Vomiting 
 
6.11 Site Reporting Requirements 
During the course of the study, the Investigator or designee will routinely monitor each 
patient for the occurrence of any AE/ADE. If an AE/ADE occurs, the Investigator or 
designee will complete the AE eCRF which includes the following: 
a. Description of the event 
b. Start and stop date of the event 
c. Timing of the event 
d. Seriousness of the event (yes, no) 
e. Severity of the event (mild, moderate, or severe) 
f. Causality of the event (related to treatment and/or related to the IP) 
g. Outcome of the event (fatal, not recovered/not resolved, recovering/resolving, 
recovered/resolved with sequelae, recovered/resolved, and unknown) 
 
All SAEs must be reported to the Baxter Global Patient Safety (GPS) within 24 hours of 
the Investigator or designee becoming aware of its occurrence. The initial 24-hour 
reporting requirement can be met by using either the electronic SAE eCRF or the paper 
SAE form. The informed site team member should also contact their site monitor by 
phone or email to notify him/her of the event. This requirement is irrespective of whether 
the AE is thought to be possibly related to the study product or not. After the initial 24-


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hour reporting, both the Baxter electronic SAE eCRF and the paper SAE report form 
must be completed for all SAEs. The paper SAE report form is to include copies of 
documents (de-identified) requested within the form (if applicable). The paper SAE 
forms should be sent by email to: 
 
 
 
 
Copy:
 
 
 
 
In case this email is down, the site must notify GPS by fax: 
. Once 
received, the SAE report will be reviewed for completeness and forwarded on to the 
Medical Monitor and Baxter Global Patient Safety within 1 calendar day of receipt. 
Follow-up or new information about a SAE should be provided by the 
investigator/designee using the paper SAE form within 24 hours of becoming aware of 
the new information. If the follow-up or new information impacts any of the fields in the 
electronic SAE eCRF the SAE eCRF should be updated within 24 hours of becoming 
aware of the new information. 
If the Investigator suspects the SAE could possibly be a SUSAR, the following should 
also be contacted as soon as possible: 
: 
, MD 
 
Baxter Healthcare Corporation 
One Baxter Parkway 
Deerfield, IL 60015 
Tel: 
 
Email: 
  
Other Contacts: 
, MS 
 
Baxter Healthcare Corporation 
Mobile: 
 
Email: 
 
, BSN, RN 
 


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Baxter Healthcare Corporation 
One Baxter Parkway, DF5-1W / Deerfield, IL 60015 
Tel: 
   / Mobile: 
 
Email: 
  
Serious Adverse Events will be reviewed and causality assessment will be completed by 
Baxter.  
6.11.1 Sponsor to FDA/
 and Investigator to IRB/Ethics Committee 
Baxter will assess each SAE reported by the Investigator to determine if the SAE 
qualifies as an Expedited Report according to FDA and/or 
 criteria. Per 
regulations, Investigators will receive a letter from Baxter describing the SUSAR. The 
Investigator should file this letter within their Investigator Study Binder. Additionally, 
the Expedited Report letter should be submitted by the Investigator to their IRB/REB, as 
appropriate per FDA or 
 regulations. 
6.12 Concomitant Therapy 
The Investigator should review any additions or changes in concomitant therapy. All 
medications should be recorded in the source documents or equivalent. Prior medications, 
defined as those taken and/or prescribed during the 7 day window prior to informed 
consent and those relevant to ICU admission, will be recorded on the eCRF. Concomitant 
medications, including dose, frequency, start and stop dates, and indication for use, will 
be recorded on the eCRF throughout the study. 
6.13 Restrictions 
Diet, Patient Activity or Concomitant Medication restrictions are not noted. 
Systemic heparin or other systemic anticoagulants are prohibited. 
6.14 Treatment Compliance 
The facility nurse will fill out a treatment record for each study treatment, including 
CRRT start time, stop time, etc. Data from that record will be transcribed and submitted 
on eCRFs. 
7. STUDY ACTIVITIES 
7.1 Training on the Administration of Prismocitrate 18 
The clinical sites will be required to be current users of Prismaflex Device Platform and 
users of citrate as an anticoagulant for CRRT circuits. The end users at these sites are 
authorized to use of the CRRT machines and regional citrate anticoagulation at their 


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institutions. Additional training on the administration of Prismocitrate 18 will be 
provided by the Sponsor. At the completion of training the site investigator and other end 
users (as delegated by an investigator) will complete an Evaluation (refer to 1407-004 
Protocol Training Assessment 2015May26). Additional assessment materials for specific 
end user groups may be provided as needed or as determined by an investigator. 
7.2 Consenting and Screening Period 
Study procedures can only begin after the site has fully consented the subject. The data 
collection points listed in Section 7.3 will be collected during the screening period (after 
consent and prior to randomization). Subjects may screen up to 96 hours prior to 
randomization. It is anticipated that most study subjects will screen and randomize in a 
24 hour period. 
If any of the data points listed in Section 7.3 were collected prior to consenting the 
subject (within 96 hours) as standard-of-care, the site staff may enter those data points 
from the patient’s chart into the eCRFs. The exception is Clinical laboratory evaluations 
which must be within 24 hours. 
7.3 Patient Information to be Collected Prior to Initiation of Treatment 
The following data will be collected and recorded on the eCRFs for each patient prior to 
treatment. 
1. Signed Patient Informed Consent Form. 
2. Patient Identification Number as assigned by the system. 
3. Inclusion/Exclusion Criteria. 
4. Patient Demographics. 
a. Gender. 
b. Illness severity score using the Acute Physiology and Chronic Health 
Evaluation (APACHE II) classification system.[15,16] 
c. Chronological age. 
d. Body measurements: weight, height, BMI (kg/m2). 
e. Race. 
f. Ethnicity. 
5. Patient Medical Information. 
a. Indication for CRRT*. 


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* If Indication for CRRT is AKI, specify cause. 
b. Known allergies. 
c. Current medications and those prescribed during the 7-day window prior to 
informed consent and those relevant to ICU admission. 
d. Medical history – past/present conditions as well as surgical procedures. 
e. Physical examination. 
f. Vital signs. 
g. Clinical laboratory evaluations as specified in Appendix 1. 
 
7.4 Treatment Period 
The following data will be collected and recorded on the eCRFs for each patient 
following randomization. 
7.4.1 Treatment Information 
1. Date & time patient randomized and treatment arm. 
2. Date & time study CRRT initiated and discontinued. 
3. Prismaflex M150 Set to include: 
a. Sequential number for Prismaflex M150 Set. 
b. Date & time of installation. 
c. Date & time for start and end of study CRRT for each Prismaflex M150 Set. 
d. Prismaflex M150 Set lot number (Prismaflex M150 Set must be used). 
4. Blood access information. 
a. Catheter-type, manufacturer, length & size. 
b. Catheter anatomical insertion location. 
5. Prismaflex System serial number (to confirm that only Prismaflex System is used 
in this study). 
6. Treatment Modality. 
a. Continuous venovenous hemodiafiltration (CVVHDF) confirmation. 
 
7.4.2 Treatment Prescription – initial and all changes during Treatment Period 
1. Patient fluid removal flow rate (mL/hour). 


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2. Post-filter replacement flow rate (mL/hour). 
3. Blood flow rate (mL/minute). 
4. Dialysate flow rate (mL/hour). 
5. Prismocitrate 18 flow rate (mL/hour). 
6. Calcium Gluconate or calcium chloride infusion details: dilution and rate 
(mL/hour). 
 
7.4.3 Dialysate Used 
1. Formulation. 
2. Brand name/Manufacturer. 
 
7.4.4 Replacement Solutions Used 
1. Formulation. 
2. Brand name/Manufacturer. 
 
7.4.5 Priming Solution 
1. Formulation. 
2. Brand Name/Manufacturer. 
 
7.4.6 Calcium Gluconate or Calcium Chloride 
1. Formulation. 
2. Brand name/Manufacturer. 
 
7.4.7 Extracorporeal Circuit (Prismaflex M150 Set) Information 
1. Reason (including date and time) for treatment termination (ie, clotting, increased 
TMP, patient required treatment/diagnostic tests external to ICU, device 
malfunction, etc). 
2. Visual assessment of extracorporeal circuit at time of treatment termination due 
to: 
a. Clotting in the Prismaflex M150 Set (ie, clotting in filter and blood tubing), 
b. Clotting in the blood access device, or 


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c. Clotting in both the blood access device and the Prismaflex M150 Set. 
3. Complications related to blood loss (bleeding or Prismaflex M150 Set clotting 
and replacement). 
a. Number, location and duration of any bleeding events. 
b. Estimated blood loss (mL). 
c. Transfusion type (whole blood, packed cells, etc.). 
d. Transfusion volume. 
e. Adverse events. 
 
7.4.8 Anticoagulation Information 
1. Prismocitrate 18 (volume of Prismocitrate 18 used), or 
2. No systemic anticoagulant. 
 
7.4.9 Patient Clotting Parameters 
1. Prothrombin time/international normalized ratio. 
2. Activated partial thromboplastin time. 
3. Platelet count. 
4. Post-filter iCa. 
5. The number of iCa determinations (whether the patient is on Prismocitrate or not). 
 
7.4.10 Treatment Blood Concentration Data – According to the Sampling Schedule 
in Appendix 1 
1. Blood Urea Nitrogen (BUN). 
2. Creatinine. 
3. Serum bicarbonate, pH and base excess. 
4. Hemoglobin and Hematocrit. 
5. Blood sodium, potassium, chloride, iCa (systemic and post-filter), total calcium, 
phosphorus, and magnesium. 
6. Total Ca/iCa ratio. 
7. Anion gap. 


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8. Liver function tests (AST, ALT, ALP, Total Bilirubin) – based on local standard-
of-care. 
 
7.4.11 Fluid Balance and Hemodynamic Parameters 
1. Total fluid input and output volume (including dialysate, replacement fluid, and 
effluent). 
2. Daily patient weights recorded each morning (eg, 8:00 am) for calculation of 
delivered CRRT dose. 
3. Post-treatment weight when study CRRT is terminated. 
4. Blood pressure including mean arterial pressure at randomization and at 6 hour 
intervals (± 1 hour) up to End of Treatment or 120 hours of study CRRT post-
randomization and at 120 hours or end of Evaluable Period. 
 
7.5 End of Treatment or Early Termination Procedures 
The following End of Treatment information will be collected and procedures or 
evaluations will be performed after completion of study CRRT during the Treatment 
Period (up to 120 hours of study CRRT): 
• Physical exam including weight. 
• Vital signs. 
• Adverse events/serious adverse events (if not previously reported). 
• Concomitant medications. 
• Clinical laboratory evaluations as specified in Appendix 1. 
• Bleeding events (if not previously reported). 
• Transfusions (if not previously reported). 
• Disposition post-study CRRT Treatment Period. 
 
If a patient discontinues from the study prematurely, every attempt should be made to 
perform all of the End of Treatment procedures and evaluations. Upon exiting the study, 
the patient will be treated per standard-of-care, which may or may not include continued 
CRRT. 


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7.6 End of Study Procedures 
After completion of study CRRT during the Treatment Period (up to 120 hours of study 
CRRT) AE/SAEs will be followed for a period of 30 days. All patients who complete up 
to 120 hours of study CRRT and the 30-day AE/SAE follow up period will successfully 
complete the study. Related AEs and SAEs will be followed post-study until resolution or 
stable. 
 
8. PLANNED STATISTICAL METHODS 
8.1 General Considerations 
Unless otherwise specified, treatment effects will be evaluated on the basis of a 2-sided 
significance level of 0.050 (when rounded to 3 decimal places). Unless otherwise noted, 
all analyses will be performed using Statistical Analysis Software (SAS), 
SAS/GRAPH and SAS/STAT software, Version 9.2 of SAS for Windows, copyright © 
2002-2008 SAS Institute Inc., on a Microsoft Windows Server. SAS and all other SAS 
Institute Inc. product or service names are registered trademarks or trademarks of SAS 
Institute Inc., Cary, NC, USA.[17] 
Further details of the planned statistical methods presented below will be provided in the 
study statistical analysis plan (SAP). The purpose of the SAP is to further elaborate the 
statistical methods described in the protocol and to describe analysis conventions to guide 
the statistical programming work. The SAP will be drafted prior to enrollment of the first 
patient and will be finalized prior to database soft lock in accordance with Baxter 
standard operating procedures. 
8.2 Determination of Sample Size 
A sample size of 80 patients in each treatment group will provide > 90% power for 
assessing the equality of the extracorporeal circuit life between treatment groups using a 
two-sided clustered log-rank test with an overall alpha level of 0.050. This is based on the 
following assumptions: median circuit lives of 
 and 
, respectively in the 
Prismocitrate and Control group, 
 filters per patient (during the Treatment Period 
of 120 hours) in the Prismocitrate and Control group, respectively, 
 of subjects 
discontinuing therapy for reasons other than due to clotting of the circuit (ie, common 
exponential dropout rate of 
), a single interim analysis when 50% of patients have 
completed treatment, and combination of results from the two study stages (prior to vs 
after interim analysis) using Fisher’s combination test.[18] 


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8.3 Analysis Populations  
The Full Analysis (FA) Set will include all randomized patients who received any study 
treatment for any period of time. 
All analyses will be performed on the FA Set unless otherwise noted.  
In addition to the FA Set, a Per Protocol (PP) Set will be used to check the robustness and 
validity of the primary analysis by repeating the analysis on the PP Set as a sensitivity 
analysis. 
The PP Set defines a subset of the FA Set including patients who: 
• fulfill all inclusion criteria. 
• do not meet any of the exclusion criteria. 
• were randomized and treated according to the randomization scheme. 
• received at least 80% of their prescribed CRRT dose. 
• do not have major protocol deviations that might impact the assessment of the 
primary endpoint (eg, mechanical malfunction of the machine). 
• have available survival data for extracorporeal circuit life of at least one circuit 
(ie, time to occurrence of Prismaflex System alarms/conditions as outlined in 
Section 6.7.1 Primary Efficacy Endpoint and alarm cause determined and 
confirmed by Independent Adjudicator as outlined in Section 9.9 Primary 
Endpoint Adjudication, or censored circuit life if no system alarms/conditions 
occurred until the circuit was used for 72 continuous hours or if CRRT was 
stopped during the Treatment Period for reasons other than system 
alarms/conditions or if Independent Adjudicator did not confirm the alarm cause). 
 
8.4 Demographics and Baseline Characteristics 
Demographic data include illness severity score (APACHE II), age, gender, race, height, 
weight and body mass index (BMI) calculated as weight (kg)/height2 (m), and ethnicity. 
Other baseline/screening data include: 
1. Underlying disease. 
2. Known allergies. 


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3. Current medications and medications prescribed during the 7-day window prior to 
informed consent and those relevant to ICU admission. 
4. General medical history; medical conditions or surgical procedures.  
5. Vital signs including height, weight, blood pressure, pulse rate, temperature, and 
respiratory rate. 
6. Physical exam. 
7. Laboratory parameters, see Appendix 1. 
 
Continuous variables will typically be summarized by treatment group using the number 
of subjects n, mean, standard deviation, minimum, median and maximum and a t-test or 
Wilcoxon rank sum test will be used to evaluate mean differences between groups, as 
applicable. Frequency and percentages will be provided for the categorical variables by 
treatment group and a Fisher's exact test will be used to evaluate differences between 
treatment groups. 
Demographics and Baseline Characteristics will be summarized by randomized treatment 
group, and for the FA Set only. 
8.5 Efficacy Endpoints 
8.5.1 Primary Efficacy Endpoint 
The primary endpoint of the study, extracorporeal circuit life, will be analyzed as a time-
to-event endpoint (survival analysis).  
In the statistical analysis extracorporeal circuit life of a filter that is replaced due to 
continuous use for 72 hours, will be censored. Likewise, filters that are in use when the 
end of the observation period of 120 hours is reached, will be censored at their current 
duration of usage at the end of the observation period. Filters that are replaced any time 
CRRT is stopped for reasons other than filter clotting (including drop-outs), will be 
censored at their current duration of usage. Only filters that are replaced due to filter 
clotting or excessive transmembrane pressure as indicated by one or both Prismaflex 
System alarms/conditions as defined under Section 6.7.1 Primary Efficacy Endpoint and 
for whom alarm causes have been confirmed by an Independent Adjudicator, will be 
considered ‘events’ in terms of the statistical analysis.  
Each filter used during the 120 hours observation period or until treatment is finished will 
be included in the statistical analysis (several filters per patient).  


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Separate estimates per treatment group will be provided for the primary endpoint based 
on Kaplan-Meier methodology. Differences between treatment groups will be assessed 
using a clustered log-rank test in order to account for the potential dependence among 
extracorporeal circuit lives of the same patient.[19] 
Analyses of the primary endpoint will be carried out on the FA Set based on the 
randomized treatment groups (intent-to-treat principle).  
An interim analysis will be carried out after 50% of subjects completed treatment. Please 
refer to Section 8.8 for further details regarding the interim analysis. 
The study will be stopped early due to overwhelming efficacy when a p value of < 0.0087 
is observed using the clustered log-rank test at the interim analysis, see section 8.8 
(critical value based on Bauer & Kohne procedure with no early stopping for futility). If 
p ≥ 0.0087 and the study continues enrollment into a second stage, Fisher’s combination 
test will be performed at the end of the study using a critical value of 0.0087 which 
guarantees that the overall type 1 error is controlled and preserved at a maximum of 
0.05.[18] 
The analysis of the primary endpoint will be repeated using the PP Set as a sensitivity 
analysis. In order to assess a potential impact of informative censoring on the primary 
efficacy analysis, a sensitivity analysis will be carried out on the FA Set using different 
assumptions for cases where therapy (ie, a filter) was discontinued for reasons other than 
circuit clotting. Further details will be provided in the SAP. 
8.5.2 Secondary Efficacy Endpoints 
A descriptive summary of systemic and post-filter blood iCa concentrations as assessed 
baseline (systemic only), initiation (systemic only), 1 hour and every 6 hours from the 
initiation of study CRRT during the 120 hour Treatment Period and at 120 hours or end 
of the Treatment Period will be provided by treatment group. Post-filter blood iCa 
concentrations will only be presented for the Prismocitrate 18 Arm. 
A mixed-effects model repeated measures (MMRM) analysis will be used to evaluate 
differences between treatment groups in the change from initiation of study CRRT in 
systemic  iCa concentrations that are collected 1 hour and every 6 hours from the 
initiation of study CRRT during the 120 hours Treatment Period and at 120 hours or end 
of the Treatment Period. If justified, separate models will be carried out for patients who 
did and did not receive standard-of-care CRRT. 


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In addition, frequencies and percentages will be provided for systemic iCa < 1.1 mmol/L 
by time point and treatment group (threshold indicative of decrease in iCa despite 
adequate calcium compensation). 
A descriptive summary of the daily delivered dose and overall delivered dose will be 
provided by treatment group. Differences between treatment groups in the percentage of 
overall prescribed dose actually administered will be assessed on a 5% significance level 
using a two-sided t-test or Wilcoxon rank sum test, as applicable. However, the statistical 
test will only be carried out conditional upon a significant test result for the primary 
endpoint at the time point of the interim analysis or final analysis. This hierarchical test 
procedure guarantees that the overall type 1 error is controlled and preserved at a 
maximum of 5%. 
Secondary Efficacy Endpoints will be analyzed on the FA Set based on the randomized 
treatment groups (intent-to-treat principle). 
8.6 Safety Endpoints 
Analysis of safety endpoints will be carried out on the FA Set based on the actual 
treatment groups for the following parameters: 
1. A MMRM analysis will be used to evaluate differences between treatment groups 
in the change from baseline in serum bicarbonate and pH that are collected every 
6 hours from the initiation of study CRRT during the 120 hour Treatment Period 
and at 120 hours or end of the Treatment Period. Frequencies and percentages will 
be provided for pH < 7.2 by time point and treatment group (thresholds indicative 
of metabolic acidosis). 
2. A MMRM analysis will be used to evaluate differences between treatment groups 
in the change from baseline in blood total calcium concentrations that are assessed 
at 1 hour and every 6 hours from the initiation of study CRRT during the 120 hour 
Treatment Period and at 120 hours or end of the Treatment Period.  
3. A MMRM analysis will be used to evaluate differences between treatment groups 
in the change from baseline in serum electrolytes (sodium, potassium, chloride, 
phosphate, and magnesium) that are collected every 6 hours from the initiation of 
study CRRT during the 120 hour Treatment Period and at 120 hours or end of the 
Treatment Period.  


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4. A descriptive summary of the total calcium/systemic iCa ratio as assessed at 
baseline, at initiation of study CRRT, 1 hour and every 6 hours from the initiation 
of study CRRT during the 120 hour Treatment Period and at 120 hours or end of 
the Treatment Period will be provided by treatment group. Frequencies and 
percentages will be provided for total calcium/systemic iCa ratio > 2.1 by time 
point and treatment group (threshold suggestive of citrate accumulation). 
Frequencies and percentages will be provided for anion gap > 11 mmol/L by time 
point and treatment group (threshold indicative of metabolic disturbance) as well 
as for base excess < -5 mmol/L. 
5. A descriptive summary of the number, location, and duration of bleeding events 
along with the estimated blood loss during the 120 hour Treatment period will be 
provided by treatment group. The number and type of blood transfusion along 
with the number of units infused will also be summarized. 
6. An analysis of covariance (ANCOVA) model will be used to evaluate differences 
between treatment groups in the change from baseline to final measurement in 
laboratory and vital signs measurements. 
7. Adverse events will be mapped to a primary SOC and Preferred Term according 
to MedDRA and will be summarized.  
 
8.7 Analysis of Training on Administration of Prismocitrate 18 
A descriptive summary of proficient completion of training on the administration of 
Prismocitrate 18 will be provided. 
8.8 Interim Analysis 
A single interim analysis will be conducted when 50% of patients have completed 
treatment. The purpose of the interim analysis is to evaluate the primary efficacy 
endpoint for overwhelming efficacy, or the need to adjust the sample size. If the primary 
analysis yields a statistically significant test result (p < 0.0087, critical value for clustered 
log rank test based on Bauer & Kohne procedure with no early stopping for futility) on 
the FA Set, and if further no safety concern or other considerations require continuation 
of enrollment, the study will be stopped for overwhelming efficacy. Otherwise 
enrollment of subjects will continue and the whole statistical analysis as described in this 
document will be carried out at the end of the study using Fisher’s combination test.[18] 
This approach guarantees that an overall type 1 error of 0.05 is preserved. 


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Sample size re-estimation at the interim analysis will be based on Fisher’s criterion 
(Fisher’s combination test). Simulation studies will be run utilizing the p value observed 
at the interim analysis (p1) and the initial assumptions for median survival times in the 
two treatment groups (
 in the Prismocitrate 18 and Control group). 
Re-assessment of the sample size will target a conditional power of 90% for rejecting the 
null hypothesis given the observed p value of the interim analysis. 
9. ADMINISTRATIVE CONSIDERATIONS 
9.1 Investigators and Study Administrative Structure 
Investigators that will be participating in this study will be sent a copy of this protocol 
along with an appropriate supply of regulatory documents. Once this protocol and 
regulatory documents have been received by a given study site, the study site will be 
contacted by their Clinical Monitor to encourage the site to complete and return the forms 
to Baxter in an expeditious manner. 
9.2 Institutional Review Board or Research Ethics Board Approval 
The IRB/REB must be constituted according to the applicable local and national 
requirements of each participating location. The Sponsor or its designee will require 
documentation noting all names and titles of members who compose the respective 
IRB/REB. If any member of the IRB/REB has direct participation in this trial, written 
notification regarding his or her abstinence from voting must also be obtained. 
The Sponsor or its designee will supply relevant documents for PIs to submit to their 
respective IRB/REB for the review and approval of the protocol. The PI must submit to a 
central or local IRB/REB this protocol, the patient ICFs, and, if applicable, patient 
recruitment materials and/or advertisements. Written approval by the IRB/REB of the 
protocol and ICFs must be obtained and submitted to the Sponsor or its designee before 
commencement of the study (ie, before shipment of the study drug). The IRB/REB 
approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, patient ICF) reviewed; and state the approval date. 
Sites must adhere to all requirements stipulated by their respective IRB/REB. This 
includes notification to the IRB/REB regarding protocol amendments, updates to the 
ICFs, recruitment materials intended for viewing by patients, SAEs, unexpected AE 
reports, and updates regarding the ongoing review of the trial at intervals specified by the 
respective IRB/REB, and submission of final study reports and summaries to IRB/REB. 
All IRB/REB approvals and relevant documentation for these items must be transmitted 
to the Sponsor or its designee via the PI. 


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9.3 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, the ethical and quality standards of good clinical 
practice (ICH E6) and all applicable regulatory requirements and laws. 
The PI will provide all necessary information on the protocol and the study drug to all 
physicians, nurses, and other personnel who participate in this study under the PI’s 
supervision and will discuss this material with them as needed, to ensure that they are 
fully informed regarding the conduct of the study and the potential effects of the study 
drug. 
9.4 Compliance with Protocol and Protocol Amendments 
The study must be conducted as described in this approved protocol. The PI should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/REB and the Sponsor or its designee, except 
where necessary to eliminate an immediate hazard(s) to study patients. 
9.5 Patient Confidentiality 
All patient information, medical records, and laboratory data will be kept confidential. 
Information and data may be discussed, analyzed, and reported. However, code numbers 
will identify the patient on the eCRFs and in any reports, and the patient’s identity will be 
kept confidential. 
9.5.1 HIPAA Authorization Procedures – US Sites Only 
Preparation of the Health Insurance Portability and Accountability Act (HIPAA) 
authorization form is the responsibility of the PI and must include all elements required 
by the Department of Health and Human Service’s Privacy Rule. Prior to the beginning 
of the study, the PI must have the IRB or the appropriate institution privacy board’s 
written approval/favorable opinion of the HIPAA authorization form. The PI must 
provide the patient or legally-authorized representative with a copy of the HIPAA 
authorization form in the language in which the patient is most proficient. The language 
must be nontechnical and easily understood. The PI should allow the time necessary for 
the patient or the patient’s legally-authorized representative to inquire about the details of 
the authorization. The HIPAA authorization must be signed and personally dated by the 
patient or by the patient’s legally-authorized representative and by the person who 
obtained the authorization. The patient or legally-authorized representative should receive 
a copy of the HIPAA authorization form prior to the patient’s participation in the trial. 


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9.5.2 Personal Health Information – Canadian Sites Only 
A valid signed ICF, approved by the Sponsor and the REB, will be obtained from each 
study patient permitting disclosure of the individual’s “personal health information” (as 
defined in the Personal Health Information Protection Act) as required by, and in 
accordance with, the study. 
9.6 Study Monitoring 
The sponsor team or designee will monitor the treatment data on site and remotely as part 
of safety management and clinical monitoring. Monitoring will occur at regularly 
scheduled intervals at the study site to allow for verification by sampling of source 
documents and comparing these with information recorded on the eCRFs. In addition, 
eCRFs will also be monitored remotely during the course of study participation. Full 
details on eCRF monitoring will be specified in the Clinical Operations Plan. If data 
discrepancies are noted, the electronic treatment data can be corrected in the clinical trial 
database via addenda, queries, source data clarification forms or an audit trail.  
The PI or a designated member of the PI’s staff must be available at some time during 
monitoring visits to review data and resolve any queries and to allow direct access to the 
patient’s records (eg, medical records, office charts, hospital charts, and study-related 
charts) for source data verification. The eCRFs must be completed prior to each visit and 
be made available to the monitor so that their accuracy and completeness may be 
checked. 
The database will be housed on a physically and logically secure computer server 
maintained in accordance with written security policies. The electronic data capture 
(EDC) system meets approved established standards for the security of health 
information and is validated per 21 CFR Part 11. The system also meets the ICH 
guideline E6R1 and applicable 
 regulations regarding electronic study data handling 
and is available for audit upon request. Patient confidentiality will be strictly maintained 
and adhere to both US and Canadian laws regarding patient data. Patient identifying 
information will not be included in the database, but must be maintained in a secure 
fashion at the Investigator site. 
All eCRF and treatment file data correction documentation will be maintained in the 
EDC system’s audit trail. System backups for data stored and records retention for the 
study data will be consistent with standard procedures. 


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9.7 Electronic Case Report Forms and Study Records 
All patient medical records will be kept strictly confidential. Personally identifiable 
information will not be transmitted to the Sponsor, or its designee, or to any third parties. 
Patient eCRFs will only be released to the Sponsor, or its designee(s), and to appropriate 
government agencies. Code numbers will be used to identify the patient on eCRFs and 
other study-related documents. 
The PI is required to prepare and maintain adequate and accurate case histories for each 
patient. Source data will be transcribed on to eCRFs by the site designee. Transcribed 
data should accurately reflect the data recorded in the source documents. All pages of the 
eCRF must be reviewed by the PI and he/she will sign off on the eCRF book to verify 
that the data is accurate, complete, and reflects the source documentation. This review 
and sign-off may be delegated to a qualified physician appointed as a Sub-Investigator by 
the PI. The PI must retain a copy of the eCRFs, including records of any changes or 
corrections. 
9.8 Data Monitoring Committee 
This study will be monitored by a Data Monitoring Committee (DMC). The DMC is a 
group of individuals with pertinent expertise that reviews on a regular basis accumulating 
data from an ongoing clinical study. The DMC can stop a trial if it finds toxicities or if 
treatment is proven to be not beneficial. For this study, the DMC will include recognized 
experts in the field of dialysis clinical care and research who are not involved in this 
study. 
The DMC will be responsible for monitoring safety at regular intervals throughout the 
study. The meeting schedule, frequency of data delivery, and data required will be at the 
discretion of the DMC to be defined by the elected DMC members. The Sponsor will 
notify the DMC when any subject experiences a related SAE. Additionally, at the 
discretion of the sponsor, the sponsor may call a meeting of the DMC for any other safety 
issues or at any time to review the safety of the protocol or IP(s). The DMC may, at any 
time, request additional information from the Sponsor. 
9.9 Primary Endpoint Adjudication 
An Independent Adjudicator highly experienced in administering CRRT to patients and 
in operating the Prismaflex machine will review eCRF data, alarm data (ie, alarm name 
as described in Section 6.7.1 Primary Efficacy Endpoint of this protocol) and the 
outcome of a Baxter technical analysis (eg, technical root cause for alarm: yes/no). The 
Independent Adjudicator will make the final determination of the alarm cause by 


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examining the applicable historical electronic data available surrounding the alarm 
events. The Independent Adjudicator will be blinded to the treatment assignment as well 
as to any potential information that might reveal a subject’s treatment assignment. In the 
event that the Independent Adjudicator becomes unblinded, a new Independent 
Adjudicator will adjudicate the case once the information that revealed the treatment 
assignment is removed.  
9.10 Protocol Violations/Deviations 
Protocol violations/deviations will be documented in source and in the investigator’s 
research study files as applicable. The clinical team will review deviations at a study 
level on a regular basis for issue trending and resolution. 
9.11 Access to Source Documentation 
Representatives of the Sponsor, or its designee, must be allowed to visit the study site 
regularly to assess the data quality and the integrity of the study. These representatives 
will review study records on site and directly compare these with the source documents, 
discuss the conduct of the study with the PI, and verify that the facilities remain 
acceptable. In addition, the study may be evaluated by the Sponsor’s internal auditors or a 
designee, and/or by government inspectors, who must be allowed access to eCRFs, 
source documents, and other study files. 
9.12 Data Generation and Analysis 
Web-based electronic data entry must be completed for all patients enrolled in the study. 
The electronic data entry will be the responsibility of the investigator. The database will 
be maintained by Baxter. 
Electronic Investigator signatures will be used to attest to the accuracy of data entered 
into the EDC system. Modifications to the data made by the investigator or his/her 
delegated assistants will be tracked in an audit trail within the EDC.  
The Study Monitor, in collaboration with the investigators, must ensure that data entered 
into the EDC system are correct. Data editing for correction or clarification purposes 
must be done before the eCRFs have been transmitted for data processing and analysis. 
Subsequent corrections must be checked in writing and validated in signing by the 
investigators. 
The investigators must ensure that they are accessible to the Study Monitor, the Study 
Manager or any authorized people at any time during the course of the study. 


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Data management will be carried out by the Baxter Clinical Development & Operations 
or assigned designee. 
Baxter or assigned designee is responsible for the creation of the study eCRF and the 
associated electronic study database. Queries will be issued through the EDC in order to 
solve questions regarding missing data and coherence. 
9.13 Retention of Data 
The PI must retain all study records including IP disposition records, and source 
documents for the maximum period required by applicable regulations and guidelines or 
institution procedures or for the period specified by Baxter, whichever is longer. The PI 
must contact the Sponsor before destroying any records associated with the study. The 
Sponsor or its designee will notify the PI when the trial records are no longer needed. If 
the PI withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another PI, IRB). Baxter will be 
notified in writing of any such transfer. 
9.14 Audits and Inspections 
In addition to the routine monitoring procedures and in accordance with GCP principles, 
GCP audits might well be performed by the Quality Assurance members of Baxter. 
These audits of clinical research activities are in accordance with applicable regulatory 
requirements, Baxter internal policies and procedures, to evaluate compliance with the 
principles of GCP. 
An independent auditor (ie, Regulatory Authority, government agency, central Ethics 
Committee) may also wish to conduct an inspection (during the study or even after its 
completion). Full consultation with appropriate personnel will be made prior to and 
during such audit. The PI must be available during the audit. If an independent auditor 
requests an inspection, the PI will contact their Site Monitor, Study Manager, and 
Medical Director immediately. 
9.15 Financial Disclosure 
In 2001, the FDA issued a guidance document entitled “Financial Disclosure by Clinical 
Investigators” which provides guidance to industry on its final rule on financial 
disclosure that became effective 02 February 1999 and was published as 
Title 21 CFR Part 54.[20] This rule applies to all Investigators participating in clinical 
studies to be submitted to the FDA in support of an application for market approval. The 


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financial disclosure statement must be updated annually during the course of the study 
and for 1 year after the completion of the study. 
According to the guidance, disclosable financial arrangements are defined as the 
following: 
• Compensation made to the Investigator in which the value of compensation could 
be affected by study outcome. 
• A proprietary interest in the tested product, including, but not limited to, a patent, 
trademark, copyright, or licensing agreement. 
• Any equity interest in the Sponsor of a covered study (ie, any ownership interest, 
stock options, or other financial interest whose value cannot be readily determined 
through reference to public prices). 
• An equity interest in a publicly held company that exceeds $50,000 in value. 
• Significant payments of other sorts, which are payments that have a cumulative 
monetary value of $25,000 or more made by the Sponsor of a covered study to the 
Investigator or the Investigators institution to support activities of the Investigator 
exclusive of the costs of conducting the clinical study or other clinical studies, 
(eg, a grant to fund ongoing research, compensation in the form of equipment or 
retainers for ongoing consultation, or honoraria) during the time the clinical 
Investigator is carrying out the study and for 1 year after completion of the study. 
 
The intent of this regulation is to ensure the proper identification and disclosure of 
financial interests of clinical Investigators that could affect the reliability of data 
submitted to the FDA in support of a market application. Companies must meet these 
financial disclosure requirements, and failure to do so may result in the refusal by the 
FDA to accept an application for market approval of the product. 
9.16 Publication and Disclosure Policy 
Any information shared by the Sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential. 
The data generated by this clinical study are the property of the Sponsor. These data may 
be used by the Sponsor, now and in the future, for presentation or publication at the 
Sponsor’s discretion or for submission to regulatory agencies. In addition, the Sponsor 


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reserves the right of prior review and approval of data from this study relative to the 
potential release of proprietary information to any publication or for any presentation. 


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10. REFERENCE LIST 
1. 
Morita Y, Johnson RW, Dorn RE, Hall DS. Regional anticoagulation during 
hemodialysis using citrate. Am J Med Sci. 1961;242:32-43. 
2. 
Tolwani A. Continuous renal-replacement therapy for acute kidney injury. N Engl J 
Med. 2012;367(26):2505-2514. 
3. 
Schilder L, Nurmohamed SA, Bosch FH, et al. Citrate anticoagulation versus 
systemic heparinisation in continuous venovenous hemofiltration in critically ill 
patients with acute kidney injury: a multi-center randomized clinical trial. Crit 
Care. 2014;18(4):472. 
4. 
Stucker F, Ponte B, Tataw J, et al. Efficacy and safety of citrate-based 
anticoagulation compared to heparin in patients with acute kidney injury requiring 
continuous renal replacement therapy: a randomized controlled trial. Crit Care. 
2015;19(1):91. 
5. 
Gattas DJ, Rajbhandari D, Bradford C, Buhr H, Lo S, Bellomo R. A Randomized 
Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for 
Continuous Renal Replacement Therapy in Critically Ill Adults. Crit Care Med. 
2015;43(8):1622-1629. 
6. 
Kutsogiannis DJ, Gibney RT, Stollery D, Gao J. Regional citrate versus systemic 
heparin anticoagulation for continuous renal replacement in critically ill patients. 
Kidney Int. 2005;67(6):2361-2367. 
7. 
Oudemans-van Straaten HM, Bosman RJ, Koopmans M, et al. Citrate 
anticoagulation for continuous venovenous hemofiltration. Crit Care Med. 
2009;37(2):545-552. 
8. 
Fealy N, Baldwin I, Johnstone M, Egi M, Bellomo R. A pilot randomized 
controlled crossover study comparing regional heparinization to regional citrate 
anticoagulation for continuous venovenous hemofiltration. Int J Artif Organs. 
2007;30(4):301-307. 
9. 
Wu MY, Hsu YH, Bai CH, Lin YF, Wu CH, Tam KW. Regional citrate versus 
heparin anticoagulation for continuous renal replacement therapy: a meta-analysis 
of randomized controlled trials. Am J Kidney Dis. 2012;59(6):810-818. 


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10. 
Zhang Z, Hongying N. Efficacy and safety of regional citrate anticoagulation in 
critically ill patients undergoing continuous renal replacement therapy. Intensive 
Care Med. 2012;38(1):20-28. 
11. 
Bai M, Zhou M, He L, et al. Citrate versus heparin anticoagulation for continuous 
renal replacement therapy: an updated meta-analysis of RCTs. Intensive Care Med. 
2015;41(12):2098-2110. 
12. 
Tolwani AJ, Campbell RC, Schenk MB, Allon M, Warnock DG. Simplified citrate 
anticoagulation for continuous renal replacement therapy. Kidney Int. 2001 
Jul;60(1):370-4. 
13. 
Khadzhynov D, Schelter C, Lieker I, et al. Incidence and outcome of metabolic 
disarrangements consistent with citrate accumulation in critically ill patients 
undergoing continuous venovenous hemodialysis with regional citrate 
anticoagulation. J Crit Care. 2014;29(2):265-271. 
14. 
Hetzel GR, Schmitz M, Wissing H, et al. Regional citrate versus systemic heparin 
for anticoagulation in critically ill patients on continuous venovenous 
haemofiltration: a prospective randomized multicentre trial. Nephrol Dial 
Transplant. 2011;26(1):232-239. 
15. 
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of 
disease classification system. Crit Care Med. 1985;13(10):818-829. 
16. 
Bouch D, Thompson J. Severity scoring systems in the critically ill. Anaesth Crit 
Care Pain. 2008;8(5):181-185. 
17. 
SAS Institute Inc. SAS OnlineDoc Version 9.2 Product Documentation. Vol. 2012. 
Cary, NC USA; 2008. 
18. 
Bauer P, Kohne K. Evaluation of experiments with adaptive interim analyses. 
Biometrics. 1994;50(4):1029-1041. 
19. 
Stedman MR, Gagnon DR, Lew RA, Jung SH, Losina E, Brookhart MA. A SAS 
macro for a clustered logrank test. Comput Methods Programs Biomed. 
2011;104(2):266-270. 
20. 
FDA Guidance Document. Financial Disclosure by Clinical Investigators.; March 
2001. 


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Appendix 1 Blood Sampling Schedule 
Parameter 
Before 
Randomization 
After 
Randomization 
But Before 
Initiation of 
Study CRRTa 
During Study 
CRRTb 
End of Study 
CRRT During 
Treatment Period 
Complete Blood 
Count (CBC) and 
blood lactate 
measurement 
Screening 
 
 
 
pH and base 
excess (ABG or 
VBG) 
 
Baseline and 
Initiation 
At 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 
66, 72, 78, 84, 90, 
96, 102, 108, 114, & 
120 hoursb 
When Study CRRT 
is terminated 
Serum 
bicarbonate 
 
Baseline and 
Initiation 
At 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 
66, 72, 78, 84, 90, 
96, 102, 108, 114, & 
120 hoursb 
When Study CRRT 
is terminated 
Systemic iCa2+ 
 
Baseline, 1 hour 
prior to initiation 
of Study CRRT  
 
 At 1, 6, 12, 18, 24, 
30, 36, 42, 48, 54, 
60, 66, 72, 78, 84, 
90, 96, 102, 108, 
114, & 120 hoursb 
When Study CRRT 
is terminated 
Post-Filter iCa2+ 
Prismocitrate 18 
Arm Only 
 
 
 At 1, 6, 12, 18, 24, 
30, 36, 42, 48, 54, 
60, 66, 72, 78, 84, 
90, 96, 102, 108, 
114, & 120 hoursb 
When Study CRRT 
is terminated 
Serum 
Electrolytes: 
Sodium, 
Potassium, 
Chloride, 
Phosphate, 
Magnesium, & 
Anion Gap 
 
Baseline and 
Initiation 
At 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66 
72, 78, 84, 90, 96, 
102, 108, 114, & 
120 hoursb 
When Study CRRT 
is terminated 


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Parameter 
Before 
Randomization 
After 
Randomization 
But Before 
Initiation of 
Study CRRTa 
During Study 
CRRTb 
End of Study 
CRRT During 
Treatment Period 
Creatinine & 
BUN 
 
Baseline and 
Initiation 
 Twice daily 
When Study CRRT 
is terminated 
Bleeding 
Parameters: 
PT/INR, PTT, 
hemoglobin, 
hematocrit, 
platelet count 
Screening 
Baseline and 
Initiation 
At least once daily 
When Study CRRT 
is terminated 
Blood total 
calcium 
Total 
calcium/iCa2+ 
ratio 
Screening 
Baseline and 
Initiation 
At 1, 6, 12, 18, 24, 
30, 36, 42, 48, 54, 
60, 66 72, 78, 84, 90, 
96, 102, 108, 114, & 
120 hoursb 
When Study CRRT 
is terminated  


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Parameter 
Before 
Randomization 
After 
Randomization 
But Before 
Initiation of 
Study CRRTa 
During Study 
CRRTb 
End of Study 
CRRT During 
Treatment Period 
Liver function 
tests (Alanine 
transaminase 
[ALT], Aspartate 
transaminase 
[AST], Alkaline 
phosphatase 
[ALP] and total 
bilirubin 
Screening 
Baseline 
As determined by 
local standard-of-
care 
As determined by 
local standard-of-
care 
ABG=arterial blood gases; ALT=alanine transaminase; AST=aspartate transaminase; ALP=alkaline 
phosphatase; CBC=complete blood count; CRRT=continuous renal replacement therapy; 
iCa2+=ionized calcium; BUN=blood urea nitrogen, PT=prothrombin time; INR=international 
normalized ratio; PTT=partial thromboplastin time; VBG=venous blood gases 
a If patient has not been on standard-of-care CRRT, the Baseline and Initiation labs are the same. If 
patient has been on standard-of-care CRRT for < 24 hours the Baseline labs are those collected prior to 
the standard-of-care CRRT with exception of systemic iCa2+, which blood must be drawn 1 hour prior 
to initiation of Study CRRT. For Baseline Labs the acceptable blood draw window is - 24 hours. For 
Initiation Labs, the acceptable blood draw window is ± 1 hour. 
b Acceptable blood draw window for Serum bicarbonate, pH, Systemic & Post-Filter iCa2+, Blood 
total calcium, Total calcium/ iCa2+ ratio and Serum electrolytes (sodium, potassium, chloride, 
phosphate, magnesium, anion gap and base excess) is ± 1 hour. 


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Appendix 2 Schedule of Events 
Evaluation 
Screening and Baseline 
During Study CRRT 
Treatment Period 
End of Study CRRT 
During Treatment 
Period 
Informed Consent 
X 
 
 
Demographics, Medical and Medication 
Historiesa 
X 
 
 
Physical Examination 
X 
 
X 
Height and BMI 
X 
 
 
Weightb 
X 
X 
X 
Vital Signs 
X 
 
X 
Randomizationc 
X 
 
 
Prismaflex System informationd 
 
X 
 
Prismaflex M150 Set information and 
extracorporeal circuit assessmente 
 
X 
 
Blood access informationf 
 
X 
 
CRRT treatment modalityg 
 
X 
 
CRRT treatment prescriptionh 
 
X 
 
Priming Solutioni 
 
X 
 
Replacement solution prescriptioni 
 
X 
 
Dialysate prescriptioni 
 
X 
 
Anticoagulation informationj 
 
X 
 
Clinical laboratory evaluationsk 
 
X 
X 
Blood pressure and mean arterial pressure l  
X 
X 
X 


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Evaluation 
Screening and Baseline 
During Study CRRT 
Treatment Period 
End of Study CRRT 
During Treatment 
Period 
Effluent volume (in mL)m 
 
X 
X 
AEs/SAEs  
 
X 
X 
Concomitant medications 
 
X 
X 
Bleeding events n 
 
X 
 
Transfusionso 
 
X 
 
Patient Fluid Removalp 
 
X 
 
 
 
a Demographics will include gender, illness severity score, chronological age at consent, pre-study CRRT weight and height. Medical history will include 
indication for CRRT, known allergies, past/present conditions as well as surgical procedures. Medication history will include all medications taken and/or 
prescribed during the 7-day window prior to informed consent and those relevant to ICU admission. 
b In addition to the pre-study CRRT weight, during the treatment period, daily weight will need to be obtained and recorded/entered each morning (eg, at 
8:00 am) in the “System Tools” screen. 
c All enrolled subjects will be randomized to one of two treatment arms (Prismocitrate Group or Control Group) in a 1:1 manner using a central 
randomization scheme. 
d Prismaflex System information will include collection of the Prismaflex System serial number as well as the date and time of study CRRT initiation and 
termination (each event over the 120 hour Treatment Period). This will include recording all disruptions in treatment (eg, circuit clotting, machine 
malfunction, patient required treatment/diagnostic tests external to ICU). 
e Prismaflex M150 Set information will include the sequential set number, product lot number, date and time for installation and replacement, and the reason 
for replacement. The end of the extracorporeal circuit life will be defined by time at which one or both of the following Prismaflex System 


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alarms/conditions occur after which the study CRRT treatment will be terminated and the patient will end the treatment period if mitigation of the 
following alarms is not possible: “Warning: Filter Clotted” and/or "Advisory TMP Too High". 
f Blood access information will include catheter-type, manufacturer, length & size, and catheter anatomical insertion location. 
g CRRT treatment modality will be confirmed as CVVHDF (Hemodiafiltration). 
h CRRT prescription will include patient fluid removal flow rate (mL/hour), post-filter replacement flow rate (mL/hour), PBP flow rate (mL/hour), BFR 
(mL/hour), dialysate flow rate (mL/hour), Prismocitrate 18 flow rate (mL/hour) and calcium gluconate or calcium chloride infusion details. 
i Priming solution formulation, brand name/manufacturer; Dialysate and replacement solution prescription information will include the brand 
name/manufacturer, formulation, and volume. The initial prescription will be recorded along with any changes throughout the Treatment Period. 
j  Anticoagulation information will include confirmation if the patient was randomized to ‘Prismocitrate 18’ or ‘no systemic anticoagulation’. 
k Clinical laboratory evaluations are presented in detail in Appendix 1. 
l Blood pressure including mean arterial pressure is collected at baseline (after randomization but before the initiation of study CRRT) and at 6 hour intervals 
during the Treatment Period up to 120 hours of study CRRT, as well as at End of Treatment. 
m Effluent volume (in mL) will be recorded from the Prismaflex System history screen. In the Prismaflex software, the starting time for the charting interval 
will be set (eg, at 8:00 am) and the volumes and doses will be stored for each day starting at that time. 
n Bleeding events information will include number, location, duration, estimated blood loss, and adverse event data (if applicable). 
o All blood transfusions information will include: (number, type, and number of units infused), relevant laboratory parameters (ie, hemoglobin/hematocrit 
and platelet values, etc.), as well as adverse event data (if applicable). 
p Patient Fluid Removal data collection will include post-treatment weight, the amount of fluid removed, and administration of input therapeutic fluids. 


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Appendix 3 Investigator’s Signature 
Study Title: 
Clinical Evaluation of Use of Prismocitrate 18 in Patients Undergoing 
Acute Continuous Renal Replacement Therapy (CRRT) 
Study Number: 
1407-004 
Final Date: 
2016 FEB 08 
Amendment 1 Date 
Approved: 
Amendment 2 Date 
Approved: 
Amendment 3 Date 
Approved: 
2016 MAY 20 
 
2017 JAN 05 
 
2018 FEB 08 
I have read the protocol described above. I agree to comply with all applicable 
regulations and to conduct the study as described in the protocol. 
 
 
Signed:  
 
Date:  
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 
<enter address> 
<enter phone number> 
 
 

SAP_001.pdf: 
Prismocitrate 18 
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1407-004: Statistical Analysis Plan 
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Statistical Analysis Plan: 1407-004  
Study Title: 
Clinical Evaluation of Use of Prismocitrate 18 in 
Patients Undergoing Acute Continuous Renal 
Replacement Therapy (CRRT) 
Study Number: 
1407-004 
Study Phase:  
III 
Study Design 
Multi-center, prospective, non-blinded, one to one 
randomized study. A total of 160 adult patients, 80 in 
each study arm, will be enrolled at up to 
15 investigational sites in the US and Canada. 
Product Name: 
Prismocitrate 18 
Formulation/Indication: 
A replacement solution indicated for regional 
anticoagulation of the extracorporeal circuit in 
patients undergoing continuous renal replacement 
therapy (CRRT) 
Statistician: 
 
Baxter Healthcare Corporation 
One Baxter Parkway 
Deerfield, IL 60015 
Tel: 
 
Email: 
 
Sponsor: 
Baxter Healthcare Corporation 
One Baxter Parkway 
Deerfield, IL 60015 
Responsible Medical Officer: 
, MD, PhD 
 
Baxter Healthcare Corporation 
Final Date: 
26 JUN 2018 
Version: 
4.0 
 
 
 
 
 
 
 
 


Prismocitrate 18 
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Table of Contents 
1. SIGNATURE PAGE .......................................................................................................... 5 
2. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 6 
3. INTRODUCTION .............................................................................................................. 8 
3.1 Background and Rationale ......................................................................................... 8 
4. TRIAL OBJECTIVES....................................................................................................... 9 
4.1 Primary Objectives ...................................................................................................... 9 
4.2 Secondary Objectives .................................................................................................. 9 
4.3 Exploratory Objectives ............................................................................................... 9 
5. STUDY DESIGN AND CONDUCT CONSIDERATIONS ......................................... 9 
5.1 Study Design ............................................................................................................... 10 
5.1.1 Baseline Definition .............................................................................................. 10 
5.2 Sample Size ................................................................................................................. 10 
5.3 Randomization Procedure ........................................................................................ 11 
5.4 Schedule of Visits and Procedures .......................................................................... 12 
5.4.1 Schedule of Events .............................................................................................. 12 
5.4.2 Schedule of Blood Sampling.............................................................................. 14 
5.5 Efficacy Measures ...................................................................................................... 16 
5.5.1 Primary Efficacy Endpoint ............................................................................... 16 
5.5.2 Secondary Efficacy Endpoints .......................................................................... 16 
5.6 Safety Measures.......................................................................................................... 17 
5.7 Pharmacokinetic Parameters ................................................................................... 18 
5.8 Other Parameters....................................................................................................... 18 
5.9 Completion and Discontinuation ............................................................................. 18 
6. STUDY POPULATIONS ................................................................................................ 18 
6.1 Subject Disposition .................................................................................................... 20 
6.2 Analysis Populations .................................................................................................. 20 
6.2.1 Full Analysis Set (FA) ........................................................................................ 20 
6.2.2 Per-Protocol Analysis Set (PP) ......................................................................... 20 
6.3 Protocol Deviations .................................................................................................... 20 
7. SUBGROUPS .................................................................................................................... 21 
8. STATISTICAL ANALYSIS ........................................................................................... 21 


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8.1 General/Types of Analyses ....................................................................................... 21 
8.2 Handling of Missing Data ......................................................................................... 21 
8.3 Interim Analysis ......................................................................................................... 21 
8.4 Pooling Strategy for Study Sites .............................................................................. 22 
8.5 Blood Sampling Schedule and Additional Blood Draws...................................... 22 
8.6 Other Issues ................................................................................................................ 22 
9. DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................ 22 
10. ANALYSIS OF PHARMACOKINETICS AND PHARMACODYNAMICS ...... 23 
11. TREATMENT COMPLIANCE AND EXPOSURE ................................................ 24 
12. CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL ..................................................................................................................... 24 
13. EFFICACY PARAMETERS ....................................................................................... 24 
13.1 Primary Analysis...................................................................................................... 24 
13.1.1 Hypothesis Regarding Primary Endpoint .................................................... 26 
13.2 Sensitivity Analysis .................................................................................................. 28 
13.3 Secondary Analysis .................................................................................................. 29 
13.4 Exploratory Analyses .............................................................................................. 33 
13.5 Interim Analysis ....................................................................................................... 33 
13.6 Subgroup Analyses .................................................................................................. 33 
14. SAFETY AND TOLERABILITY ............................................................................... 33 
14.1 Adverse Events (AEs) .............................................................................................. 34 
14.2 Bleeding Events and Transfusions ........................................................................ 35 
14.3 Serum Bicarbonate, pH, Blood Total Calcium and Serum Electrolytes ......... 35 
14.4 Vital Signs, Creatinine, Blood Urea Nitrogen and Bleeding Parameters ....... 36 
15. OTHER RELEVANT DATA ANALYSES/SUMMARIES ..................................... 36 
16. REFERENCES ............................................................................................................... 37 
18. LIST OF TABLES, FIGURES AND LISTINGS ...................................................... 39 
19. DOCUMENT HISTORY .............................................................................................. 44 
 


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 List of Tables 
Table 1 Schedule of Events ................................................................................................. 12 
Table 2 Schedule of Blood Sampling ................................................................................. 14 
 List of Figures 
Figure 1. University of Alabama at Birmingham Continuous Venovenous 
Hemodiafiltration Protocol ......................................................................................... 32 
 


Prismocitrate 18 
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1. SIGNATURE PAGE 
 
Study Title: 
Clinical Evaluation of Use of Prismocitrate 18 in Patients 
Undergoing Acute Continuous Renal Replacement Therapy 
(CRRT) 
Study Number: 
1407-004 
Statistician: 
 
 
I have read this statistical analysis plan and confirm that to the best of my knowledge it 
accurately describes the planned statistical analysis of the study. 
 
 
Prepared by: 
 
Date: 
 
 
 
Baxter Research & Development 
Baxter Healthcare Corporation 
 
 
Approved by: 
 
Date: 
 
, MD, PhD 
 
Baxter Research & Development 
Baxter Healthcare Corporation 
 
 
Approved by: 
 
Date: 
 
  
 
Baxter Research & Development 
Baxter Healthcare Corporation 
 






Prismocitrate 18 
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2. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
ABBREVIATION 
DEFINITION 
ABG 
Arterial Blood Gases 
AE 
Adverse Event 
AKI 
Acute Kidney Injury 
ANCOVA 
Analysis of Covariance 
APACHE II 
Acute Physiology and Chronic Health Evaluation II Classification System 
β-hCG 
Serum Beta Human Chorionic Gonadotropin 
BFR 
Blood Flow Rate 
BL 
Baseline 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
Ca2+ 
Calcium  
CRF 
Case Report Form 
CRRT 
Continuous Renal Replacement Therapy 
CVVHDF 
Continuous Venovenous Hemodiafiltration 
ECMO 
Extracorporeal Membrane Oxygenation 
EOS 
End of Study 
EOT 
End of CRRT During Evaluation Period 
g/dL 
Grams per Deciliter 
HD 
Hemodialysis 
ICF 
Informed Consent Form 
iCa or iCa2+ 
Ionized Calcium 
ICU 
Intensive Care Unit 
INR 
International Normalized Ratio 
Kg 
Kilogram 
L 
Liter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mEq 
Milliequivalent 
mg 
Milligram 
mL 
Milliliter 
mmHg 
Millimeter of Mercury 


Prismocitrate 18 
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ABBREVIATION 
DEFINITION 
mmol 
Millimole 
MMRM 
Mixed-Effects Model Repeated Measures 
mOsm 
Milliosmol 
PBP 
Pre-blood Pump 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QB 
Blood Flow Rate (Real Blood Flow Pumped Out of the Patient) 
QD 
Dialysate Rate 
QE 
Effluent Rate 
QFR 
Fluid Removal Rate 
QPBP 
Pre-Blood Pump Infusion Rate 
QR 
Replacement Fluid Rate 
RCA 
Regional Citrate Anticoagulation 
RRT 
Renal Replacement Therapy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
TMP 
Transmembrane Pressure (mmhg) 
US 
United States 
 


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3. INTRODUCTION 
This Statistical Analysis Plan is intended to describe the planned statistical analysis of 
study 1407-004. 
3.1 Background and Rationale 
Prismocitrate 18 Solution is intended to be used as a replacement solution for regional 
anticoagulation of the extracorporeal circuit in acute kidney injury (AKI) patients treated 
with continuous renal replacement therapy (CRRT). Prismocitrate 18 is a CRRT solution 
developed by Gambro AB (now part of Baxter Healthcare Corporation) for use as both a 
replacement solution and an anticoagulant to prevent clotting of the extracorporeal 
circuit. Regional citrate anticoagulation (RCA) has been in use for renal replacement 
therapy (RRT) since 19611 for conventional hemodialysis (HD) and for CRRT since 
19902. Multiple publications in the literature document the use of RCA in RRT and 
CRRT. Recent meta-analyses of randomized controlled trials demonstrate benefits for 
RCA over standard heparin anticoagulation with respect to bleeding and circuit longevity 
in AKI patients treated with CRRT. 3-8 
The mechanism underlying the efficacy of citrate as an extracorporeal anticoagulant is 
chelation of calcium, an integral physiologic component of the clotting cascade. During 
CRRT with RCA, delivery of citrate to the “arterial” blood prior to the CRRT filter 
results in chelation of calcium, rendering blood passing through the filter effectively 
anticoagulated. After blood leaves the filter in the “venous” bloodline, the anticoagulant 
effect is reversed when the citrate containing blood is returned to the patient. The ionized 
calcium levels in the patient are maintained within normal levels by a calcium infusion.  
Due to the pivotal role played by calcium, frequent monitoring of both systemic (patient) 
and post-filter blood ionized calcium (iCa) concentrations is typically performed during 
RCA. Post-filter blood iCa concentration is considered an appropriate surrogate for 
assessing the level of anticoagulation achieved. 
Continuous renal replacement therapy comprises several different therapies used 
primarily for the management of AKI patients. These therapies differ with respect to the 
primary mechanism for solute removal (ie, diffusion and/or convection). The modality to 
be applied in this trial will be continuous venovenous hemodiafiltration (CVVHDF) in 
which solute clearance occurs by both diffusion and convection, achieved by the use of 
dialysate and replacement fluid, respectively. Prismocitrate 18 will serve as a 
replacement and anticoagulation solution containing citrate as both an anticoagulant and 
buffer source, the latter being necessary for the treatment of metabolic acidosis that 
routinely accompanies AKI or other serious conditions in CVVHDF, use of a cleared 


Prismocitrate 18 
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bicarbonate-containing dialysate not only provides additional solute clearance but also 
specifically affords the capability to modulate acid-base balance with changes in 
dialysate flow rate or composition. 
4. TRIAL OBJECTIVES 
4.1 Primary Objectives 
The primary objective of this study is to evaluate the efficacy of Prismocitrate 18 in 
prolonging extracorporeal circuit life in patients treated with CRRT. The Control Group 
will be patients receiving CRRT with no anticoagulation. 
4.2 Secondary Objectives 
The secondary objectives of this study are to evaluate the efficacy of Prismocitrate 18 in 
achieving appropriate anticoagulation through assessments of systemic and post-filter 
blood iCa concentrations, and to evaluate the efficacy of using Prismocitrate 18 in 
delivering the prescribed CRRT dose, with delivered dose based on total (daily) effluent 
volume and expressed as mL/kg/hour. Additionally, the safety profile will be evaluated 
through assessments of metabolic parameters, including serum bicarbonate, pH, base 
excess, iCa, total calcium, magnesium, chloride and other relevant serum electrolytes 
along with anion gap. The potential for the development of citrate accumulation will be 
evaluated specifically through assessment of the total calcium/iCa2+ ratio (both 
measurements in mmol/L), anion gap and base excess (along with pH). Finally, the 
potential for bleeding events (number, location, duration), and the number and type of 
blood transfusions along with the number of units infused will also be assessed.  
From the functional perspective, another secondary objective is to complete training on 
administration of Prismocitrate 18 and demonstrate the understanding of the user groups 
on how to use the solution by passing an assessment at the end of training. The user 
groups who need to be assessed prior to use of Prismocitrate 18 in the clinical trial setting 
will be comprised of physicians, nurses, and other clinicians who may be part of 
prescribing, initiating, or modifying treatment during the 120 hours evaluation period. 
4.3 Exploratory Objectives 
Not applicable. 
5. STUDY DESIGN AND CONDUCT CONSIDERATIONS 


Prismocitrate 18 
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5.1 Study Design 
This study is a multi-center, prospective, non-blinded, one to one randomized study. A 
total of 160 adult patients, 80 in each study arm, will be enrolled at up to 
15 investigational sites in the United States (US) and Canada. Patients meeting all of the 
inclusion criteria and none of the exclusion criteria of this protocol, and deemed treatable 
by either CRRT with Prismocitrate 18 solution or CRRT with no systemic 
anticoagulation, are eligible for enrollment in the study. If a patient is already receiving 
standard-of-care CRRT, they must be randomized within 24 hours of initiation of their 
standard-of-care CRRT. All patients will be treated with predilution CVVHDF as the 
study CRRT modality. Patients enrolled in the study will receive either Prismocitrate 18 
anticoagulation or no systemic anticoagulation during their study CRRT, and 
extracorporeal circuit life will be monitored for up to 120 hours of study CRRT 
(treatment period). During the treatment period, the adequacy of anticoagulation in the 
Prismocitrate 18 patients will be assessed by monitoring extracorporeal circuit pressures 
and by assessment of systemic and post-filter blood iCa concentrations. Patients will be 
monitored for acid-base parameters and serum electrolytes at baseline prior to any 
CRRT), initiation (after randomization but before the initiation of study CRRT) and at 
pre-determined intervals during treatment. Information on bleeding events (number, 
location, duration) and the number and type of blood transfusions along with the number 
of units infused will also be collected.  
5.1.1 Baseline Definition 
Baseline (BL) will be defined as the last measurement before the initiation of CRRT. If a 
patient has not been on standard-of-care CRRT, the Baseline and Initiation labs will be 
the same. In this case, the acceptable baseline laboratory measurements can be up to 1 
hour after initiation of CRRT.   
5.2 Sample Size 
A sample size of 80 patients in each treatment group will provide > 90% power for 
assessing the equality of the extracorporeal circuit life between treatment groups using a 
two-sided clustered log-rank test with an overall alpha level of 0.050. This is based on the 
following assumptions: median circuit lives of 
 and 
 in the  
Prismocitrate 18 and Control group, 
 filters per patient (during the Evaluation 
period of 120 hours) in the Prismocitrate 18 and Control group, 
 of subjects 
discontinuing therapy for reasons other than due to clotting of the circuit (i.e., common 
exponential dropout rate of 
), a single interim analysis when 50% of patients have 


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completed treatment, and combination of results from the two study stages (prior to vs 
after interim analysis) using Fisher’s combination test9. 
5.3 Randomization Procedure 
All enrolled subjects will be randomized to one of two treatment arms (Prismocitrate 18 
or Control Group) in a 1:1 manner using a site-stratified central randomization scheme. 


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5.4 Schedule of Visits and Procedures 
5.4.1 Schedule of Events 
The schedule of events is presented below in Table 1. 
Table 1 Schedule of Events 
Evaluation 
Screening and 
Baseline 
During Study CRRT 
Treatment Period 
End of Study CRRT 
During Treatment 
Period 
Informed Consent 
X 
 
 
Demographics, Medical and Medication 
Historiesa 
X 
 
 
Physical Examination 
X 
 
X 
Height and BMI 
X 
 
 
Weightb 
X 
X 
X 
Vital Signs 
X 
 
X 
Randomizationc 
X 
 
 
Prismaflex System Informationd 
 
X 
 
Prismaflex M150 Set Information and 
Extracorporeal Circuit Assessmente 
 
X 
 
Blood Access Informationf 
 
X 
 
CRRT Treatment Modalityg 
 
X 
 
CRRT Treatment Prescriptionh 
 
X 
 
Priming Solutioni 
 
X 
 
Replacement Solution Prescriptioni 
 
X 
 
Dialysate Prescriptioni 
 
X 
 
Anticoagulation Informationj 
 
X 
 
Clinical Laboratory Evaluationsk 
 
X 
X 
Blood Pressure and Mean Arterial 
Pressurel  
X 
X 
X 
Effluent Volume (in ml)m 
 
X 
X 
AEs/SAEs  
 
X 
X 
Concomitant Medications 
 
X 
X 
Bleeding Eventsn 
 
X 
 
Transfusionso 
 
X 
 
Patient Fluid Removalp 
 
X 
 


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Evaluation 
Screening and 
Baseline 
During Study CRRT 
Treatment Period 
End of Study CRRT 
During Treatment 
Period 
a Demographics will include gender, illness severity score, chronological age at consent, pre-study CRRT weight 
and height. Medical history will include indication for CRRT, known allergies, past/present conditions as well as 
surgical procedures. Medication history will include all medications taken and/or prescribed during the 7-day 
window prior to informed consent and those relevant to ICU admission. 
b In addition to the pre-study CRRT weight, during the treatment period, daily weight will need to be obtained and 
recorded/entered each morning (eg, at 8:00 am) in the “System Tools” screen. 
c All enrolled subjects will be randomized to one of two treatment arms (Prismocitrate Group or Control Group) in 
a 1:1 manner using a central randomization scheme. 
d Prismaflex System information will include collection of the Prismaflex System serial number as well as the date 
and time of study CRRT initiation and termination (each event over the 120 hours treatment period). This will 
include recording all disruptions in treatment (eg, circuit clotting, machine malfunction, patient required 
treatment/diagnostic tests external to ICU). 
e Prismaflex M150 Set information will include the sequential set number, product lot number, date and time for 
installation and replacement, and the reason for replacement. The end of the extracorporeal circuit life will be 
defined by time at which one or both of the following Prismaflex System alarms/conditions occur after which the 
study CRRT treatment will be terminated and the patient will end the treatment period if mitigation of the 
following alarms is not possible: “Warning: Filter Clotted” and/or "Advisory TMP Too High". 
f Blood access information will include catheter-type, manufacturer, length & size, and catheter anatomical 
insertion location. 
g CRRT treatment modality will be confirmed as CVVHDF (Hemodiafiltration). 
h CRRT prescription will include patient fluid removal flow rate (mL/hour), post-filter replacement flow rate 
(mL/hour), PBP flow rate (mL/hour), BFR (mL/hour), dialysate flow rate (mL/hour), Prismocitrate 18 flow rate 
(mL/hour) and calcium gluconate or calcium chloride infusion details. 
i Priming solution formulation, brand name/manufacturer; Dialysate and replacement solution prescription 
information will include the brand name/manufacturer, formulation, and volume. The initial prescription will be 
recorded along with any changes throughout the treatment period. 
j  Anticoagulation information will include confirmation if the patient was randomized to ‘Prismocitrate 18’ or ‘no 
systemic anticoagulation’. 
k Clinical laboratory evaluations are presented in detail in Table 2.  
l Blood pressure including mean arterial pressure is collected at baseline (after randomization but before the 
initiation of study CRRT) and at 6 hour intervals during the treatment period up to 120 hours of study CRRT, as 
well as at End of Treatment. 
m Effluent volume (in mL) will be recorded from the Prismaflex System history screen. In the Prismaflex software, 
the starting time for the charting interval will be set (e.g., at 8:00 am) and the volumes and doses will be stored 
for each day starting at that time. 
n Bleeding events information will include number, location, duration, estimated blood loss, and adverse event data 
(if applicable). 
o All blood transfusions information will include: (number, type, and number of units infused), relevant laboratory 
parameters (i.e., hemoglobin/hematocrit and platelet values, etc.), as well as adverse event data (if applicable). 
p Patient Fluid Removal data collection will include post-treatment weight, the amount of fluid removed, and 
administration of input therapeutic fluids. 
 
 


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5.4.2 Schedule of Blood Sampling  
The schedule of blood sampling is presented below in Table 2. 
Table 2 Schedule of Blood Sampling 
Parameter 
Before 
Randomization 
After 
Randomization 
but Before 
Initiation of 
Study CRRTa 
During Study CRRTb 
End of Study CRRT 
During Treatment 
Periodc 
Complete Blood 
Count (CBC)  
Blood Lactate 
Measurement 
Screening 
 
 
 
pH  
Base Excess  
(ABG or VBG) 
 
Baseline and 
Initiation 
At 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66, 
72, 78, 84, 90, 96, 102, 
108, 114, & 
120 Hoursb 
When Study CRRT is 
Terminated 
Serum 
Bicarbonate 
 
Baseline and 
Initiation 
At 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66, 
72, 78, 84, 90, 96, 102, 
108, 114, & 
120 Hoursb 
When Study CRRT is 
Terminated 
Systemic iCa2+ 
 
Baseline, 1 Hour 
Prior to Initiation 
of Study CRRT  
 
 At 1, 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66, 
72, 78, 84, 90, 96, 102, 
108, 114, & 
120 Hoursb 
When Study CRRT is 
Terminated 
Post-Filter iCa2+ 
(Prismocitrate 18 
Arm Only) 
 
 
 At 1, 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66, 
72, 78, 84, 90, 96, 102, 
108, 114, & 
120 Hoursb 
When Study CRRT is 
Terminated 
Serum 
Electrolytes: 
Sodium    
Potassium   
Chloride   
Phosphate 
Magnesium 
Anion Gap 
 
Baseline and 
Initiation 
At 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66 
72, 78, 84, 90, 96, 102, 
108, 114, & 
120 Hoursb 
When Study CRRT is 
Terminated 
Creatinine  
BUN 
 
Baseline and 
Initiation 
 Twice Daily 
When Study CRRT is 
Terminated 


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Parameter 
Before 
Randomization 
After 
Randomization 
but Before 
Initiation of 
Study CRRTa 
During Study CRRTb 
End of Study CRRT 
During Treatment 
Periodc 
Bleeding 
Parameters:  
PT/INR             
PTT      
Hemoglobin  
Hematocrit    
Platelet Count 
Screening 
Baseline and 
Initiation 
At Least Once Daily 
When Study CRRT is 
Terminated 
Blood Total 
Calcium 
Total 
Calcium/iCa2+ 
Ratio 
Screening 
Baseline and 
Initiation 
At 1, 6, 12, 18, 24, 30, 
36, 42, 48, 54, 60, 66 
72, 78, 84, 90, 96, 102, 
108, 114, & 
120 Hoursb 
When Study CRRT is 
Terminated  
Liver Function 
Tests:            
Alanine 
Transaminase 
[ALT]       
Aspartate 
Transaminase 
[AST]   
Alkaline 
Phosphatase   
[ALP]              
Total Bilirubin 
Screening 
Baseline 
As Determined by 
Local Standard-of-care 
As Determined by 
Local Standard-of-care 
ABG=arterial blood gases; ALT=alanine transaminase; AST=aspartate transaminase; ALP=alkaline 
phosphatase; CBC=complete blood count; CRRT=continuous renal replacement therapy; iCa2+=ionized 
calcium; BUN=blood urea nitrogen, PT=prothrombin time; INR=international normalized ratio; PTT=partial 
thromboplastin time; VBG=venous blood gases 
a If patient has not been on standard-of-care CRRT, the Baseline and Initiation labs are the same. If patient has 
been on standard-of-care CRRT for < 24 hours the Baseline labs are those collected prior to the standard-of-care 
CRRT with exception of systemic iCa2+, which blood must be drawn 1 hour prior to initiation of Study CRRT. 
For Baseline Labs, the acceptable blood draw window is - 24 hours. For Initiation Labs, the acceptable blood 
draw window is ± 1 hour. 
b Acceptable blood draw window for serum bicarbonate, pH, systemic & post-filter iCa2+, blood total calcium, 
total calcium/ iCa2+ ratio and serum electrolytes (sodium, potassium, chloride, phosphate, magnesium, anion 
gap and base excess) is ± 1 hour. 
c If a parameter has not been measured when study CRRT was terminated, the last available measurement 
collected during the treatment period will be used as the end of study measurement  


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5.5 Efficacy Measures 
5.5.1 Primary Efficacy Endpoint 
The Prismaflex M150 Set extracorporeal circuit life will be assessed as a time-to-event 
endpoint over a maximum 120 hours by the duration of time for which each 
Prismaflex M150 Set can be used continuously over a maximum 72 hours period in each 
patient. The Prismaflex M150 Set will be replaced any time CRRT is stopped during the 
treatment period (regardless of duration) or any time a circuit is used for 72 continuous 
hours (i.e., "Advisory Time to Change Set"). The end of the extracorporeal circuit life 
will be defined by the occurrence of one or both of the following Prismaflex System 
alarms/conditions if the alarm cannot be mitigated. At this point, CRRT will be 
terminated and the extracorporeal circuit replaced: 
• “Warning: Filter is Clotted” and/or 
• "Advisory TMP Too High" 
Note: The nurse at the clinical site will document the alarm and rationale to stop 
treatment on the eCRF. In addition, the Prismaflex logging information from the 
data cards (one card per patient) will be collected on an ongoing basis and 
anonymized data will be sent to Baxter for technical analysis. An Independent 
Adjudicator will make the final determination of the alarm cause by examining 
the applicable historical electronic data available surrounding the alarm events 
(for further details please see Section 9.9 Primary Endpoint Adjudication of study 
protocol). 
The extracorporeal circuit life will be censored for cases where the Prismaflex M150 Set 
has been replaced for reasons other than reaching the end of the extracorporeal circuit 
life. Only filters for which the end of the extracorporeal circuit life was reached (i.e., one 
or both Prismaflex System alarms/conditions occurred as defined above and alarm causes 
have been confirmed by an Independent Adjudicator) will be considered ‘events’ in terms 
of the statistical analysis. 
5.5.2 Secondary Efficacy Endpoints 
Systemic and post-filter blood iCa concentrations will be assessed at baseline (systemic 
only), 1 hour and every 6 hours during the 120 hours Evaluation period and at 120 hours 
or end of the Evaluation period from the initiation of CRRT in each patient as indications 
of both the extent of calcium chelation prior to the CRRT filter and calcium restoration 
after the CRRT filter. 


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Delivery of the prescribed CRRT dose will be based on daily recordings of both the 
effluent volume (in mL) and the patient's weight. These data will be used to calculate 
delivered dose (mL/kg/hour). 
5.6 Safety Measures 
1. Serum bicarbonate and pH will be measured at baseline and every 6 hours during 
the 120 hours Evaluation period and at 120 hours or end of the Evaluation period. 
2. Blood total calcium concentrations will be measured at baseline, 1 hour and every 
6 hours during the 120 hours evaluation period and at 120 hours or end of the 
Evaluation period from the initiation of CRRT.  
3. Serum electrolytes (sodium, potassium, chloride, phosphate and, magnesium) will 
be measured at baseline and every 6 hours during the 120 hours evaluation period 
and at 120 hours or end of the evaluation period. 
4. As indicators of citrate accumulation (along with pH), the total calcium/ iCa2+ 
ratio (both measurements in mmol/L) will be measured at baseline, 1 hour and 
every 6 hours during the 120 hours evaluation period and at 120 hours or end of 
evaluation period, anion gap and base excess will be measured at baseline and 
every 6 hours during the 120 hours evaluation period and at 120 hours or end of 
evaluation period. 
5. The number, location and duration of bleeding events during the 120 hours 
Evaluation period will be collected. If a blood transfusion is needed during the 
120 hours Evaluation period, the number and type of transfusions along with the 
number of units infused will be collected. 
6. Change from baseline to final measurement in laboratory and vital signs 
measurements will be collected. 
7. The incidence of adverse events (AEs) and serious adverse events (SAEs) from 
the time the patient signs the informed consent form (ICF) until the end of the 
study will be collected. 
 


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5.7 Pharmacokinetic Parameters 
Not applicable. 
5.8 Other Parameters 
The end users who need to be assessed prior to use of Prismocitrate 18 in the clinical trial 
setting (as delegated by an investigator) will be comprised of physicians, nurses, and 
other clinicians who may be part of prescribing, initiating, or modifying treatment during 
the 120 hours Evaluation period. A descriptive summary of training results on 
administration of Prismocitrate 18 will be provided in the Clinical Study Report 
following completion of the study. 
5.9 Completion and Discontinuation 
The number of completed and discontinued subjects along with reasons for 
discontinuation will be summarized. Individual reasons for study discontinuation will be 
listed. 
6. STUDY POPULATIONS 
The following inclusion and exclusion criteria were applied in the selection of study 
patients: 
Inclusion Criteria 
1. Patient, or legally-authorized representative, has signed a written ICF. 
2. Patient must be receiving medical care in an intensive care unit (ICU) [e.g., 
medical ICU, surgical ICU, cardiothoracic ICU, Trauma ICU, Mixed ICU, other]. 
3. Patient age ≥ 18 years. 
4. Adult patients with AKI or other serious conditions who require treatment with 
CRRT. 
5. Patients are expected to remain in the ICU and on CRRT for at least 72 hours 
after randomization. 
6. Patients already receiving standard-of-care CRRT must be randomized within 24 
hours of initiation of their standard-of-care CRRT. 
Exclusion Criteria 
1. Patients requiring systemic anticoagulation with antithrombotic agents for reasons 
other than CRRT. The exception is patients receiving subcutaneous heparin for 


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deep vein thrombosis prophylaxis according to institutional practice or patients on 
aspirin may be enrolled. 
2. Patients in whom citrate anticoagulation is contraindicated such as patients with a 
known allergy to citrate or who have experienced adverse events associated with 
citrate products including patients with a prior history of citrate toxicity or 
patients with uncorrected severe hypocalcemia (whether in the context of current 
citrate administration or due to the underlying disease state). 
3. Patients who are not candidates for CRRT. 
4. Patients who are receiving extracorporeal membrane oxygenation (ECMO) 
therapy. 
5. Patients with severe coagulopathy [i.e., platelets < 30,000/mm3, international 
normalized ratio (INR) > 2, partial thromboplastin time (PTT) > 50 seconds]; 
including severe thrombocytopenia (platelets < 30,000/mm3), HIT (hereditary 
idiopathic thrombocytopenia), ITP (idiopathic thrombocytopenia purpura), and 
TTP (thrombotic thrombocytopenia purpura) should not be enrolled in the trial. 
6. Patients with fulminant acute liver failure or acute on chronic liver failure as 
documented by a Child-Pugh Liver Failure Score > 10. 
7. Patients with refractory shock associated with persistent, worsening lactic acidosis 
(lactate >4 mmol/L).  However, patients with improving subsequent serum lactate 
levels may be enrolled.   
8. Patients unlikely to survive at least 72 hours. 
9. Female patients who are pregnant, lactating, or planning to become pregnant 
during the study period. Note: A female patient of childbearing potential, defined 
as a woman less than 55 years old who has not had partial or full hysterectomy or 
oophorectomy, must have a negative serum beta human chorionic gonadotropin 
(β-hCG) pregnancy test during the screening period (after consent and prior to 
randomization) and before CRRT treatment begins. A female patient of 
childbearing potential must use medically acceptable means of contraception 
during their participation in the study. 
10. Patients who are currently participating in another interventional clinical study. 
11. Patients with a medical condition that may interfere with the study objectives. 


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6.1 Subject Disposition 
The number of study patients included in the two (2) different analysis sets will be 
summarized by treatment group.   
6.2 Analysis Populations 
Statistical analyses will be carried out based on two (2) different analysis sets: 
6.2.1 Full Analysis Set (FA) 
The Full Analysis Set (FA) will include all randomized patients who received any study 
treatment for any period of time.  The Full Analysis set will be analyzed based upon the 
subjects randomized treatment.   
6.2.2 Per-Protocol Analysis Set (PP) 
The Per-Protocol Analysis Set (PP) defines a subset of the FA including patients who  
• fulfill all inclusion criteria 
• do not meet any of the exclusion criteria 
• were randomized and treated according to the randomization scheme 
• received at least 80% of their prescribed CRRT dose  
• do not have major protocol deviations that might impact the assessment of the 
primary endpoint (e.g., mechanical malfunction of the machine) 
• have available survival data for extracorporeal circuit life of at least one circuit 
(i.e., time to occurrence of Prismaflex System alarms/conditions as outlined in 
Section 5.5.1 Primary Efficacy Endpoint, or censored circuit life if no system 
alarms/conditions occurred until the circuit was used for 72 continuous hours or if 
CRRT was stopped during the evaluation period for reasons other than system 
alarms/conditions). 
The Per Protocol Set will be analyzed based upon the subjects randomized treatment.   
6.3 Protocol Deviations 
Protocol Deviations will be classified as major and minor deviations.    
Subjects with any major protocol deviation that may impact the primary endpoints will be 
excluded from the per-protocol analysis set, including but not limited to the following: 


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• Violations of inclusion and/or exclusion criteria 
• Use of prohibited medication known to influence the primary endpoint 
• Randomization or treatment errors 
• Improper administration of study product  
• Improper assessment of the primary endpoint 
• Any other protocol deviations that may impact the primary endpoints  
Frequencies of protocol deviations will be presented by study site and across all study 
sites on a deviation as well as on a subject basis.  
7. SUBGROUPS 
No specific subgroup analyses are planned for this study.  
8. STATISTICAL ANALYSIS 
Unless specifically stated otherwise, throughout the document, Prismocitrate 18 relates to 
the study group receiving CRRT with Prismocitrate 18 solution whereas Control relates 
to the study group receiving CRRT with no systemic anticoagulation before a potential 
cross-over of treatments.  
8.1 General/Types of Analyses 
Unless otherwise specified, treatment effects will be evaluated on the basis of a 2-sided 
significance level of 0.050 (when rounded to 3 decimal places). All analyses will be 
performed using Statistical Analysis Software (SAS®), SAS/GRAPH® and SAS/STAT® 
software, Version 9.2 of SAS for Windows, Copyright© 2018 SAS Institute Inc., on a 
Microsoft Windows Server. SAS and all other SAS Institute Inc. product or service 
names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA10. 
8.2 Handling of Missing Data 
Missing data will neither be estimated nor replaced. No imputation of missing values will 
be performed. The survival type nature of data of the primary efficacy endpoint allows 
inclusion of any available information on extracorporeal circuit life in the statistical 
analysis according to the defined analysis populations.   
8.3 Interim Analysis 
A single interim analysis will be conducted when 50% of patients have completed 
treatment. The purpose of the interim analysis is to evaluate the primary efficacy 


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endpoint for overwhelming efficacy, or the need to adjust the sample size. Sample size 
re-estimation at the interim analysis will be based on Fisher’s criterion (Fisher’s 
combination test). For further details please refer to Section 13.5 Interim Analysis. 
8.4 Pooling Strategy for Study Sites 
Data will be pooled across all study sites unless indicated otherwise. Protocol deviations 
will be presented in total across all study sites and split by study sites. 
8.5 Blood Sampling Schedule and Additional Blood Draws 
The compliance of the study sites with the specified blood sampling schedule will be 
analyzed using frequencies and percentages. The number of subjects with blood draws 
inside and outside the defined blood sampling time window will be summarized per 
blood sampling time point and study site. 
Laboratory measurements resulting from additional blood draws will not be presented in 
descriptive summaries, though will be listed and used in mixed-effects model repeated 
measures (MMRM) analysis.   
8.6 Other Issues 
Not applicable. 
9. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Demographic and Baseline Characteristics will be summarized by randomized treatment 
group, and for the FA only.   
Demographic data include age, gender, ethnicity, race, height, weight, body mass index 
(BMI) calculated as weight(kg)/height(m)2 and illness severity score Acute Physiology 
and Chronic Health Evaluation II classification system (APACHE II).  
Other baseline/screening data include: 
1. Indication for CRRT (cause of AKI will be specified) 
2. Known allergies 
3. Current medications and medications prescribed during the 30-day period prior to 
informed consent 
4. Medical history 
5. Physical examination 


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6. Vital signs 
7. Laboratory parameters 
The following describes the summary of the various types of baseline data either as 
continuous data or as frequency tabulation: 
1. Age will be summarized as a continuous variable across subjects, and as 
frequencies within age groups (18-35, 36-45, 46-55, 56-65, >65 years).  
2. Height, weight, BMI and illness severity score APACHE II will be summarized as 
a continuous variable across subjects.  
3. The frequencies for gender, ethnicity and race will be tabulated. 
4. The frequencies for current medications and medications prescribed during the 
30-day period prior to informed consent will be tabulated based on the medication 
names coded according to the WHO Drug Dictionary. 
5. Physical examinations will be tabulated as those findings which are deemed: 
‘Normal’, ‘Abnormal, Not Clinically Significant’, ‘Abnormal, and Clinically 
Significant’. 
6. Vital signs will be summarized as a continuous variable across subjects.  
7. Laboratory parameters will be summarized as a continuous variable across 
subjects.   Laboratory results will also be listed with clinical significance.   
Continuous data will typically be summarized using the number of subjects n, mean, 
standard deviation, minimum, median and maximum. Treatment comparisons will be 
based on t-test or Wilcoxon rank sum test, as applicable. Frequencies will be compared 
between treatment groups utilizing Fisher’s exact test. 
The following describes the baseline data that will only be listed: 
1. Indication for CRRT (including specification for AKI subjects) 
2. Known allergies 
3. Medical history including Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class, MedDRA Preferred Term, medical 
condition/surgical procedure reported term, date of onset and information if the 
medical history is still present and if it was treated. 
10. ANALYSIS OF PHARMACOKINETICS AND PHARMACODYNAMICS 
Not applicable. 


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11. TREATMENT COMPLIANCE AND EXPOSURE 
Due to the ICU setting of the study, patient treatment compliance is not applicable.  
Treatment exposure will be analyzed based on the percentage of the prescribed dose 
actually administered to the patient. Please refer to Section 13.3 Secondary Analysis for 
further details. Additionally, the number and percentage of subjects completing a certain 
overall CRRT treatment duration and the number and percentage of subjects using a 
certain number of extracorporeal circuits during the 120 hours evaluation period will be 
provided.  
The number and percentage of subjects completing a certain extracorporeal circuit   
treatment time of the defined maximum 72 hours period for which each Prismaflex M150 
Set can be used continuously along with reasons for treatment termination and location of 
clotting (Prismaflex M150 set or blood access device or in both) will be provided as well.  
Overall CRRT treatment duration and the number of extracorporeal circuits used during 
the 120 hours evaluation period will be summarized using the number of subjects n, 
mean, standard deviation, median, minimum and maximum. 
12. CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE 
PROTOCOL 
No changes in conduct or planned analyses from the protocol.     
13. EFFICACY PARAMETERS 
13.1 Primary Analysis 
The primary endpoint of the study, extracorporeal circuit life, will be analyzed as a time-
to-event endpoint (survival analysis).  
The extracorporeal circuit life of a filter that is replaced due to continuous use for 72 
hours, will be censored for the statistical analysis. Likewise, filters that are in use when 
the end of the observation period of 120 hours is reached, will be censored at their current 
duration of usage at the end of the observation period. Filters that are replaced any time 
CRRT is stopped for reasons other than filter clotting (including drop-outs and switches 
to therapies other than Prismocitrate 18 or control), will be censored at their current 
duration of usage. Only filters that are replaced due to filter clotting or excessive 
transmembrane pressure as indicated by system alarms/conditions and confirmed by an 
Independent Adjudicator will be considered ‘events’ in the statistical survival analysis. 
The context and data/time of two alarms (as below) used in the independent adjudication  


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• Warning: Filter Clotted” and/or  
• “Advisory TMP Too High”  
will be derived from the data card. The date and time of first occurrence of one or both 
alarms above that could not be successfully mitigated by the study site, will be 
considered as the end of the filter life if the event (alarm) is confirmed to be caused by 
filter clotting by the independent adjudicator. Also, the date and time recorded on data 
card for filter start, replace and/or end will be used to calculate the filter life during the 
independent adjudication.  
If the reason for a filter change recorded on the eCRF is different from the indication 
from adjudication result (e.g. eCRF recorded a reason for filter change for any reasons 
other than the two alarm, but the adjudication result showed as filter clotted), the 
adjudication result will be used to determine if it is considered an ‘event’ in the statistical 
survival analysis.  
In some scenarios, where no independent adjudication could be performed (e.g. missing 
data card file), the eCRF recorded filter start, end, and change reason will be used in the 
analysis of filter life.  
Filters used after a patient crossed-over treatment to the other study treatment group 
(switch from Prismocitrate 18 to Control, or switch from Control to Prismocitrate 18) will 
be analyzed under the original, randomized treatment assignment following the intent-to-
treat principle. Each filter used during the 120 hours observation period or until treatment 
is finished will be included in the statistical analysis (several filters per patient). The 
potential dependence between extracorporeal circuit lives within the same patient will be 
accounted for using a clustered log rank test. 
Separate estimates per treatment group will be provided for the primary endpoint based 
on Kaplan-Meier methodology. These estimates of the survival functions will be 
graphically displayed and tabulated as cumulative distribution functions. Characteristic 
values of these functions such as Q1, median survival time and Q3, will be provided and 
differences between estimated survival functions will be assessed using a clustered log 
rank test 11.  
This clustered log rank test provides advantages over readily available methods to 
analyze clustered survival data, such as the PHREG procedure using the covariance 
sandwich estimator option and the NLMIXED procedure for accelerated failure time 
frailty models, both available in SAS, due to its complete non-parametric nature. No 


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assumptions about the distribution of the data or the structure of the covariance matrix 
have to be made. Details on the underlying clustered log rank test are provided in Section 
13.1.1 Hypothesis Regarding Primary Endpoint.  
Analyses of the primary endpoint will be carried out on the FA based on the randomized 
treatment groups (intent-to-treat principle) as well as the PP. 
An interim analysis will be carried out after 50% of subjects completed treatment. Please 
refer to Section 13.5 Interim Analysis for further details regarding the interim analysis. 
The study will be stopped early due to overwhelming efficacy when a p value of < 0.0087 
is observed using the clustered log-rank test at the interim analysis (critical value based 
on Bauer & Koehne9 procedure with no early stopping for futility). If p ≥ 0.0087 and the 
study continues enrollment into a second stage, Fisher’s combination test will be 
performed at the end of the study using a critical value of 0.0087 (cα) which guarantees 
that the overall Type I error is controlled and preserved at a maximum of 0.05: 
)]
1(
2
1
exp[
2
4
2
1






c
p
p
 
where p1 is the observed error probability for the test in the subsample of subjects 
investigated before the interim analysis, 
and p2 is the observed error probability for the test in the subsample of subjects enrolled 
after the interim analysis, 
and 
)
1(
2
4



 is the (1-α)-quantile of the central χ2 distribution with 4 degrees of 
freedom.  
If p1 ≤ cα one could already stop at the interim analysis with the rejection of the null 
hypothesis since p2 ≤ 1 holds per definition. 
13.1.1 Hypothesis Regarding Primary Endpoint 
The following hypothesis will be tested to compare the Prismaflex M150 Set 
extracorporeal circuit life between Prismocitrate 18 and Control group. 
 
Null hypothesis 
 
 
H0:  ΛP = ΛC 
 
Alternative hypothesis 
 
HA:  ΛP ≠ ΛC 


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where ΛP relates to the cumulative hazard function for the Prismocitrate 18 group and ΛC 
relates to the cumulative hazard function for the Control group. 
To test the null hypothesis, the following test statistic for the clustered log rank test will 
be calculated:  




2
1
1
g
K
k
gk
g
LR
CLR
 
where g represents the treatment group (g = 1 for Prismocitrate 18 and g = 2 for Control) 
and LRgk is a partition of the log rank statistic for group g and cluster k. The number of 
clusters Kg can differ between treatment groups g. 
The total variance can be estimated from the within cluster mean squared error MSEgk. 
Since the clusters and treatment groups are independent the MSEgk can be summed across 
clusters to find the total variance for CLR: 




2
1
1
)
var(
g
K
k
gk
g
MSE
CLR
 
2)
(
gk
gk
LR
E
MSE

 
The log rank statistic for group g and cluster k can be derived as follows: 








2
1
'
1
'
1
'
''
'
''
'
''
'
''
'
''
'
1
'
'
'
)
(
)
(
)
(
)
(
)
(
)
(
g
K
k
n
i
i
k
g
i
k
g
g
i
k
g
i
k
g
gk
i
k
g
n
i
gki
g
gki
gki
gk
g
k
g
gk
t
Y
t
Y
t
W
t
Y
t
Y
t
W
n
LR


 
where W is a weight function specific to the log rank test: 
)
(
)
(
)
(
)
(
2
1
gki
gki
gki
gki
t
Y
t
Y
t
Y
t
W

 
and n is the total number of observations, 
ngk is the number of observations in cluster k within treatment group g, 
δgki is the number of failures in group g and cluster k, 


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Yg(tgki) is the number at risk in group g at the observed time (either censoring or failure) 
for observation i in group g and cluster k, 
Ygk(tg’k’i’) is the number at risk in group g and cluster k at some time t where g’, k’ and i’ 
can vary independent of g, k and i to any value within the range of g, k and i. 
It has been proven that CLR converges to a normal distribution under H0. Thus, the Wald 
test resolves to a standard normal distribution: 
)1,0
(
~
)
var(
N
CLR
CLR
Z 
 
According to the standard procedure for any statistical test we will reject H0 when Z 
exceeds the critical value for a given level of Type I error.  
At Interim Analysis: 
The p-value p1 will be based on the test statistic Z above and on the subset of subjects 
completing treatment at the time point of the interim analysis (50% of subjects). 
If p1 < 0.0087, reject H0 and claim difference in cumulative hazard function between 
treatment groups 
If p1 ≥ 0.0087, do not reject H0 and continue enrollment of subjects 
At Final Analysis (End of Study): 
The p-value p2 will be based on the test statistic Z above and on the subset of subjects 
enrolled after the interim analysis (50% of subjects). 
If p1p2 < 0.0087, reject H0 and claim difference in cumulative hazard function between 
treatment groups 
If p1p2 ≥ 0.0087, do not reject H0 
13.2 Sensitivity Analysis 
In order to check the robustness and validity of the primary analysis the analysis 
described under Section 13.1 Primary Analysis will be repeated using the PP.  For this 
analysis filters used after a patient crossed over treatment to the other study treatment 
group will not be included. 


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In order to assess a potential impact of informative censoring on the primary efficacy 
analysis, a sensitivity analysis will be carried out on the FA. The analysis of the primary 
efficacy endpoint will be repeated for 4 scenarios using the following assumptions for 
cases where therapy (ie, a filter) was discontinued for reasons other than filter 
clotting:    
1. Assume for each of these cases in the Prismocitrate 18 group that filter clotting 
(the primary event of interest; please see Section 5.5.1 Primary Efficacy 
Endpoint) occurred at the time of therapy discontinuation for reasons other than 
filter clotting; Assume for each of these cases in the Control group that filter 
clotting occurred at the time of therapy discontinuation for reasons other than 
filter clotting. 
2. Assume for each of these cases in the Prismocitrate 18 group that filter clotting 
occurred at the time of therapy discontinuation for reasons other than filter 
clotting; Assume for each of these cases in the Control group that filter clotting 
occurred at the largest event time observed in the Control group. 
3. Assume for each of these cases in the Prismocitrate 18 group that filter clotting 
occurred at the largest event time observed in the Prismocitrate 18 group; Assume 
for each of these cases in the Control group that filter clotting occurred at the time 
of therapy discontinuation for reasons other than filter clotting. 
4. Assume for each of these cases in the Prismocitrate 18 group that filter clotting 
occurred at the largest event time observed in the Prismocitrate 18 group; Assume 
for each of these cases in the Control group that filter clotting occurred at the 
largest event time observed in the Control group. 
13.3 Secondary Analysis 
A descriptive summary of systemic and post-filter blood iCa2+ concentrations as assessed 
at baseline (systemic only), 1 hour and every 6 hours during the 120 hours evaluation 
period and at 120 hours or end of the Evaluation period will be provided by treatment 
group. This summary will use the number of subjects n, mean, standard deviation, 
minimum, median and maximum. Changes from baseline will be analyzed by the number 
of subjects n, mean and standard deviation and t-test or Wilcoxon rank sum test, as 
applicable. 
The individual blood iCa2+ concentrations will further be displayed graphically over time 
for each of the two treatment groups. 


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A MMRM analysis will be deployed to evaluate differences between treatment groups in 
blood iCa2+ concentrations that are collected at baseline, 1 hour and every 6 hours during 
the 120 hours Evaluation period and at 120 hours or end of the Evaluation period from 
the initiation of CRRT. The model will include the illness severity score APACHE II, 
baseline iCa2+ concentration, treatment group and time point as fixed effects, and an 
interaction between time point and treatment group will be included in the model only if 
treatment effects differ statistically significantly over time (p < 0.01).    
In addition, frequencies and percentages will be provided for iCa2+ < 1.1 mmol/L by time 
point and treatment group (threshold indicative of decrease in iCa2+ despite adequate 
calcium compensation). 
Daily delivered dose and overall delivered dose (both in mL/kg/hour) will be summarized 
using the number of subjects n, mean, standard deviation, minimum, median and 
maximum, as applicable. Treatment exposure will be analyzed carrying out the same 
descriptive summary for the percentages of the prescribed dose actually administered to 
the patient.  
Effluent rate is considered an appropriate surrogate for the CRRT dose. Therefore, 
prescribed and delivered CRRT dose will be derived as follows based on the University 
of Alabama at Birmingham Continuous Venovenous Hemodiafiltration Protocol12 used in 
the study: 
R
FR
D
PBP
E
Q
Q
Q
Q
Q




 
where QE is the effluent rate (mL/hour), 
QPBP is the pre-blood pump infusion rate which is the Prismocitrate 18 flow rate 
(mL/hour), 
QD is the dialysate flow rate (mL/hour), 
QFR is the patient fluid removal rate (mL/hour), and 
QR is the post-filter replacement fluid rate (mL/hour). 
If one of the rate is missing, effluent rate will not be able to calculate. 
The prescribed dose (effluent rate) is calculated as: 
𝑃𝑟𝑒𝑠𝑐𝑟𝑖𝑏𝑒𝑑 𝐸𝑓𝑓𝑙𝑢𝑒𝑛𝑡 𝑅𝑎𝑡𝑒= 𝐵𝑜𝑑𝑦 𝑊𝑒𝑖𝑔ℎ𝑡 × 25 𝑚𝐿/𝑘𝑔/ℎ𝑟 


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If there are multiple records of effluent rate per day (e.g. due to infusion rate change) the 
average value will be used to calculate the delivered dose for that day. 
The percentage of the prescribed dose actually administered to the patient will be 
calculated by dividing the actual effluent rate by the prescribed effluent rate. Differences 
between treatment groups in the percentage of overall prescribed dose actually 
administered will be assessed on a 5% significance level using a two-sided t-test or 
Wilcoxon rank sum test, as applicable. However, the statistical test will only be carried 
out conditional upon a significant test result for the primary endpoint at the time point of 
the interim analysis or final analysis. This hierarchical test procedure guarantees that the 
overall Type I error is controlled and preserved at a maximum of 5%.  
The analysis of secondary efficacy endpoints will be carried out on the FA based on the 
randomized treatment groups (intent-to-treat principle). 




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13.4 Exploratory Analyses 
Not applicable. 
13.5 Interim Analysis 
The analysis described under 13.1 Primary Analysis will be carried out after 50% of 
patients have completed treatment. The purpose of the interim analysis is to evaluate the 
primary efficacy endpoint for overwhelming efficacy, or the need to adjust the sample 
size. If the primary analysis yields a statistically significant test result (p < 0.0087, critical 
value for clustered log rank test based on Bauer & Koehne procedure with no early 
stopping for futility) on the FA, and if further no safety concern or other considerations 
require continuation of enrollment, the study will be stopped for overwhelming efficacy. 
Otherwise enrollment of subjects will continue and the whole statistical analysis as 
described in this document will be carried out at the end of the study using Fisher’s 
combination test (please see Section 13.1 Primary Analysis for details). This approach 
guarantees that an overall Type I error of 0.05 is preserved.    
In order to re-assess the sample size for the subset of subjects recruited after the interim 
analysis, simulation studies will be run utilizing the p-value observed at the interim 
analysis (p1). The re-assessment of the sample size will be carried out using the original 
assumptions for median circuit life times in the two treatment groups (
 
 in the Prismocitrate 18 and control group) and will target a conditional power of 
90% for rejecting the null hypothesis given the observed results of the interim analysis.   
13.6 Subgroup Analyses 
No specific subgroup analyses are planned. 
14. SAFETY AND TOLERABILITY 
Parameters to be tabulated for safety include the following: AEs/SAEs; bleeding events 
and transfusions; serum bicarbonate, pH and base excess, blood total calcium, blood total 
calcium/iCa2+ ratio, and serum electrolytes; anion gap; vital signs, creatinine, blood urea 
nitrogen, and bleeding parameters. 
Any statistical analysis of safety endpoints will be carried out on the FA based on the 
actual treatment groups. 


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14.1 Adverse Events (AEs) 
The outcome/resolution of all AEs and SAEs will be determined by the Investigator and 
documented on the AE case report form (CRF)/SAE report form.  
An overview of the number of subjects with at least one AE, at least one SAE, at least 
one study product-related AE, at least one study product-related SAE, and withdrawn due 
to SAE will be summarized (frequency and percentage of subjects). 
An overview of the number of AEs, SAEs, study product-related AEs, and study product-
related SAEs along with rates of events per subject treatment days will be tabulated. 
The number of subjects with at least one AE (Serious and Non-Serious) will be 
summarized by MedDRA System Organ Class and MedDRA Preferred Term (frequency 
and percentage of subjects). The number of AEs (Serious and Non-Serious) and the rates 
of AEs per subject treatment days will be summarized by MedDRA System Organ Class 
and MedDRA Preferred Term. In addition, the number of subjects with at least one AE 
(Serious and Non-Serious) will be summarized by MedDRA System Organ Class, 
MedDRA Preferred Term and Severity (mild, moderate, severe) (frequency and 
percentage of subjects). 
The number of subjects with at least one study-product related AE (Serious and Non-
Serious) will be summarized by MedDRA System Organ Class and MedDRA Preferred 
Term (frequency and percentage of subjects). The number of study-product related AEs 
(Serious and Non-Serious) and the rates of study-product related AEs per subject 
treatment days will be summarized by MedDRA System Organ Class and MedDRA 
Preferred Term. In addition, the number of subjects with at least one study-product 
related AE (Serious and Non-Serious) will be summarized by MedDRA System Organ 
Class, MedDRA Preferred Term and Severity (mild, moderate, severe) (frequency and 
percentage of subjects). 
Any subject-based analysis of AEs (e.g., number of subjects with at least one AE) will be 
based on the worst severity reported for the subject for the event analyzed. If, for 
example, a subject reports two mild and one moderate AE(s), in the subject-based 
analysis the event will be presented only once under moderate severity. Study product-
related AEs will be considered those AEs classified as probably or possibly associated 
with the device or drug. AEs unrelated to study product will be considered those with a 
causality assessment of unlikely or not associated. If the relationship to the drug/device is 
not available or not assessable, the respective AE will be classified as study product-
related.  


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Data listings for AEs and SAEs will contain MedDRA System Organ Class, MedDRA 
Preferred Term, diagnosis, start date, stop date, severity, action taken regarding study 
product, relationship to study product and outcome. 
Adverse events reported between signing the ICF and first study treatment will be listed 
separately. 
14.2 Bleeding Events and Transfusions 
The location of bleeding events and the type of transfusions will be summarized using 
frequencies and percentages. The number of subjects with bleeding events, the number of 
bleeding events, the duration of bleeding events, the number of subjects requiring 
transfusions and the number of transfusions will be summarized presenting frequencies 
and percentages for categorized data observed, and summarizing the original data using 
the number of values n, mean, standard deviation, median, minimum and maximum. The 
estimated blood loss and the units transfused will be summarized using the same 
statistics.  Bleeding events and transfusions resulting from complications related to blood 
loss will be listed by patient. 
14.3 Serum Bicarbonate, pH, Blood Total Calcium and Serum Electrolytes 
Serum bicarbonate, pH (ABG), blood total calcium concentrations and serum electrolytes 
(sodium, potassium, chloride, phosphate, magnesium) will be analyzed in the exact same 
manner as blood iCa2+ concentrations.  
Along the lines of Section 13.3 Secondary Analysis descriptive summaries will be carried 
out for each parameter at the different assessment time points, and changes from baseline 
will be analyzed. A MMRM analysis will be deployed for the different parameters 
following the description under Section 13.3.  
The total calcium/iCa2+ ratio will only be summarized descriptively. Frequencies and 
percentages will be provided for pH < 7.2 by time point and treatment group (threshold 
indicative of metabolic acidosis). Frequencies and percentages will further be provided 
for total calcium/iCa ratio > 2.1 by time point and treatment group (threshold suggestive 
of citrate accumulation) as well as for anion gap > 11 mmol/L (threshold indicative of 
metabolic disturbance) and base excess < -5 mmol/L. 
Complete blood count and blood lactate measurements obtained at screening will be 
listed by patient.   


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14.4 Vital Signs, Creatinine, Blood Urea Nitrogen and Bleeding Parameters 
Descriptive summaries of vital signs (systolic and diastolic blood pressure, mean arterial 
pressure, respiratory rate, pulse, body temperature, weight and height), creatinine, BUN 
and bleeding parameters (PT/INR, PTT, hemoglobin, hematocrit, platelet count) as 
assessed at the different measurement time points will be provided. These summaries will 
use the number of subjects n, mean, standard deviation, minimum, median and 
maximum. Changes from baseline will be analyzed by the number of subjects n, mean 
and standard deviation and t-test or Wilcoxon rank sum test, as applicable. 
An analysis of covariance (ANCOVA) model will be deployed to evaluate differences 
between treatment groups in the final measurements available for the parameters listed 
above. The model will include the independent variable treatment group and the 
covariates illness severity score APACHE II and parameter baseline value and will 
evaluate mean differences in the final parameter measurements.    
15. OTHER RELEVANT DATA ANALYSES/SUMMARIES 
The site level user groups will be trained on the use of Prismocitrate 18 in CRRT and 
their understanding assessed prior to use in the clinical trial setting. The user groups will 
be comprised of physicians, nurses, and other clinicians who may be part of prescribing, 
initiating, or modifying treatment during the 120 hours evaluation period. A descriptive 
summary of training results on administration of Prismocitrate 18 will be provided in the 
Clinical Study Report. This summary will cover Citrate Training/Assessment Questions, 
and CRRT Clinical Cases provided by Dr. 
, 
, in her role as 
 for this study. 
Individual data collected on initial treatment prescriptions and changes during the 
evaluation period, on dialysate, replacement solution, priming solution, calcium 
gluconate or calcium chloride used during the evaluation period will be provided in data 
listings. Likewise, detailed CRRT treatment information, Prismaflex M150 Set 
information, blood access information and CRRT machine and treatment modality will be 
listed.  
 
 


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16. REFERENCES 
1. 
Morita Y, Johnson RW, Dorn RE, Hall DS. Regional Anticoagulation During 
Hemodialysis Using Citrate. Am J Med Sci. 1961;242:32-43. 
2. 
Tolwani A. Continuous Renal-Replacement Therapy for Acute Kidney Injury. N 
Engl J Med. 2012;367(26):2505-2514. 
3. 
Schilder L, Nurmohamed SA, Bosch FH, et al. Citrate Anticoagulation Versus 
Systemic Heparinisation in Continuous Venovenous Hemofiltration in Critically Ill 
Patients with Acute Kidney Injury: A Multi-Center Randomized Clinical Trial. Crit 
Care. 2014;18(4):472. 
4. 
Stucker F, Ponte B, Tataw J, et al. Efficacy and Safety of Citrate-Based 
Anticoagulation Compared to Heparin in Patients with Acute Kidney Injury 
Requiring Continuous Renal Replacement Therapy: A Randomized Controlled 
Trial. Crit Care. 2015;19(1):91. 
5. 
Gattas DJ, Rajbhandari D, Bradford C, Buhr H, Lo S, Bellomo R. A Randomized 
Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for 
Continuous Renal Replacement Therapy in Critically Ill Adults. Crit Care Med. 
2015;43(8):1622-1629. 
6. 
Kutsogiannis DJ, Gibney RT, Stollery D, Gao J. Regional Citrate Versus Systemic 
Heparin Anticoagulation for Continuous Renal Replacement in Critically Ill 
Patients. Kidney Int. 2005;67(6):2361-2367. 
7. 
Oudemans-van Straaten HM, Bosman RJ, Koopmans M, et al. 
Citrateanticoagulation for Continuous Venovenous Hemofiltration. Crit Care Med. 
2009;37(2):545-552. 
8. 
Fealy N, Baldwin I, Johnstone M, Egi M, Bellomo R. A Pilot Randomized 
Controlled Crossover Study Comparing Regional Heparinization to Regional 
Citrate Anticoagulation for Continuous Venovenous Hemofiltration. Int J Artif 
Organs. 2007;30(4):301-307. 
9. 
Bauer P, Köhne K. Evaluation of Experiments with Adaptive Interim Analyses. 
Biometrics. 1994;50(4):1029-1041. 
10. 
SAS Institute Inc. SAS/STAT 9.2 User’s Guide. Cary, NC USA; 2008 


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11. 
Stedman M, Gagnon D, Lew R, Jung SH, Losina E, Brookhart M. A SAS macro 
for a clustered logrank test. Computer Methods and Programs in Biomedicine. 
2011;104(2):266-270 and http://www.drugepi.org/wp-
content/uploads/2011/04/logrank_macro2.txt 
12. 
Tolwani AJ, Prendergast MB, Speer RR, Stofan BS, Wille KM. A Practical Citrate 
Anticoagulation Continuous Venovenous Hemodiafiltration Protocol for Metabolic 
Control and High Solute Clearance. Clin J Am Soc Nephrol 1: 79–87, 2006. 
13. 
Bai M, Zhou M, He L, et al. Citrate versus heparin anticoagulation for continuous 
renal replacement therapy: an updated meta-analysis of RCTs. Intensive Care Med. 
2015;41(12):2098-2110. 
14. 
SAS Institute Inc. SAS OnlineDoc Version 9.2 Product Documentation. Vol. 2012. 
Cary, NC USA; 2008. 
 
 
 
 
 
 
 
 
 


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18. LIST OF TABLES, FIGURES AND LISTINGS 
Table Number 
Table Name 
Table 14.1.1 
Subject Overview 
Table 14.1.2 
Categorical Demographic Characteristics at Baseline 
Table 14.1.3 
Continuous Demographic Characteristics at Baseline 
Table 14.1.4 
Physical Examination at Baseline 
Table 14.1.5 
Vital Signs at Screening/Baseline 
Table 14.1.6 
Laboratory Parameters at Baseline 
Table 14.2.1 
Delivery of Prescribed CRRT Dose Based on Daily Delivered Dose 
Table 14.2.2 
Treatment Exposure (Categorical)  
Table 14.2.3 
Treatment Exposure (Continuous)  
Table 14.2.4 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (FA) 
Table 14.2.5 
Quartile Estimates for Kaplan-Meier Based Survival Estimates of the 
Primary Efficacy Endpoint (FA) 
Table 14.2.6 
Clustered Log-Rank Test over Treatment Groups for Kaplan-Meier Based 
Survival Estimates of the Primary Efficacy Endpoint (FA) 
Table 14.2.7 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (PP) 
Table 14.2.8 
Quartile Estimates for Kaplan-Meier Based Survival Estimates of the 
Primary Efficacy Endpoint (PP) 
Table 14.2.9 
Clustered Log-Rank Test over Treatment Groups for Kaplan-Meier Based 
Survival Estimates of the Primary Efficacy Endpoint (PP) 
Table 14.2.10 
Patient and Extracorporeal Circuit Concentrations (iCa2+) and 
Corresponding Changes from Baseline 
Table 14.2.11 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Blood Ionized Calcium Concentrations (iCa2+) 
Table 14.2.12.1 
Subject Frequency of iCa2+ < 1.1 mmol/L by Time Point 
Table 14.2.12.2 
Subject Frequency of pH Measurements Below the Threshold Indicative of 
Metabolic Acidosis (pH < 7.2) 
Table 14.2.12.3 
Subject Frequency of Total Calcium/iCa2+ Ratio Above the Threshold 
Suggestive of Citrate Accumulation (Total Calcium/iCa2+ Ratio > 2.1) 
Table 14.2.12.4 
Subject Frequency of Anion Gap Above the Threshold Indicative of 
Metabolic Disturbance (Anion Gap > 11 mmol/L) 
Table 14.2.12.5 
Subject Frequency of Base Excess < -5 mmol/L 
Table 14.2.13 
Percentage of Prescribed Dose Actually Administered to the Patient 
Table 14.3.1.1 
Bleeding Events During the 120 Hours Evaluation Period 
Table 14.3.1.2 
Frequency and Duration of Bleeding Events and Estimated Blood Loss 


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Table Number 
Table Name 
During the 120 Hours Evaluation Period 
Table 14.3.1.3 
Blood Transfusions During the 120 Hours Evaluation Period 
Table 14.3.1.4 
Frequency and Number of Blood Transfusions and Number of Units Infused 
During the 120 Hours Evaluation Period 
Table 14.3.1.5 
Number of Subjects With At Least One Adverse Event 
Table 14.3.1.6 
Number of Adverse Events (Serious and Non-Serious) 
Table 14.3.1.7 
Number of Subjects With At Least One Adverse Event (Serious and Non-
Serious) by MedDRA System Organ Class and MedDRA Preferred Term 
Table 14.3.1.8 
Number of Adverse Events (Serious and Non-Serious) by MedDRA System 
Organ Class and MedDRA Preferred Term 
Table 14.3.1.9 
Number of Subjects With At Least One Adverse Event (Serious and Non-
Serious) by MedDRA System Organ Class, MedDRA Preferred Term and 
Severity 
Table 14.3.1.10 
Number of Subjects With At Least One Study Product-Related Adverse 
Event (Serious and Non-Serious) by MedDRA System Organ Class and 
MedDRA Preferred Term 
Table 14.3.1.11 
Number of Study Product-Related Adverse Events (Serious and Non-
Serious) by MedDRA System Organ Class and MedDRA Preferred Term 
Table 14.3.1.12 
Number of Subjects With At Least One Study Product-Related Adverse 
Event (Serious and Non-Serious) by MedDRA System Organ Class, 
MedDRA Preferred Term and Severity 
Table 14.3.5.1 
Serum Bicarbonate, pH, Base Excess and Corresponding Changes from 
Baseline 
Table 14.3.5.1.1 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Base Excess. 
Table 14.3.5.2 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Serum Bicarbonate 
Table 14.3.5.3 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
pH 
Table 14.3.5.4 
Blood Total Calcium Concentrations and Total/Ionized Calcium Ratio and 
Corresponding Changes from Baseline 
Table 14.3.5.5 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Blood Total Calcium Concentration 
Table 14.3.5.6 
Serum Electrolytes and Corresponding Changes from Baseline 
Table 14.3.5.6.1 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Anion Gap 
Table 14.3.5.7 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Sodium 


Prismocitrate 18 
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Table Number 
Table Name 
Table 14.3.5.8 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Potassium 
Table 14.3.5.9 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Chloride 
Table 14.3.5.10 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Phosphate 
Table 14.3.5.11 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Magnesium 
Table 14.3.5.12 
Vital Signs and Corresponding Changes from Screening 
Table 14.3.5.13 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Systolic 
Blood Pressure  
Table 14.3.5.14 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Diastolic Blood Pressure 
Table 14.3.5.15 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Mean 
Arterial Pressure 
Table 14.3.5.16 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Respiratory Rate 
Table 14.3.5.17 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Pulse 
Table 14.3.5.18 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Body 
Temperature 
Table 14.3.5.19 
Creatinine and Blood Urea Nitrogen and Corresponding Changes from 
Baseline 
Table 14.3.5.20 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Creatinine 
Table 14.3.5.21 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Blood 
Urea Nitrogen (BUN) 
Table 14.3.5.22 
Bleeding Parameters and Corresponding Changes from Baseline 
Table 14.3.5.23 
Model Parameters of Analysis of Covariance (ANCOVA) Model of INR 
Table 14.3.5.24 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Partial 
Thromboplastin Time 
Table 14.3.5.25 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Hemoglobin 
Table 14.3.5.26 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Hematocrit 
Table 14.3.5.27 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Platelet 
Count 
Table 14.3.5.28 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 


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Table Number 
Table Name 
Prothrombin Time 
Table 14.3.5.29 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Activated Partial Thromboplastin Time 
Table 14.4.1 
Protocol Deviations 
Table 14.4.2 
Citrate Training/Assessment Questions 
Table 14.4.3 
CRRT Clinical Cases Training/Assessment Questions 
Table 14.4.4 
Blood Sampling Schedule Compliance by Site 
 
Figure Number 
Figure Name 
Figure 14.2.1 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (FA) 
Figure 14.2.2 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (PP) 
Figure 14.2.3 
Patient and Extracorporeal Circuit Concentrations (iCa2+) Across the Whole 
CRRT Period 
 
Listing Number 
Listing Name 
Listing 16.2.1.1 
Subject Disposition 
Listing 16.2.2.1 
Protocol Deviations 
Listing 16.2.3.1 
Subject Overview 
Listing 16.2.4.1 
Demographic Characteristics at Baseline 
Listing 16.2.4.2 
AKI Medical History 
Listing 16.2.4.3 
Known Allergies 
Listing 16.2.4.4 
Current Medications and Medications Prescribed During the 30-Day Period 
Prior to Informed Consent 
Listing 16.2.4.5 
Medical History 
Listing 16.2.4.6 
Physical Examination at Baseline 
Listing 16.2.4.7 
Vital Signs at Screening/Baseline 
Listing 16.2.4.8 
Laboratory Parameters at Baseline 
Listing 16.2.4.9 
Complete Blood Count and Blood Lactate Measurement at Screening 
Listing 16.2.6.1 
Prismaflex M150 Extracorporeal Circuit Life Measurements (Primary 
Efficacy Endpoint) (FA) 
Listing 16.2.6.2 
Prismaflex M150 Extracorporeal Circuit Life Measurements (Primary 
Efficacy Endpoint) (PP) 
Listing 16.2.6.3 
Daily Delivered CRRT Dose 
Listing 16.2.7.1 
Adverse Events Reported Between Signing the ICF and First Study 


Prismocitrate 18 
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Listing Number 
Listing Name 
Treatment 
Listing 16.2.7.2 
Non-Serious Adverse Events 
Listing 16.2.7.3 
Serious Adverse Events 
Listing 16.2.7.4 
Complications Related to Blood Loss: Bleeding Events 
Listing 16.2.7.5 
Complications Related to Blood Loss: Transfusions 
Listing 16.2.8.1 
Patient and Extracorporeal Circuit Concentrations (iCa2+) and 
Corresponding Changes from Baseline 
Listing 16.2.8.2 
Serum Bicarbonate, pH, Base Excess and Corresponding Changes from 
Baseline 
Listing 16.2.8.3 
Blood Total Calcium Concentrations and Total/Ionized Calcium Ratio and 
Corresponding Changes from Baseline 
Listing 16.2.8.4 
Serum Electrolytes and Corresponding Changes from Baseline 
Listing 16.2.8.5 
Creatinine and Blood Urea Nitrogen and Corresponding Changes from 
Baseline 
Listing 16.2.8.6 
Bleeding Parameters and Corresponding Changes from Baseline 
Listing 16.2.8.7 
Liver Function Tests and Corresponding Changes from Baseline 
Listing 16.2.9.1 
Vital Signs and Corresponding Changes from Screening/Baseline 
Listing 16.2.9.2 
End of Treatment Compliance 
Listing 16.2.9.3 
Initial Treatment Prescription and Changes During Evaluation Period 
Listing 16.2.9.4 
Dialysate Used During Evaluation Period  
Listing 16.2.9.5 
Replacement Solution Used During Evaluation Period 
Listing 16.2.9.6 
Priming Solution Used During Evaluation Period 
Listing 16.2.9.7 
Calcium Gluconate or Calcium Chloride Used During Evaluation Period 
Listing 16.2.9.8 
CRRT Treatment Information 
Listing 16.2.9.9 
Prismaflex M150 Set Information 
Listing 16.2.9.10 
Blood Access Information 
Listing 16.2.9.11 
CRRT Machine and Treatment Modality 
Listing 16.2.9.12 
Prismaflex M150 Set Independent Adjudication Results 
Listing 16.2.9.13 
Blood Sampling Schedule Compliance 
Listing 16.2.9.14 
Pre-Blood Pump Solution Used During Evaluation Period 
 
 


Prismocitrate 18 
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19. DOCUMENT HISTORY 
 
Version 
No. 
Change(s) in the Document 
Reason for Change(s) 
Approval 
Date 
1.0 
N/A (Initial Release) 
N/A 
17 JUN 2015 
2.0 
1) Added last paragraph to Section 
5.5.1 Primary Efficacy Endpoint;  
 
2) Removed first paragraph from 
Section 13. Efficacy Parameters; 
3) Added first two paragraphs to 
Section 13.1 Primary Analysis;  
4) Added wording on statistical 
testing of potential differences in 
the percentage of overall 
prescribed dose actually 
administered at the end of Section 
13.3 Secondary Analysis.  
 
1) Further clarification of the nature of 
the primary efficacy endpoint and of the 
event definition based on FDA request;  
2) Covered by the paragraph added. 
Initial paragraph no longer needed; 
3) Provision of additional details on the 
primary analysis based on FDA request; 
4) Pre-specify secondary endpoints that 
could lead to additional labeling claims 
and control the Type I error rate for 
testing such endpoints as recommended 
by the FDA   
07 AUG 2015 
3.0 
1) Added description of 
determination of alarm cause by 
Independent Adjudicator to 
Section 5.5.1 Primary Efficacy 
Endpoint;  
2) Added anion gap to Section 4.2 
Secondary Objectives and Section 
5.6 Safety Measures; 
3) Updated exclusion criteria in 
Section 6. Study Populations; 
4) Added wording on sensitivity 
analysis for potential impact of 
informative censoring at the end of 
Section 13.2 Sensitivity Analysis; 
5) Added analysis for iCa relating 
to threshold indicative of decrease 
in iCa despite adequate calcium 
compensation to Section 13.3 
Secondary Analysis;  
6) Updated Section 13.5 Interim 
1) Process improvement in assessment 
of primary efficacy endpoint upon FDA 
request; 
 
                                                                    
2) Additional parameter included upon 
FDA request;  
 
 
3) Clarified and detailed out exclusion 
criteria based on FDA request; 
 
 4) Additional assessment of the 
potential impact of informative 
censoring on the primary efficacy 
endpoint upon FDA request;  
 
 
5) Additional analysis included based on 
FDA request;  
 
 
 
 
 
6) Provision of specific process/rule 
10 FEB 2016 


Prismocitrate 18 
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Analysis with a specific 
process/rule for re-assessment of 
the sample size; 
7) Added analysis relating to 
potential citrate accumulation and 
metabolic issues to Section 14.3 
Serum Bicarbonate, pH, Blood 
Total Calcium and Serum 
Electrolytes. 
 
upon FDA request;  
 
 
 
7) Additional analysis included based on 
FDA request. 
 
4.0 
1.) Updated: Author to Mengqi 
Xiao and Responsible Medical 
Officer to Qing Li.  
2.) Updated Study Design, applied 
new template and changed 
corresponding the section 
numbering.  
 
3.) Updated 
Formulation/Indication  
4.) Updated wording in: 
Background and Rational, Primary 
Objective, Primary Efficacy 
Endpoint 
5.) Updated Schedule of Events  
 
6.) Updated Section 6 (Inclusion 
criteria) 
7.) Updated Section 9 
(Demographics) 
 
8.) Updated Tables for 5.4.1 and 
5.4.2 
1.) Reflect Study Team changes 
 
 
2.) Updating wording to match that of 
protocol amendment 2 
3.) Updating wording to match that of 
protocol amendment 2 
4.) Updated wording to match that of 
protocol amendment 2  
 
5.) Updated wording to match that of 
protocol amendment 2 
6.) Updated wording to match that of 
protocol amendment 2 
 
7.) Updated wording to match that of 
protocol amendment 2 
 
8.) Updated the schedule of events and 
blood sampling tables to reflect those 
tables found within the protocol.   
26 JUN 2018 
 


Prismocitrate 18 
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Statistical Analysis Plan: 1407-004  
Study Title: 
Clinical Evaluation of Use of Prismocitrate 18 in 
Patients Undergoing Acute Continuous Renal 
Replacement Therapy (CRRT) 
Study Number: 
1407-004 
Study Phase:  
III 
Study Design 
Multi-center, prospective, non-blinded, one to one 
randomized study. A total of 160 adult patients, 80 in 
each study arm, will be enrolled at up to 
15 investigational sites in the US and Canada. 
Product Name: 
Prismocitrate 18 
Formulation/Indication: 
A replacement solution indicated for regional 
anticoagulation of the extracorporeal circuit in 
patients undergoing continuous renal replacement 
therapy (CRRT) 
Statistician: 
 
 
Baxter Healthcare Corporation 
One Baxter Parkway 
Deerfield, IL 60015 
Tel: 
 
Email: 
 
Sponsor: 
Baxter Healthcare Corporation 
One Baxter Parkway 
Deerfield, IL 60015 
Responsible Medical Officer: 
 MD, PhD 
 
Baxter Healthcare Corporation 
Final Date: 
 2018 AUG 02 
Version: 
4.0 Amendment 1 
 
 
 
 
 
 
 
 


Prismocitrate 18 
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1. SIGNATURE PAGE 
 
Study Title: 
Clinical Evaluation of Use of Prismocitrate 18 in Patients 
Undergoing Acute Continuous Renal Replacement Therapy 
(CRRT) 
Study Number: 
1407-004 
Statistician: 
 
 
I have read this statistical analysis plan and confirm that to the best of my knowledge it 
accurately describes the planned statistical analysis of the study. 
 
 
Prepared by: 
 
Date: 
 
 
 
Baxter Research & Development 
Baxter Healthcare Corporation 
 
 
Approved by: 
 
Date: 
 
 MD, PhD 
 
Baxter Research & Development 
Baxter Healthcare Corporation 
 
 
Approved by: 
 
Date: 
 
  
 
Baxter Research & Development 
Baxter Healthcare Corporation 
 
 
 
 
 
 
 
 




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2.  LIST OF TABLES, FIGURES AND LISTINGS 
 
Table Number 
Table Name 
Table 14.1.1 
Subject Overview 
Table 14.1.2 
Categorical Demographic Characteristics at Baseline 
Table 14.1.3 
Continuous Demographic Characteristics at Baseline 
Table 14.1.5 
Vital Signs at Screening/Baseline 
Table 14.1.6 
Laboratory Parameters at Baseline 
Table 14.2.1 
Delivery of Prescribed CRRT Dose Based on Daily Delivered Dose 
Table 14.2.2 
Treatment Exposure (Categorical) 
Table 14.2.3 
Treatment Exposure (Continuous) 
Table 14.2.4 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (FA) 
Table 14.2.5 
Quartile Estimates for Kaplan-Meier Based Survival Estimates of the 
Primary Efficacy Endpoint (FA) 
Table 14.2.6 
Clustered Log-Rank Test over Treatment Groups for Kaplan-Meier Based 
Survival Estimates of the Primary Efficacy Endpoint (FA) 
Table 14.2.7 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (PP) 
Table 14.2.8 
Quartile Estimates for Kaplan-Meier Based Survival Estimates of the 
Primary Efficacy Endpoint (PP) 
Table 14.2.9 
Clustered Log-Rank Test over Treatment Groups for Kaplan-Meier Based 
Survival Estimates of the Primary Efficacy Endpoint (PP) 
Table 14.2.10 
Patient and Extracorporeal Circuit Ionized Calcium Concentrations (iCa2+) 
and Corresponding Changes from Baseline  
Table 14.2.11 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Patient Ionized Calcium Concentrations (iCa2+) 
Table 14.2.12.1 
Subject Frequency of iCa2+ < 1.1 mmol/L by Time Point 
Table 14.2.12.2 
Subject Frequency of pH Measurements Below the Threshold Indicative of 
Metabolic Acidosis (pH < 7.2) 
Table 14.2.12.3 
Subject Frequency of Total Calcium/iCa2+ Ratio Above the Threshold 
Suggestive of Citrate Accumulation (Total Calcium/iCa2+ Ratio > 2.1) 
Table 14.2.12.4 
Subject Frequency of Anion Gap Above the Threshold Indicative of 
Metabolic Disturbance (Anion Gap > 11 mmol/L) 
Table 14.2.12.5 
Frequency of Base Excess < -5 mmol/L 
Table 14.2.13 
Percentage of Prescribed Dose Actually Administered to the Patient 
 
 


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Table Number 
Table Name 
Table 14.2.14 
Sensitivity Analysis: Kaplan-Meier Survival Estimates for the Primary 
Efficacy Endpoint 
Table 14.2.15 
Sensitivity Analysis: Quartile Estimates for Kaplan-Meier Based Survival 
Estimates of the Primary Efficacy Endpoint 
Table 14.2.16 
Sensitivity Analysis: Clustered Log-Rank Test over Treatment Groups for 
Kaplan-Meier Based Survival Estimates of the Primary Efficacy Endpoint  
Table 14.3.1.1 
Bleeding Events During the 120 Hours Evaluation Period 
Table 14.3.1.2 
Frequency and Duration of Bleeding Events and Estimated Blood Loss 
During the 120 Hours Evaluation Period 
Table 14.3.1.3 
Blood Transfusions During the 120 Hours Evaluation Period 
Table 14.3.1.4 
Frequency and Number of Blood Transfusions and Number of Units Infused 
During the 120 Hours Evaluation Period 
Table 14.3.1.5 
Number of Subjects With At Least One Adverse Event 
Table 14.3.1.6 
Number of Adverse Events (Serious and Non-Serious) 
Table 14.3.1.7 
Number of Subjects With At Least One Adverse Event (Serious and Non-
Serious) by MedDRA System Organ Class and MedDRA Preferred Term 
Table 14.3.1.8 
Number of Adverse Events (Serious and Non-Serious) by MedDRA System 
Organ Class and MedDRA Preferred Term 
Table 14.3.1.9 
Number of Subjects With At Least One Adverse Event (Serious and Non-
Serious) by MedDRA System Organ Class, MedDRA Preferred Term and 
Severity 
Table 14.3.1.10 
Number of Subjects With At Least One Study Drug Related Adverse Event 
(Serious and Non-Serious) by MedDRA System Organ Class and MedDRA 
Preferred Term 
Table 14.3.1.11 
Number of Study Drug Related Adverse Events (Serious and Non-Serious) 
by MedDRA System Organ Class and MedDRA Preferred Term 
Table 14.3.1.12 
Number of Subjects With At Least One Study Drug Related Adverse Event 
(Serious and Non-Serious) by MedDRA System Organ Class, MedDRA 
Preferred Term and Severity 
Table 14.3.1.13 
Number of Subjects With At Least One Serious Adverse Event by MedDRA 
System Organ Class and MedDRA Preferred Term 
Table 14.3.1.14 
Number of Serious Adverse Events by MedDRA System Organ Class and 
MedDRA Preferred Term 
Table 14.3.1.15 
Number of Subjects With At Least One Serious Adverse Event by MedDRA 
System Organ Class, MedDRA Preferred Term and Severity 
Table 14.3.1.16 
Number of Adverse Events (Serious and Non-Serious) by MedDRA System 
Organ Class, MedDRA Preferred Term and Severity 
 
 


Prismocitrate 18 
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Table Number 
Table Name 
Table 14.3.1.17 
Number of Serious Adverse Events by MedDRA System Organ Class, 
MedDRA Preferred Term and Severity 
Table 14.3.1.18 
Number of Subjects With At Least One Study Drug Related Serious 
Adverse Event by MedDRA System Organ Class and MedDRA Preferred 
Term 
Table 14.3.1.19 
Number of Study Drug Related Serious Adverse Events by MedDRA 
System Organ Class and MedDRA Preferred Term 
Table 14.3.1.20 
Number of Subjects With At Least One Study Drug Related Serious 
Adverse Event by MedDRA System Organ Class, MedDRA Preferred Term 
and Severity 
Table 14.3.1.21 
Number of Study Drug Related Adverse Events (Serious or Non-Serious) by 
MedDRA System Organ Class, MedDRA Preferred Term and Severity 
Table 14.3.1.22 
Number of Study Drug Related Serious Adverse Events by MedDRA 
System Organ Class, MedDRA Preferred Term and Severity 
Table 14.3.5.1 
Serum Bicarbonate, pH, Base Excess and Corresponding Changes from 
Baseline 
Table 14.3.5.3.1 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Base Excess 
Table 14.3.5.2 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Serum Bicarbonate 
Table 14.3.5.3 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
pH 
Table 14.3.5.4 
Blood Total Calcium Concentrations and Total/Ionized Calcium Ratio and 
Corresponding Changes from Baseline 
Table 14.3.5.5 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Blood Total Calcium Concentration 
Table 14.3.5.6 
Serum Electrolytes and Corresponding Changes from Baseline 
Table 14.3.5.6.1 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Anion Gap 
Table 14.3.5.7 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Sodium 
Table 14.3.5.8 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Potassium 
Table 14.3.5.9 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Chloride 
Table 14.3.5.10 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Phosphate 
Table 14.3.5.11 
Model Parameters of Mixed-Effects Model Repeated Measures Analysis of 
Magnesium 


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Table Number 
Table Name 
Table 14.3.5.12 
Vital Signs and Corresponding Changes from Screening 
Table 14.3.5.13 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Systolic 
Blood Pressure  
Table 14.3.5.14 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Diastolic Blood Pressure 
Table 14.3.5.15 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Mean 
Arterial Pressure 
Table 14.3.5.16 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Respiratory Rate 
Table 14.3.5.17 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Pulse 
Table 14.3.5.18 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Body 
Temperature 
Table 14.3.5.19 
Creatinine and Blood Urea Nitrogen and Corresponding Changes from 
Baseline 
Table 14.3.5.20 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Creatinine 
Table 14.3.5.21 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Blood 
Urea Nitrogen (BUN) 
Table 14.3.5.22 
Bleeding Parameters and Corresponding Changes from Baseline 
Table 14.3.5.23 
Model Parameters of Analysis of Covariance (ANCOVA) Model of INR 
Table 14.3.5.24 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Partial 
Thromboplastin Time 
Table 14.3.5.25 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Hemoglobin 
Table 14.3.5.26 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Hematocrit 
Table 14.3.5.27 
Model Parameters of Analysis of Covariance (ANCOVA) Model of Platelet 
Count 
Table 14.3.5.28 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Prothrombin Time 
Table 14.3.5.29 
Model Parameters of Analysis of Covariance (ANCOVA) Model of 
Activated Partial Thromboplastin Time 
Table 14.4.1 
Protocol Deviations 
Table 14.4.4 
Blood Sampling Schedule Compliance by Site 
 
 
 


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Figure Number 
Figure Name 
Figure 14.2.1 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (FA) 
Figure 14.2.2 
Kaplan-Meier Survival Estimates for the Primary Efficacy Endpoint (PP) 
Figure 14.2.3 
Patient and Extracorporeal Circuit Ionized Calcium Concentrations (iCa2+) 
Across the Whole CRRT Period 
Figure 14.2.4 
Sensitivity Analysis: Kaplan-Meier Survival Estimates for the Primary 
Efficacy Endpoint  
 
 
Listing Number 
Listing Name 
Listing 16.2.1.1 
Subject Disposition 
Listing 16.2.1.2 
Reasons for Withdrawal  
Listing 16.2.2.1 
Protocol Deviations 
Listing 16.2.3.1 
Subject Overview 
Listing 16.2.4.1 
Demographic Characteristics at Baseline 
Listing 16.2.4.2 
AKI Medical History 
Listing 16.2.4.3 
Known Allergies 
Listing 16.2.4.4 
Current Medications and Medications Prescribed Prior to Informed Consent 
Listing 16.2.4.5 
Medical History 
Listing 16.2.4.7 
Vital Signs at Screening/Baseline 
Listing 16.2.4.8 
Laboratory Parameters at Baseline 
Listing 16.2.4.9 
Complete Blood Count and Blood Lactate Measurement at Screening 
Listing 16.2.6.1 
Prismaflex M150 Extracorporeal Circuit Life Measurements (Primary 
Efficacy Endpoint) (FA) 
Listing 16.2.6.2 
Prismaflex M150 Extracorporeal Circuit Life Measurements (Primary 
Efficacy Endpoint) (PP) 
Listing 16.2.6.3 
Daily Delivered CRRT Dose 
Listing 16.2.6.4 
Sensitivity Analysis: Prismaflex M150 Extracorporeal Circuit Life 
Measurements (Primary Efficacy Endpoint) 
Listing 16.2.7.1 
Adverse Events Reported Between Signing the ICF and First Study 
Treatment 
Listing 16.2.7.2 
Adverse Events (Serious and Non-Serious) 
Listing 16.2.7.3 
Serious Adverse Events 
Listing 16.2.7.4 
Complications Related to Blood Loss: Bleeding Events 
Listing 16.2.7.5 
Complications Related to Blood Loss: Transfusions 
Listing 16.2.7.6 
Deaths 


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Listing Number 
Listing Name 
Listing 16.2.7.7 
Adverse Events (Serious and Non-Serious) Outcome 
Listing 16.2.7.8 
Adverse Events Related to Baxter Device/Product   
Listing 16.2.8.1 
Systemic and Post-Filter Blood Ionized Calcium Concentrations (iCa2+) and 
Corresponding Changes from Baseline 
Listing 16.2.8.2 
Serum Bicarbonate, pH (ABG) and Base Excess and Corresponding 
Changes from Baseline 
Listing 16.2.8.3 
Blood Total Calcium Concentrations and Total Calcium/Ionized Calcium 
Ratio and Corresponding Changes from Baseline 
Listing 16.2.8.4 
Serum Electrolytes and Anion Gap and Corresponding Changes from 
Baseline 
Listing 16.2.8.5 
Creatinine and Blood Urea Nitrogen and Corresponding Changes from 
Baseline 
Listing 16.2.8.6 
Bleeding Parameters and Corresponding Changes from Baseline 
Listing 16.2.8.7 
Liver Function Tests and Corresponding Changes from Baseline 
Listing 16.2.9.1 
Vital Signs and Corresponding Changes from Screening/Baseline 
Listing 16.2.9.2 
End of Treatment Compliance 
Listing 16.2.9.3 
Initial Treatment Prescription and Changes During Evaluation Period 
Listing 16.2.9.4 
Dialysate Used During Evaluation Period  
Listing 16.2.9.5 
Replacement Solution Used During Evaluation Period 
Listing 16.2.9.6 
Priming Solution Used During Evaluation Period 
Listing 16.2.9.7 
Calcium Gluconate or Calcium Chloride Used During Evaluation Period 
Listing 16.2.9.8 
CRRT Treatment Information 
Listing 16.2.9.9 
Prismaflex M150 Set Information 
Listing 16.2.9.10 
Blood Access Information 
Listing 16.2.9.11 
CRRT Machine and Treatment Modality 
Listing 16.2.9.12 
Prismaflex M150 Set Independent Adjudication Results 
Listing 16.2.9.13 
Blood Sampling Schedule Compliance 
Listing 16.2.9.14 
Pre-Blood Pump Solution Used During Evaluation Period 
Listing 16.2.9.15 
Citrate and CRRT Clinical Cases Training/Assessment Questions