Clinical trial NCT02651428
Conditions: Kidney Failure, Chronic Catheter-Related Infections
Keywords: Kidney Failure, Chronic Catheter-Related Infections Central Venous Catheter
Sponsor: CorMedix
Start date: 2015-12-01; Completion date: 2018-10-01
Enrollment: 806 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is determine safety and effectiveness of Neutrolin, a catheter lock solution, for prevention of central venous catheter associated bloodstream infection in hemodialysis patients.

Detailed description:
The objective of this study is to demonstrate the efficacy and safety of Neutrolin® as a catheter lock solution (CLS) on prevention of catheter-related bloodstream infection (CRBSI), and the incidence of treatment-emergent adverse events in subjects receiving hemodialysis (HD) for the treatment of End Stage Renal Disease (ESRD) when compared with heparin 4,000 USP Units/4mL (1,000 USP Units/mL).

This is a randomized, double-blind, active control, parallel-arm, multicenter study. Six hundred and thirty two subjects will be randomized in a 1:1 ratio to receive either Neutrolin® or the active control heparin (Heparin sodium USP 1,000 units/mL, Benzyl alcohol 9.45 mg/mL and Sodium chloride 9.0 mg/mL) as a CLS.

Approximately 632 randomized subjects are planned for this trial. In this study, one-half of the subjects (316 subjects) will receive Neutrolin as a study drug and the other half will receive heparin 4,000 USP Units/4mL (1,000 USP Units/mL) with benzyl alcohol preservative as a comparator. Subjects will be assigned in a 1:1 ratio using permuted blocks without additional stratification for both groups.

The primary objective of this study is to demonstrate the effectiveness of Neutrolin® as a CLS in ESRD subjects undergoing HD treatment using a permanent, cuffed, tunneled silicone or polyurethane HD catheter. The study will evaluate whether Neutrolin® is superior to the active control heparin by documenting the time to CRBSI and consequently delaying the time until the occurrence of CRBSI.

Arms: arm 1: Neutrolin: Neutrolin will be added to the central venous catheter after dialysis as a lock solution arm 2: Heparin: Heparin will be added to the central venous catheter after dialysis as a lock solution
Interventions: intervention 1: Neutrolin intervention 2: Heparin
Intervention descriptions: intervention 1: Neutrolin® will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session intervention 2: Heparin will be instilled into central venous HD catheters at the discontinuation of all dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session

Protocol documents:
Prot_000.pdf: 
 
 
 
Study Assessing Safety & Effectiveness of 
a Catheter Lock Solution in Dialysis 
Patients to Prevent Bloodstream 
Infection 
 
Document Date: October 6, 2017 
 
NCT02651428 
 


 
Protocol Number: LOCK-IT-100
 
October 06, 2017 (Version 8) 
 
 
 
 
Page 1 of 67 
CLINICAL STUDY PROTOCOL 
A Phase 3, prospective, multicenter, double-blind, randomized, 
active control study to demonstrate the safety and effectiveness of 
Neutrolin® in preventing catheter-related bloodstream infections 
in subjects receiving hemodialysis therapy as treatment for end 
stage renal disease  
 
Protocol Number: 
LOCK-IT-100 
Date of Protocol: 
October 06, 2017 (Version 8) 
Investigational Product: 
Neutrolin® (1.35% (13.5 mg/mL) taurolidine, 3.5% (26.1 
mg/mL) citrate and heparin 4,000 USP Units/4mL (1,000 
USP Units/mL))  
Indication: 
Prevention of Catheter-Related Bloodstream Infection in 
Subjects Receiving Hemodialysis Therapy as Treatment for 
End Stage Renal Disease  
IND No.: 
113,764 
Development Phase: 
Phase 3 
Sponsor: 
CorMedix Inc. 
1430 U.S. 206, Suite 200 
Bedminster, NJ 07921 
Phone: +1 908 517 9500 
 
Sponsor Signatory: 
Antony Pfaffle, MD 
Chief Scientific Officer 
CorMedix Inc. 
1430 U.S. 206, Suite 200 
Bedminster, NJ 07921 
Phone: +1 908 517 9500 
 
Global Medical Monitor: 
Edward Matheis, MD 
1400 Perimeter Park Drive 
Morrisville, NC 27560-7200 
United States   
GCP Certification: 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are proprietary and 
confidential and may not be disclosed unless such disclosure is required by applicable law or regulations, or with 
the prior written permission of CorMedix.  In any event, persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them.  These restrictions on 
disclosure will apply equally to all future information supplied to you which is indicated as confidential.


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SIGNATURE PAGE 
STUDY TITLE: A Phase 3, prospective, multicenter, double-blind, randomized, active control 
study to demonstrate the safety and effectiveness of Neutrolin® in preventing catheter-
related bloodstream infections in subjects receiving hemodialysis therapy as treatment for 
end stage renal disease. 
 
We, the undersigned, have read this protocol and agree that it contains all necessary 
information required to conduct the study. 
 
 
Signature: 
 
 
 
 
 
 
 
Date: 
 
Antony E. Pfaffle, MD 
Chief Scientific Officer 
CorMedix, Inc. 
 
Eugene C. Poggio, PhD 
Chief Biostatistician 
Biostatical Consulting Inc.  
 
 


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INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out 
this study. I will conduct the study as outlined herein and will complete the study within 
the time designated. I will comply with all relevant ICH and GCP requirements during 
the conduct of this study. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the investigational product (IP) and 
the conduct of the study. 
 
Investigator’s Signature 
 
Date 
Name of Investigator (Typed or Printed) 
 
 
Institution, Address* 
 
 
Phone Number* 
 
 
 
 
 
Coordinating Investigator’s Signature (where required) 
 
Date 
Name of Coordinating Investigator (Typed or Printed) 
 
 
Institution 
 
 
 
*If the address or phone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor and will not require protocol 
amendment(s). 
 
 


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Protocol Synopsis 
 
Name of 
Sponsor/Company: 
CorMedix Inc. 
Name of Finished 
Product: 
Neutrolin®  
Name of Active 
Ingredients: 
Taurolidine (1.35% (13.5 mg/mL), 3.5% (26.1 mg/mL) 
citrate and heparin 4,000 USP Units/4 mL (1,000 USP 
Units/mL))  
Title of Study: 
 
A 
Phase 
3, 
prospective, 
multicenter, 
double-blind, 
randomized, active control study to demonstrate the safety 
and effectiveness of Neutrolin® in preventing catheter-related 
bloodstream infections in subjects receiving hemodialysis 
therapy as treatment for end stage renal disease. 
Protocol No: 
 
LOCK-IT-100 
Investigators: 
Multicenter 
Study centers: 
 
Up to 85 centers in the US 
Study duration:  
Subjects will be followed until a CRBSI has occurred, the 
catheter is removed, the subject withdraws, or the study is 
ended. 
Objectives: 
The primary objective of this study is to demonstrate the efficacy and safety of 
Neutrolin® as a catheter lock solution (CLS) for prevention of catheter-related 
bloodstream infection (CRBSI) in subjects receiving hemodialysis (HD) for the treatment 
of End Stage Renal Disease (ESRD) when compared with heparin 4,000 USP Units/4 mL 
(1,000 USP Units/mL). The study will demonstrate whether Neutrolin® is superior to the 
active control heparin in reducing the incidence of CRBSI.   
Study Design:  
This is a randomized, double-blind, active control, parallel-arm, multicenter study. 
Approximately 900 subjects will be randomized in a 1:1 ratio to receive either 
Neutrolin® or the active control heparin (Heparin sodium USP 1,000 units/mL, Benzyl 
alcohol 9.45 mg/mL and Sodium chloride 9.0 mg/mL) as a CLS.  Neutrolin® or heparin 
will be instilled into central venous HD catheters at the discontinuation of all dialysis 
sessions and will be withdrawn prior to the initiation of the next dialysis session.  
 
All subjects will receive standard of care consistent with clinical practice guidelines 
recommended by KDOQI for the placement, care and use of central venous catheters 
(CVC) for HD therapy.  
Number of subjects planned and assignment to treatment:  
Approximately 900 randomized subjects are planned for this trial.  In this study, one-half 
of the subjects (450 subjects) will receive Neutrolin® and the other half will receive 
heparin 4,000 USP Units/4mL (1,000 USP Units/mL) with benzyl alcohol preservative as 
a comparator. Subjects will be assigned in a 1:1 ratio using permuted blocks without 


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Protocol Synopsis 
 
Name of 
Sponsor/Company: 
CorMedix Inc. 
Name of Finished 
Product: 
Neutrolin®  
Name of Active 
Ingredients: 
Taurolidine (1.35% (13.5 mg/mL), 3.5% (26.1 mg/mL) 
citrate and heparin 4,000 USP Units/4 mL (1,000 USP 
Units/mL))  
additional stratification for both groups. For the purpose of this blinded study, the term 
investigational product will refer to either Neutrolin® or the comparator. 
Diagnosis and main criteria for inclusion and exclusion: 
Adult subjects (≥ 18 years) with ESRD undergoing chronic HD with a permanent, 
tunneled silicone or polyurethane catheter that has demonstrated the ability to achieve a 
minimum blood flow of at least 250 mL/min for at least two consecutive dialysis sessions 
to enable successful HD. Subjects may not be entered into this trial if they have been 
treated with antibiotics within 14 days of randomization for any systemic infection or 
have active exit site infection around the CVC, or received thrombolytic treatment within 
30 days of randomization. 
Test product, dose and mode of administration:  
Neutrolin® and the active control will be packaged in identical vials, and will be used as 
a catheter locking solution for HD catheters in the following manner: 
• Day 1 (day of first administration of blinded, randomized therapy): following 
randomization and entry into the trial, instill CLS following the index HD 
episode, as described in the protocol; 
• Subsequent HD sessions: CLS will be removed prior to HD and instilled in the 
catheter following the HD session, as described in the protocol. 
Duration of treatment:  
Subjects are to be followed from randomization until either:  
• The development of a CRBSI; 
• Withdrawal from the study; 
• Catheter removal; or  
• The end of the study, whichever occurs first.   
The study has been designed to continue until approximately 56 subjects have 
experienced a CRBSI. It is expected that some subjects may be treated for 2 years or 
more.  
Reference therapy, dose, and mode of administration:  
Heparin 4,000 USP Units/4mL (1,000 USP Units/mL) as a CLS for the active control.  
Criteria for evaluation: 
Primary endpoint:  Time to CRBSI: 
The primary objective of this study is to demonstrate the effectiveness of Neutrolin® as a 
CLS in ESRD subjects undergoing HD treatment using a permanent, cuffed, tunneled 


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Protocol Synopsis 
 
Name of 
Sponsor/Company: 
CorMedix Inc. 
Name of Finished 
Product: 
Neutrolin®  
Name of Active 
Ingredients: 
Taurolidine (1.35% (13.5 mg/mL), 3.5% (26.1 mg/mL) 
citrate and heparin 4,000 USP Units/4 mL (1,000 USP 
Units/mL))  
silicone or polyurethane HD catheter.  The study will evaluate whether Neutrolin® is 
superior to the active control heparin by documenting the time to CRBSI and 
consequently delaying the time until the occurrence of CRBSI. 
The definition of CRBSI used in this study requires that the same organism is grown 
from at least one blood culture from: 
• a peripheral site or bloodline sample 
and 
• either the arterial or venous catheter hub (or the venous or arterial dialysis circuit 
blood lines if on dialysis).     
Blood cultures must be taken from two sites to enhance the validity of the culture testing 
results. One aerobic and 1 anaerobic blood culture bottle should be taken from each site. 
 
If the subject has clinical symptoms, while on or off dialysis, blood cultures will be 
obtained using peripheral venipuncture from a source not intended for future vascular 
access, and the venous or arterial hub of the HD CVC (or the venous or arterial dialysis 
circuit blood line if on dialysis). If a peripheral site is not available, as soon as the patient 
is evaluated, blood cultures can be obtained from both the venous and arterial hubs of the 
HD CVC (or the dialysis circuit blood lines if on dialysis), preferably before the study 
subject receives antibiotics.  Ten to twenty mL of blood should be collected, without 
discarding any of the CLS.   
   
Necessary clinical indication for suspicion of infection includes the following: 
 
One of the following symptoms: 
• Fever (defined as ≥37.8° C)  
or 
• Rigors, defined as shivering from a feeling of being cold, often 
with copious sweating, as documented by a medical professional 
 
OR two or more of the following symptoms:  
 
• Tachycardia defined as a heart rate greater than 100 beats per 
minute  
• Tachypnea, as defined as a RR greater than 24 breaths per minute 


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Protocol Synopsis 
 
Name of 
Sponsor/Company: 
CorMedix Inc. 
Name of Finished 
Product: 
Neutrolin®  
Name of Active 
Ingredients: 
Taurolidine (1.35% (13.5 mg/mL), 3.5% (26.1 mg/mL) 
citrate and heparin 4,000 USP Units/4 mL (1,000 USP 
Units/mL))  
• Low blood pressure as defined as a systolic blood pressure less 
than 90, as measured by a clinician (RN or MD) with a BP cuff, or 
a decrease in blood pressure greater than 30 mmHg 
• An obvious change in mental status from previously documented 
baseline.   
 
All attempts will be made to document as many signs and/or symptoms as possible at the 
time of suspected CRBSI.  
  
An investigator may choose to obtain blood cultures on other suspicions of CRBSI, but 
the CRBSI case definition requires the clinical indication for suspicion of infection 
criteria listed above in addition to the blood culture criteria listed above. An alternate 
source of infection should not be clinically suspected. 
 
Clinical Adjudication Committee 
While sites will seek to identify that a CRBSI is present and will be responsible for 
collecting the clinical data and blood cultures as outlined in the protocol, each case will 
be reviewed by a Clinical Adjudication Committee (CAC) for the final assessment of 
CRBSI status.  The CAC is a multi-disciplinary committee of specialists who will review 
both the clinical documentation as well as the blood culture results to determine if the 
case is a CRBSI.  However, because the CAC determination is based on data obtained 
from the clinical sites, and the review cannot be initiated without blood culture results, it 
is imperative that the sites follow the protocol definition of CRBSI, and collect blood 
cultures when a CRBSI is suspected. 
 
Secondary Endpoints 
  
1. Catheter Removal: 
Catheter removal for any reason, for example as a result of CRBSI, catheter malfunction, 
or the catheter is no longer needed for hemodialysis, during the follow up period of the 
trial. 
2. Catheter Patency: 
Loss of catheter patency following enrollment in the study. Loss of catheter patency is 
defined as required use of a tissue plasminogen activating factor (tPA) or removal of 
catheter due to dysfunction. 


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Protocol Synopsis 
 
Name of 
Sponsor/Company: 
CorMedix Inc. 
Name of Finished 
Product: 
Neutrolin®  
Name of Active 
Ingredients: 
Taurolidine (1.35% (13.5 mg/mL), 3.5% (26.1 mg/mL) 
citrate and heparin 4,000 USP Units/4 mL (1,000 USP 
Units/mL))  
Statistical Methods: 
Subject demographic, clinical and laboratory data will be summarized by treatment arm 
using descriptive statistics.   
 
Primary effectiveness analysis: 
 
CRBSI 
The time to CRBSI will be compared between the treatment arms using a log-rank test at 
a 2-sided 5% alpha level.  The null hypothesis is that there is no difference in the risk of 
CRBSI over time between the two treatment groups.  Subjects will be treated as censored 
in this analysis if the catheter is removed for reasons other than CRBSI (e.g., catheter 
removed because no longer required) or follow-up for CRBSI discontinues. 
 
The primary analysis will be based upon the Full Analysis Population defined as 
randomized subjects receiving at least one dose of assigned treatment.  While testing will 
be based upon the log-rank test, the estimated treatment effect will be the incidence of 
CRBSI calculated as the number of subjects with a CRBSI episode divided by the 
duration of follow-up over subjects (follow-up will be based upon the same time as used 
for the log-rank test).  The rate will be presented as the event rate per 1,000 days with  
95% confidence interval presented for the comparison of rates between the treatment 
arms.  This confidence interval will be derived assuming that the number of days until 
CRBSI follows an exponential distribution. 
 
Similar methods of analysis will be used to estimate the overall rate of catheter loss for 
any reason and the rate of loss of catheter patency. The fixed sequence testing procedure 
will be used for the comparison of the two treatments with respect to the effectiveness 
endpoints.  Therefore, the analysis comparing the two treatments for catheter loss for any 
reason will be formally conducted only if the analysis for the primary effectiveness 
endpoint yields a statistically significant result favoring Neutrolin®, and the analysis 
comparing the two treatments for loss of patency will be formally conducted only if the 
analysis for catheter loss for any reason also yields a statistically significant result 
favoring Neutrolin®.   
 
Sample Size 
This trial has been designed to achieve 80% power for the comparison between treatment 


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Protocol Synopsis 
 
Name of 
Sponsor/Company: 
CorMedix Inc. 
Name of Finished 
Product: 
Neutrolin®  
Name of Active 
Ingredients: 
Taurolidine (1.35% (13.5 mg/mL), 3.5% (26.1 mg/mL) 
citrate and heparin 4,000 USP Units/4 mL (1,000 USP 
Units/mL))  
arms subject to the following specifications: testing will be conducted at a 2-sided overall 
5% alpha level, Neutrolin® is associated with a 55% reduction in the risk (i.e., incidence) 
of CRBSI relative to the control arm, and one interim analysis will be performed at the 
midpoint of the trial with adjustment of the alpha level using the method of Pocock. 
Fifty-six CRBSI events in total will be needed to achieve the desired power, and the 
event rates will be monitored over the course of the trial to determine the times of the 
interim and final statistical analyses. It is expected that approximately 900 subjects will 
be randomized for this trial. 
 
Safety analyses 
The safety information will be presented based upon descriptive analysis characterizing 
the relative rates of deaths, adverse events, serious adverse events and loss of patency 
between the treatment arms.  The treatment arms will also be evaluated with respect to 
changes in laboratory parameters.  


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TABLE OF CONTENTS 
1.0         LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................... 13 
2.0         INTRODUCTION ............................................................................................................. 15 
2.1          Clinical Need for Prevention of Catheter-Related Bloodstream Infections ............... 15 
2.2 
Background on Catheter Lock Solutions ................................................................. 16 
2.3 
Overview and Rationale for Use of Neutrolin® as a Catheter Lock Solution ............. 20 
2.4         Safety of Neutrolin® ................................................................................................ 22 
2.5         Rationale for the Formulation of Neutrolin® ............................................................ 24 
3.0 
STUDY OBJECTIVES ......................................................................................................... 25 
3.1 
Primary Objectives ................................................................................................. 25 
3.2 
Safety Objectives ..................................................................................................... 25 
3.3 
Primary Endpoint ................................................................................................... 25 
4.0        INVESTIGATIONAL PLAN ............................................................................................. 27 
4.1       Overall Study Design and Plan .................................................................................. 27 
4.2         Discussion of Study Design ...................................................................................... 28 
5.0         SELECTION OF STUDY POPULATION ......................................................................... 29 
5.1         Inclusion Criteria .................................................................................................... 29 
5.2         Exclusion Criteria ................................................................................................... 30 
5.3  
Study Completion, Early Withdrawal, New Catheter Placement .............................. 31 
6.0          STUDY TREATMENTS .................................................................................................. 33 
6.1         Identity of Investigational Products ......................................................................... 33 
6.2         Blinding .................................................................................................................. 33 
6.3         Treatments to Be Administered ............................................................................... 33 
6.4         Method of Assigning Subjects to Treatment Group ................................................. 34 
6.5         Selection of Neutrolin® Composition and Control .................................................... 34 
6.6         Selection and Timing of the Catheter Lock Solution ................................................ 34 
6.7         Prior and Concomitant Therapy/PROCEDURES .................................................... 34 
6.8         Standard of Care for Prevention of CRBSI .............................................................. 35 
6.9      Standard of Care for Hemodialysis ............................................................................ 35 
6.10        Treatment Compliance ........................................................................................... 35 
6.11        Investigational Product Accountability ................................................................... 36 
7.0          EFFECTIVENESS AND SAFETY VARIABLES ............................................................. 37 
7.1         Schedule of Assessments .......................................................................................... 37 
7.2         Screening/Baseline Assessments .............................................................................. 44 


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7.3         Effectiveness Measurements .................................................................................... 45 
7.4         Safety Measurements .............................................................................................. 47 
7.5   Appropriateness of Measurements ................................................................................ 52 
8.0       DATA QUALITY ASSURANCE ........................................................................................ 53 
8.1     Monitoring ................................................................................................................. 53 
8.2      Data Management and Coding ................................................................................... 54 
8.3     Quality Assurance Audit ............................................................................................. 54 
9.0     STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ......................... 55 
9.1     Determination of Sample Size ..................................................................................... 55 
9.2    Interim Analysis .......................................................................................................... 55 
9.3   Analysis Populations ..................................................................................................... 55 
9.4   Subject Disposition ....................................................................................................... 56 
9.5   Subject Characteristics ................................................................................................. 56 
9.6    Compliance and Duration of Exposure ........................................................................ 56 
9.7    Analysis of Primary Endpoint ...................................................................................... 56 
9.8   Safety ........................................................................................................................... 57 
10.0   ETHICS ............................................................................................................................... 59 
10.1   Independent Ethics Committee or Institutional Review Board .................................... 59 
10.2    Ethical Conduct of the Study ..................................................................................... 59 
10.3   Subject Information and Consent ............................................................................... 59 
11     STUDY ADMINISTRATION ................................................................................................ 60 
11.1   Protocol Modifications ................................................................................................ 60 
11.2    Regulatory Approval and Notification ........................................................................ 60 
11.3    Required Prestudy Documentation ............................................................................. 60 
11.4    Subject Identification Register and Subject Screening Log ......................................... 61 
11.5    Case Report Form Completion ................................................................................... 61 
11.6    Record Retention ....................................................................................................... 62 
11.7    Study Completion ...................................................................................................... 62 
11.8    Study Termination ..................................................................................................... 62 
11.9    Use of Information and Publication ............................................................................ 63 
11.10    Privacy of Personal Data .......................................................................................... 64 
12       REFERENCES .................................................................................................................... 65 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Currently available catheter lock solutions 
 
 
 
19 
Table 2 
Study Flow Chart 
 
 
 
 
 
 
38 


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1.0         LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine transaminase (or SGPT) 
ANCOVA 
analysis of covariance 
AST 
aspartate transaminase (or SGOT) 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CDC 
Centers for Disease Control 
CAC 
Clinical Adjudication Committee 
CFR 
Code of Federal Regulations 
CKD 
chronic kidney disease 
CK-MB 
creatine kinase, muscle and brain (subunits)  
CLS 
CMS 
CRBSI 
CRP 
CVC 
dL 
Catheter lock solution 
Center for Medicare and Medicaid Services 
catheter related bloodstream infection 
C-reactive protein 
central venous catheter 
deciliter 
DSMB 
Data Safety and Monitoring Board 
DRG 
ECG 
Diagnosis-related grouping 
Electrocardiogram 
CRF 
case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ESA 
ESRD 
Erythropoiesis-stimulating agent 
end-stage renal disease 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
HD 
ICH 
hemodialysis 
International Conference on Harmonisation 
ID 
user identification 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISN 
International Society of Nephrology 
ITT 
intent-to-treat (population) 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Millilitre 
MRSA/MRSE 
NCR 
Methicillin resistant S. aureus/S.epidermidis 
carbonless (no carbon required) 
PIN 
Personal identification number 
PP 
per-protocol (population) 
PVP 
Qb 
RCT 
SAE 
Polyvinylpyrrolidone 
blood flow 
randomized controlled trial 
serious adverse event 
SAP 
statistical analysis plan 
SGOT 
serum glutamic oxaloacetic transaminase (or AST) 
SGPT 
serum glutamic pyruvic transaminase (or ALT) 
SmPC 
summary of product characteristics 


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SOP 
Standard Operating Procedure 
Sp Kt/V 
Single pool Kt/V 
TEAE 
treatment-emergent adverse event 
tPA 
WHO 
Tissue plasminogen activator (Cathflo®) 
World Health Organization 
 


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2.0         INTRODUCTION 
2.1          CLINICAL NEED FOR PREVENTION OF CATHETER-RELATED 
BLOODSTREAM INFECTIONS 
 
As of December 31, 2010, there were 593,086 End Stage Renal Disease (ESRD) patients 
in the United States (U.S.), of whom 383,992 were receiving hemodialysis (HD) therapy 
[1]. For patients on HD, the arteriovenous fistula is the best possible vascular access, due 
to its high blood flow, low complication rate and longevity [2].  Because of these 
characteristics the Center for Medicare & Medicaid Services (CMS) and ESRD networks 
implemented a national vascular access improvement process called “Fistula First” in 
2003 [3].  Although this program has increased the numbers of fistulas in both prevalent 
(patients currently receiving chronic dialysis) and incident (patients starting chronic 
dialysis) HD patients, an unintended consequence has been to increase the number of 
patients using central venous catheters (CVC) as their primary source of vascular access.  
In 2006, 82% of patients in the US started chronic HD with a CVC, while more than 25% 
of prevalent HD patients used a CVC as their primary vascular access [4]. 
Infection is the second most common cause of death in HD patients, and the presence of a 
CVC is a significant risk factor for infection-associated mortality [5, 6].  The frequency 
of catheter-related bloodstream infection (CRBSI) generally ranges between 2 and 5.5 
episodes/1,000 catheter days, which equates to approximately 1 or 2 infections/year in 
CVC-dependent patients [5, 7].  Given the current prevalent HD population, it is 
estimated that there are up to 160,000 episodes of CRBSI/year in catheter-dependent 
patients, and that up to 20% require hospitalization or have serious complications 
including endocarditis, septic arthritis, epidural abscess, osteomyelitis or severe sepsis [6, 
7].  A single episode of CVC-related CRBSI in the U.S. has been estimated to cost up to 
$45,000, and the aggregate yearly cost for all episodes of CRBSI in this population is 
nearly $800 million [3, 7]. 
The pathogenesis of CRBSI in CVC-dependent patients is believed to be due to bacterial 
colonization of the CVC due to biofilm formation [7-9].  Biofilm forms rapidly, usually 
within 24 hours in all CVCs, and represents a complex bacterial community embedded in 
a film made up of polysaccharides, minerals and bacteria [8, 10]. Biofilm protects 
bacteria and is essential for the virulence of most organisms [10].  In HD CVCs, it is 
recognized that colonization of the catheter occurs commonly, but does not cause overt 
symptoms or sepsis until reaching a critical colony count [11]. It also appears that 
bacterial colonization of biofilm can induce chronic inflammation as manifest by 
resistance to erythropoietin [9, 12].  
Current catheter use is associated with a significant increase in morbidity and mortality 
[3, 13].  All-cause mortality is increased 2-3 fold in patients with CVCs, and is reduced 
by about 50% in patients that switch from a CVC to either a fistula or graft [4].  
Additionally, the relative risk of infection-related hospitalization and death is increased 
2-3 fold, and even cardiovascular mortality is increased in this population [3-5, 13].  
Chronic inflammation is important in the pathogenesis of cardiovascular disease, and 
may be the reason that cardiovascular mortality is increased in HD patients with CVCs 
[4, 13, 14].  CVC use is also associated with catheter malfunction and thrombosis, central 


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venous stenosis, reduced quality of life, greater risk for inadequate dialysis, and both 
local and systemic infection [3, 4]. 
Given the significant morbidity, mortality and cost associated with CRBSI in CVC-
dependent patients, it is obvious why prevention of CRBSI is considered one of the most 
important unmet medical needs in the dialysis population [7, 15]. 
 
2.2         BACKGROUND ON CATHETER LOCK SOLUTIONS 
The current standard of catheter care is designed to minimize CRBSI and catheter 
dysfunction due to thrombosis.  This generally involves: 
• Locking the CVC interdialytically with a heparin-saline solution 
• Infection control precautions are taken pre- and post-HD treatment to prevent 
contamination of the exit site and catheter hub 
• Per HD organization-specific policy and procedure if a dressing is ordered by the 
physician, infection control precautions are taken when catheter dressings are 
changed around the catheter 
• In extremely rare situations, an antibiotic lock might be used for patients with a 
history of intercurrent CVC infection, particularly if a CVC is the last vascular 
access possible for the patient. 
In the US, heparin is the current standard of care as a CLS to prevent thrombosis.  
Although there are no large randomized controlled trials supporting a specific dose, 
heparin has historically been used at a concentration of 5,000 USP Units/mL, and more 
recently at 1,000 USP Units/mL, with the amount of heparin solution instilled matched to 
the catheter filling volume [16].  Recently, the American Society of Diagnostic and 
Interventional Nephrology issued a guidance document recommending the use of 1,000 
u/mL heparin (or 4.0% citrate) as the standard CLS, and this standard has been widely 
adopted in U.S. dialysis units [17].  While heparin is generally considered effective to 
maintain catheter patency, bacteria such as staphylococcal species survive and commonly 
create a biofilm in heparin-locked catheters.  It is thought that the preservatives in 
commercially available heparin solutions may provide some degree of antimicrobial 
activity, but current rates of CRBSI suggests that it has minimal antimicrobial activity 
[18]. 
Heparin, however, does not have any anti-infective properties. The search for a locking 
solution that would contain both anti-thrombotic and anti-infective properties has been 
ongoing for decades.  Antibiotic solutions have been tried but the inevitable growth of 
resistant bacterial species associated with their prolonged use has limited enthusiasm for 
their use for prophylaxis against CRBSIs.  Concentrated 30% citrate, functions as both an 
anti-coagulant and anti-infective agent, but when flushing the catheter lock, it may lead to 
cardiac arrhythmias by inducing severe hypocalcemia. While aspiration of the catheter 
locking solution prior to catheter use is the standard clinical preference and practice, 
flushing of catheter lock occurs when either 1) clots or fibrin make aspiration impossible, 
2) lapses in medical protocol inevitably occur, or 3) IV access is urgent and medical 
personnel who are not familiar with hemodialysis do not aspirate and discard the locking 
solution. Furthermore, catheter overfills at the time of locking and/or subsequent leakage 


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at the tip or through catheter side-holes are additional concerns.  These concepts also 
apply to higher concentrations of heparin, where a flush of both catheter lumens 
containing 6 cc of solution will bolus the patient with 30,000 unit of heparin.  Thus a 
locking solution with the least pharmacologic effect and toxicity when injected is most 
desirable, even though under most circumstances this solution is withdrawn and 
discarded. 
Although there are potentially a number of possible strategies to reduce the incidence of 
CRBSI in CVC-dependent patients, antimicrobial CLS appear to have the most potential 
[4].  During the last 8 years, there have been a number of small randomized controlled 
trials (RCTs) that have clearly demonstrated the effectiveness of antimicrobial CLS in 
reducing CRBSI [7, 12].  Five of these studies used antibiotics, one used 30% citrate and 
the other used taurolidine/citrate. Although they appeared to be effective in the short-
term, traditional antibiotic CLS have the risk of bacterial resistance or systemic toxicity, 
and 30% citrate may represent a safety risk [7].  
Antimicrobial resistance is a growing concern, and dialysis patients are among those at 
highest risk for resistant infections.  In 2005, just over 15% of the methicillin-resistant 
Staphylococcus aureus (MRSA) infections were seen in dialysis patients [15].  The 
portion of the HD population at greatest risk appears to be those using CVCs. The same 
2005 reports shows that approximately 85% of HD patients with MRSA infections had an 
invasive device or catheter in place at the time of the infection [15]. The long-term use of 
prophylactic or therapeutic antibiotics, such as vancomycin, is a risk factor for 
development of staphylococcal subpopulations with decreased susceptibility against 
glycopeptide antibiotics, particularly in the patient populations with devices such as 
CVCs [19].  This data reflects that it will be important to control CRBSIs in a manner 
that limits the likelihood of greater antimicrobial resistance in the HD patient population.  
CLS are also used to reduce the rate of catheter dysfunction due to thrombosis.  Catheter 
dysfunction due to thrombosis can be treated by the instillation of a thrombolytic agent 
(such as urokinase or tPA) into the catheter lumen [4].  Ultimately, if all interventions are 
unsuccessful, the occluded catheter is exchanged or replaced. 
Based upon current clinical evidence, a product possessing the following characteristics 
would be an optimal CLS: 
• Broad spectrum antibacterial/antifungal: 
– Prevent formation of biofilm  
– Prevent CRBSI 
• Maintain catheter useable life: 
– Reduced need for thrombolytics and catheter replacement 
– Reduced need for catheter removal due to CRBSI 
• Maintain adequate flow rate: 
– Maximal  Qb >300 mL/min to ensure effective dialysis 
• Safe: 
– No bleeding risk 
– Lack of significant exposure to the systemic circulation 
• Does not promote emergence of resistant bacterial infections. 


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Thus, to solve this problem, CorMedix has proposed a catheter locking solution 
(Neutrolin®) consisting of a combination of: 
 
• Taurolidine as an anti-infective 
• Heparin in standard concentrations as an anticoagulant and  
• Citrate in relatively low doses to adjust the pH and enhance the solubility of 
Taurolidine in solution. 
Neutrolin® (composed of taurolidine 1.35%, citrate 3.5%, and heparin 4,000 USP 
Units/4mL (1,000 USP Units/mL)) is a novel antimicrobial and anticoagulant solution, 
which will potentially satisfy these characteristics.  Taurolidine is a non-toxic, broad-
spectrum antibacterial and anti-fungal compound that has also been demonstrated to 
prevent biofilm formation [18, 20]. Taurolidine does not have any known anticoagulant 
properties. Indeed, early studies of Taurolidine with the addition of citrate as a catheter 
lock, but without the addition of heparin, were associated with higher rates of catheter 
thrombosis than those obtained in patients using standard heparin locks. These 
preliminary observations prompted the addition of heparin to the Taurolidine-citrate lock 
as noted above.  Two RCTs and considerable experiential data have demonstrated the 
safety and effectiveness of taurolidine and citrate when used as a CLS to prevent CRBSI 
[21-24]. 
The most extensive information to date on the risk reduction that might be expected in 
the current study is perhaps that provided by Murray et al [25].   In their study that 
included 158 Staphylococcal bacteremia events in 135,446 catheter-days among tunneled 
central venous catheter patients, they found a 56% reduction in risk with respect to 
Staphylococcal bacteremia rates when 5000 IU/ml of heparin was replaced with 1.35% 
taurolidine/4% citrate/500 IU/ml heparin (p=0.004).  An observational study by Solomon 
et al [26]. similarly found a  59% reduction in risk of bacteremia when comparing 106 
patients (12,036 catheter-days) treated with 1.35% taurolidine/4% citrate/500 IU/ml 
heparin to 34 patients (6,471 catheter-days) treated with 5000 IU/ml of heparin. 
In the past decade, several CLS containing antimicrobial agents have been marketed in 
countries outside of the US.  CorMedix is not aware of any of these products being 
discontinued or withdrawn for safety-related reasons from any country where they are 
marketed.  These products contain one, two or all three active ingredients of Neutrolin®.  
These products are listed Table 1. 
 


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Table 1: Currently available catheter lock solutions 
Product 
Company 
Mechanism 
and 
composition 
Launched 
Comments 
Citra-Lok™ 
Dirinco 
Group – 
Dutch-Swiss 
Company 
Anticoagulant 
and 
antimicrobial 
effect 
30 and 46.7% 
citrate 
Available in non 
US markets. Direct 
customer sales in 
EU and 
distributors 
elsewhere 
Anticoagulant 
Unable to launch in US 
due to citrate 
concentration 
restriction 
TauroSept® 
Geistlich/ 
Gambro 
Antimicrobial: 
2% taurolidine 
+ PVP  
Available in non 
US markets. 
Launched in EU 
Taurolidine + PVP 
TauroLock™ 
TauroPharm 
Antimicrobial 
& 
anticoagulant: 
1.35% 
taurolidine + 
4% citrate  
Available in non 
US markets.  
Launched in EU & 
Middle East 2006 
Antimicrobial + 
anticoagulant 
 
TauroLock-
Hep™ 100/500 
TauroPharm 
Antimicrobial 
& 
anticoagulant: 
1.35% 
taurolidine +  
4% citrate + 
heparin 
100/500 u/mL 
Available in non 
US markets.  
Launched in EU in 
Nov 2007 
Antimicrobial + 
anticoagulant 
 
DuraLock-C™ MedComp – 
US based 
company 
Anticoagulant 
and 
antimicrobial 
effect 
46.7% citrate 
Available in non 
US markets 
Has a unique luer lock 
vial – direct fit to 
catheter line 
Loxxit™ 
Citra 
Anticoagulan
ts, Inc. – US 
based 
company 
Anticoagulant: 
46.5% 
trisodium 
citrate 
Available in non 
US markets 
Was the original 
company to sell citrate 
to MedComp prior to 
removal from the 
market 
Heparin 
Generic 
Anticoagulant 
1,000-5,000 
u/mL 
Generic.  
Available in US 
Anticoagulant only 
 
 
 


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2.3 OVERVIEW AND RATIONALE FOR USE OF NEUTROLIN® AS A 
CATHETER LOCK SOLUTION 
 
Neutrolin®, as noted above, is comprised of 1.35% taurolidine, 3.5% citrate, and heparin 
4,000 USP Units/4mL (1,000 USP Units/mL).  Taurolidine is a derivative of 
aminosulfonamide-taurinamide, and is a unique, non-toxic compound with both anti-
adherence and antimicrobial properties against a broad range of bacteria and fungi.  
Additionally, studies have also shown that taurolidine inhibits Staphylococcus coagulase 
(a clotting activator) and other clotting pathways, which may be of further benefit in the 
maintenance of catheter patency.  The antimicrobial properties of taurolidine are 
hypothesized to be related to its methylol transfer groups that bind irreversibly to 
bacterial or fungal cell walls.[18]  In vitro experiments have shown taurolidine to be 
efficacious in eradicating catheter biofilm caused by a variety of gram-positive and gram-
negative bacteria, as well as Candida albicans.[18] 
Citrate is an effective anticoagulant [27].  Citrate acts as a chelating agent, in particular 
binding calcium and magnesium.  Citrate removes locally available calcium that is 
required to complete the coagulation cascade. Given this mechanism, the FDA warned 
against widespread use of citrate at higher concentrations due to the risk of hypocalcemia, 
when a patient died of cardiac arrest after an inadvertent systemic instillation of 46.7% 
citrate [28]. Neutrolin® contains 3.5% citrate which would be safe even under the worst-
case assumptions for inadvertent instillation and subsequent effects on serum calcium. 
[29, 30] 
The concentration of heparin in Neutrolin® is 4,000 USP Units/4mL (1,000 USP 
Units/mL), which is now widely used as standard of care in most U.S. dialysis centers.  It 
is thought that this dose will provide a complementary anticoagulation effect to citrate, 
while reducing the risk that would be associated with inadvertent systemic administration 
of higher doses of heparin. The active control in this trial is heparin 4,000 USP 
Units/4mL (1,000 USP Units/mL).  
The effectiveness and safety of Neutrolin® as a CLS in subjects with a tunneled silicone 
or polyurethane HD catheter is being studied for the following reasons:  
1. There is a critical unmet medical need to reduce the incidence of CRBSI 
2. There is substantial clinical experience with taurolidine/citrate ± heparin CLS 
– they are currently used extensively in many European countries for this 
indication, and for which there is considerable safety and effectiveness data 
3. Ease of use – instillation methodology is identical to current heparin lock 
solutions used in clinical practice 
4. Good safety profile in the case of inadvertent systemic administration – large 
doses of taurolidine given as a systemic infusion have shown no measurable 
effect in large randomized trials, and there is no known systemic activity on 
the coagulation system or on routine laboratory measurements. [31] The other 
active ingredients (citrate and heparin) are at low concentrations that would 
not be expected to cause significant systemic risk 


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5. Unlikely to cause bacterial resistance – taurolidine is a broad-spectrum 
antimicrobial agent, which has not demonstrated the emergence of bacterial 
resistance to date  
6. The potential to prevent or reduce colonization of bacteria and fungi within 
the catheter lumen, thereby reducing the risk from the formation of a 
microbial biofilm on the luminal surface and  
7. The potential to reduce inflammation associated with biofilm formation on 
HD catheters. [32] 
Taurolidine has been used since the 1970’s in Europe as an antimicrobial lavage and gel.  
A solution similar to Neutrolin® (without heparin) was used in combination with the 
Dialock Hemodialysis Access Device, an implantable hemodialysis access port, in a 
clinical trial of HD subjects in Germany, performed by Dr. Klaus Sodemann.  This pilot 
study enrolled and examined 70 subjects over a two year period, with very favorable 
results [20].  In a separate study, Dr. Sodemann described his anecdotal experience 
treating 53 HD catheter subjects with a taurolidine, citrate CLS combination, which also 
showed an extremely low rate of CRBSI [22].  A CLS with the active ingredients 1.35% 
taurolidine, 4% citrate, and heparin (100 or 500 USP Units/mL) is currently marketed in 
Europe and the Middle East (TauroLock®). 
A solution of Taurolidine citrate was granted the CE mark in 2004 and is sold by Tauro-
Implant GmbH; the manufacturer of a Taurolidine locking solution for the former 
Biolink.  Subsequently, Tauro-Implant launched a solution containing Taurolidine-citrate 
and heparin in 2007.  CorMedix obtained a CE mark approval for its Taurolidine-Citrate-
heparin product (Neutrolin) on July 5, 2013.  Neutrolin was granted a CE mark as a Class 
III Drug-Device with separate reviews by both the Medicinal Evaluation Board of 
Netherlands and TUV-SUD Germany.  It has been in commercial distribution in 
Germany since December 2013.  Neutrolin was initially approved for use in the 
prevention of CRBSI and maintenance of catheter patency in hemodialysis patients using 
a tunneled, cuffed central venous catheter for vascular access.   
On September 10, 2014, CorMedix was granted label expansion to include approval for 
additional indications for use in oncology patients receiving chemotherapy, IV hydration 
and IV medications via central venous catheters.  The expansion also included patients 
receiving medication and IV fluids via central venous catheters in intensive or critical 
care units (cardiac care unit, surgical care unit, neonatal critical care unit, and urgent care 
centers).  An indication for use in total parenteral nutrition was also approved. 
A feasibility trial using taurolidine 1.35% and citrate 3.5% (without heparin) as a CLS in 
ESRD subjects undergoing HD via a CVC was conducted in the United States by Allon 
[33].  This trial was performed to evaluate the incidence of CRBSI when 
taurolidine/citrate solution was used as a CLS in HD catheters over a 90-day period.  The 
study was a prospective, non-randomized, open-label, single arm feasibility study 
conducted at two centers, and was designed to evaluate the preliminary safety and 
potential effectiveness of taurolidine/citrate solution to reduce the incidence of CRBSI in 
subjects using CVCs.   
The results of the study suggested that taurolidine/citrate solution had significant 
antimicrobial effects.  In 1,679 catheter days of follow-up, there was only a single 


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episode of catheter-related bacteremia.  These results were compared to three other 
bodies of data: 1) infection rates reported from the literature; 2) each subject’s own 
experience in their previous 90 days (when only heparin was used as the CLS); and 3) a 
concurrent cohort of 30 subjects at the Principal Investigator’s dialysis center in whom 
only heparin was used to lock their CVCs.  In comparison to each of these groups, the 
taurolidine/citrate treated subjects had a much lower rate of CRBSI. 
The study also evaluated access patency and the incidence of serious adverse events.   All 
adverse events reported in the study were reviewed by an independent medical monitor 
and adjudicated as to the severity of the event and relation to the investigational product, 
if any.  No serious adverse events, apart from the single episode of CRBSI, were 
observed in the taurolidine/citrate-treated subjects. 
Access patency rates were evaluated by looking at both catheter removal due to presumed 
thrombotic catheter dysfunction, and the requirement for use of thrombolytic therapy.  
Freedom from catheter removal represents the overall effectiveness of maintaining the 
subject’s catheter for use as an effective HD access.  Catheter removal in the 
taurolidine/citrate group was similar to literature reports and to concurrent HD subjects at 
the Principal Investigator’s institution who were receiving standard heparin locks.  
Thrombolytic intervention, however, was higher than expected in the taurolidine/citrate 
group.  
For the current trial, the taurolidine/citrate solution has been optimized by adjusting the 
pH to be closer to that of blood (adjusted the pH from 5.1-5.6 to the current pH of 5.8-
6.3).  In vitro studies have demonstrated that the optimized pH reduces taurolidine-citrate 
interactions with red blood cells that may have led to clot formation in the earlier trial.  
Additionally, in vitro studies as well as experiential clinical data have suggested that at 
least some subjects benefit from the inclusion of heparin to the locking solution, [23, 24] 
to complement the antithrombotic properties of citrate. Therefore, heparin is included in 
the Neutrolin® formulation. 
As in the previous study, Neutrolin® is intended to be used in a manner identical to a 
conventional heparin CLS, and will be instilled into the HD catheter at the 
discontinuation of each dialysis session and removed prior to the initiation of the next 
dialysis session.  The control arms for this trial will be heparin at a concentration of 
heparin 4,000 USP Units/4mL (1,000 USP Units/mL).  Subjects in both study arms will 
have the CLS instilled into their catheters in a volume equal to the catheter fill volume.  
Both the investigational lock solution and the control lock solution are to be withdrawn 
prior to initiating the next dialysis session. 
2.4         SAFETY OF NEUTROLIN® 
The three active ingredients in Neutrolin® (1.35% taurolidine, 3.5% citrate, and heparin 
4,000 USP Units/4mL (1,000 USP Units/mL)) have been evaluated in pre-clinical studies 
conducted to assess their stability in solution (data on file). These studies evaluated the 
active ingredients at various concentrations and conditions with regards to physical and 
chemical compatibility, biocompatibility, impact on effectiveness for microbial growth 
inhibition, and impact on anticoagulant properties.  These pre-clinical in vitro studies 
demonstrated that the solutions are physically and chemically stable when mixed at 


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various concentrations and conditions, the component ingredients are biocompatible, the 
antimicrobial effectiveness of taurolidine is maintained when mixed with citrate and 
heparin, and combining the active ingredients does not affect the ability of the solution 
components to prevent coagulation. 
In clinical trials using a taurolidine/citrate CLS solution without heparin, an increased 
need for thrombolytic treatment has been reported in some, but not all studies; however, 
the rate of catheter replacement due to thrombotic catheter dysfunction has not been 
different in any of the studies [20, 21, 23, 24, 34].  Based upon discussions with 
numerous users of the taurolidine/citrate CLS available in the EU, we believe that at least 
certain populations of HD patients do have an increased requirement for thrombolytic 
treatment when heparin is not included in the formulation. No other adverse events were 
associated with the use of the taurolidine/citrate CLS in these previous clinical trials or 
reports.   
Taurolidine is a broad spectrum antimicrobial agent and is commercially available in 
Germany, Austria, Switzerland, Poland, and the Netherlands as a 2% solution (Taurolin® 
Geistlich Pharma AG, CH-6110 Wolhusen, Switzerland).  Taurolin® is intended for local 
use, particularly for intraperitoneal use and within the urinary bladder.  Intraperitoneal 
administration of taurolidine has been shown to significantly reduce morbidity associated 
with peritonitis [36].   
Taurolidine has been given systemically to humans in doses up to 30 grams per day with 
no significant adverse outcomes [31].  The concentration of taurolidine in Neutrolin® is 
approximately 400 times less than what has been used previously without safety issues, 
and considered negligible from a safety perspective.  It should not be anticipated that 
taurolidine at 1.35% poses any risk in case of unintended bolus administration.  
As noted previously, citrate is known to chelate calcium, and hypocalcemia is a known 
risk associated with the use of high concentrations of citrate (30% or greater).  4% citrate 
(alone) has been demonstrated to be equivalent to heparin as a CLS [29, 30] and is more 
than 10-fold lower than the concentration issued a warning by the FDA [28].  This low 
citrate concentration is regarded as safe in case of unintended bolus administration, as the 
citrate would be expected to rapidly distribute in the extracellular space and be 
metabolized by the liver within minutes [20].  However, it is possible that mild 
hypocalcemia symptoms might be seen with rapid flushing of Neutrolin®, although such 
use is not anticipated or recommended [38]. 
When used as a CLS, heparin has the potential to cause a prolongation of clotting times 
due to inadvertent escape from the catheter at instillation and between dialysis treatments.  
Depending on the half-life of the heparin used, there could be an increased bleeding risk 
for 12-24 hours [16]. The heparin concentration in Neutrolin® is identical to the 
concentration currently used in clinical practice (1,000 USP Units/mL).  Therefore, the 
bleeding risk associated with inadvertent systemic administration of Neutrolin® should be 
no greater than current standard of care. 
When taurolidine/citrate is used as a CLS for CVCs in other indications where catheter 
flushing is routine, some subjects have reported an “unusual taste” following infusion, as 
well as pain with inadvertent injection into a peripheral vein [38]. 


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In studies evaluating the pharmacokinetics of taurolidine given by rapid and high dose 
peripheral infusion, burning, pain and erythema at the infusion site as well as facial 
flushing, numbness and pain in the shoulder of the infusion arm have been reported [38].  
This is obviously a very different situation from the dosing, site of infusion and intended 
use compared with Neutrolin®. 
The HD catheters utilized in this study are commercially available, tunneled catheters 
made from silicone or polyurethane.  Testing has been performed to demonstrate the 
compatibility of Neutrolin® ingredients with silicone or polyurethane materials to enable 
the product to be used with any HD catheter that is made of one of these two materials 
(data on file).  The catheters are not considered part of the drug under investigation and 
consequently will not be supplied by CorMedix. 
Since the initial CE mark approval in Germany in 2013, there has been no serious or 
unexpected adverse events reported.  As part of CorMedix's post approval surveillance 
program or what the company refers to as the Neutrolin Use Monitoring Program 
(NUMP), 163 patients on Hemodialysis with chronic cuffed central venous catheter 
(CVCs), who are being treated with Neutrolin as their catheter lock solution, are being 
followed.  So far, with 163 patients enrolled and 36 reported on representing 1,625 
dialysis patient days, no infections have been reported.  Occasionally, patients report a 
mild transient change in taste, which resolves in a few minutes.  Based on the prevalence 
data found in the literature, 2.5-5.5 infections per 1000 dialysis patient days would be 
expected [5]. No thrombosis or clots were observed in the patient population where, 
based on information in the literature, we would have expected to see 6.7-26.6/1000 
dialysis patient days in a similar number of dialysis patients receiving HD with CVCs 
over that same time period [40]. 
2.5         RATIONALE FOR THE FORMULATION OF NEUTROLIN®  
Neutrolin® is a CLS that has been developed for use with vascular access devices.  
Neutrolin® is a proprietary solution containing 1.35% taurolidine, 3.5% citrate and 
heparin 4,000 USP Units/4mL (1,000 USP Units/mL), as active ingredients.  The 
Neutrolin® solution, as well as the heparin control solution, depending on treatment 
group, is to be instilled into CVCs for subjects undergoing HD, in a volume equal to the 
manufacturer’s stated catheter lumen volume.  Thus, the instilled solutions are not 
intended to be infused systemically (although the complete contents of each catheter 
lumen containing Neutrolin® could be injected without safety concerns). This inadvertent 
intravenous dose would be 100 fold less than the no observed adverse effect level in the 
most sensitive animals in toxicology studies.  
Taurolidine is primarily used for its broad spectrum, bactericidal, anti-biofilm and anti-
adherence properties. Additional benefits include a lack of cross-resistance to commonly 
used antibiotics. As previously noted, both citrate and heparin are effective 
anticoagulants.  The concentrations of the active ingredients in the Neutrolin® solution 
are expected to effectively prevent (or increase the time to) catheter-related bloodstream 
infection, while maintaining catheter patency in a manner that is not inferior to heparin.  
Further, it is expected that the active ingredients at the planned concentrations will be 
safe within the planned subject population. 


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3.0       STUDY OBJECTIVES 
3.1        PRIMARY OBJECTIVES 
The primary objective of this study is to demonstrate the efficacy and safety of 
Neutrolin® as a catheter lock solution (CLS) for prevention of catheter-related 
bloodstream infection (CRBSI) in subjects receiving hemodialysis (HD) for the treatment 
of End Stage Renal Disease (ESRD) when compared with heparin 4,000 USP Units/4 mL 
(1,000 USP Units/mL).  The study will demonstrate whether Neutrolin® is superior to the 
active control heparin in reducing the incidence of CRBSI.   
3.2         SAFETY OBJECTIVES 
The safety objectives of this study are to characterize any increased risks associated with 
the use of Neutrolin® used as a CLS with respect to adverse events and laboratory 
assessments as well as catheter removal for reasons other than CRBSI.   
3.3         PRIMARY ENDPOINT 
CRBSI is defined as follows:  
CRBSI requires that the same organism is grown from at least one blood culture from: 
• a peripheral site or bloodline sample 
and 
• either the arterial or venous catheter hub (or the venous or arterial dialysis circuit 
blood lines if on dialysis)  
Blood culture procedures are outlined in Section 7.1.4.  
Necessary clinical indication for suspicion of infection includes the following: 
 
One of the following symptoms: 
• Fever (defined as ≥37.8° C)  
or 
• Rigors, defined as shivering from a feeling of being cold, often 
with copious sweating, as documented by a medical professional 
 
OR two or more of the following symptoms:  
 
• Tachycardia defined as a heart rate greater than 100 beats per 
minute  
• Tachypnea, as defined as a RR greater than 24 breaths per minute 
• Low blood pressure as defined as a systolic blood pressure less 
than 90, as measured by a clinician (RN or MD) with a BP cuff, or 
a decrease in blood pressure greater than 30 mmHg 
• An obvious change in mental status from previously documented 
baseline.   


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All attempts will be made to document as many signs and/or symptoms as possible at the 
time of suspected CRBSI.   
 
An investigator may choose to obtain blood cultures on other suspicions of CRBSI, but 
the CRBSI case definition requires the clinical indication for suspicion of infection 
criteria listed above in addition to the blood culture criteria listed above. 
 
If the subject has clinical symptoms, while on or off dialysis, blood cultures will be 
obtained using peripheral venipuncture from a source not intended for future vascular 
access, and the venous or arterial hub of the HD CVC (or the venous or arterial dialysis 
circuit blood line if on dialysis). If a peripheral site is not available, as soon as the patient 
is evaluated, blood cultures can be obtained from both the venous and arterial hubs of the 
HD CVC (or the dialysis circuit blood lines if on dialysis), preferably before the study 
subject receives antibiotics.  Ten to twenty mL of blood should be collected, without 
discarding any of the CLS.   
 
3.3.1 Clinical Adjudication Committee 
  
While sites will seek to identify that a CRBSI is present and will be responsible for 
collecting the clinical data and blood cultures as outlined in the protocol, each case will 
be reviewed by a Clinical Adjudication Committee (CAC) for the final assessment of 
CRBSI status.  The CAC is a multi-disciplinary committee of specialists who will review 
both the clinical documentation as well as the blood culture results to determine if the 
case is a CRBSI.  However, because the CAC determination is based on data obtained 
from the clinical sites, and the review cannot be initiated without blood culture results, it 
is imperative that the sites follow the protocol definition of CRBSI, and collect blood 
cultures when a CRBSI is suspected. 


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4.0        INVESTIGATIONAL PLAN  
4.1       OVERALL STUDY DESIGN AND PLAN 
This is a randomized, double-blind, active-control, parallel-arm, multicenter study. 
Subject will be followed until a CRBSI has occurred, the catheter is removed, the subject 
withdraws, or the study is ended..  Approximately 900 subjects with end stage renal 
disease undergoing HD using a tunneled silicone or polyurethane HD catheter are 
anticipated be randomized from up to 85 centers in the United States. 
Subjects will attend a screening visit up to fourteen days prior to dosing.  At this visit 
entry criteria will be checked and baseline characteristics will be collected.  If the subject 
meets eligibility criteria, at the Baseline Visit, subjects will be randomized and begin the 
first day of dosing.  Study visits will occur on dialysis treatment days.  Every four weeks 
at one of these dialysis visits a more extensive visit will occur including the collection of 
vital signs and labs, as outlined in section 7.1.5. Subjects are to remain in the study until 
they have met the primary endpoint, withdrawn from the study, their catheter is removed, 
or until the study completes.   
All subjects will receive standard of care therapy consistent with current practice 
guidelines, and will be randomized to either Neutrolin® (1.35% taurolidine, 3.5% citrate, 
heparin 4,000 USP Units/4mL (1,000 USP Units/mL)) or the active control heparin 4,000 
USP Units/4mL (1,000 USP Units/mL) in a 1:1 ratio.  
 
4.1.2       Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be formed to periodically review the 
accumulating study data.  The primary responsibilities of the DSMB will be to monitor 
subject safety and study conduct and to oversee the interim analysis.  The DSMB will 
have access to both unblinded safety and efficacy data. The DSMB will be independent 
of the sponsor and will consist of 4 individuals, three physicians and one statistician, with 
relevant clinical and statistical expertise.  
The DSMB will oversee the interim analyses for efficacy and for futility that will be 
performed when 28 CAC-adjudicated CRBSI events have occurred. If statistical 
significance is obtained for the primary efficacy endpoint, the recommendation will be to 
stop the study early for efficacy. If the futility analysis indicates that it is futile to 
continue the study, the recommendation will be to stop the study early for futility. In 
either case, the DSMB will report its recommendation only to the CorMedix Executive 
Committee, which will make the final decision as to whether or not to stop the study in 
consultation with FDA.  
An independent statistical team will prepare the data summaries for DSMB review.  No 
additional study (or sponsor) staff will have access to the unblinded DSMB summaries.    
A DSMB charter with standard operating procedures to control potential biases will be 
developed and implemented prior to any data analysis.  
 


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4.1.3 Clinical Adjudication Committee 
A Clinical Adjudication Committee (CAC) will be formed to review each case of 
suspected CRBSI and make a final determination of the case status, after a thorough 
review of the clinical and laboratory data obtained for each suspected case.  The CAC 
will consist of experts in the fields of nephrology and infectious disease.  The CAC will 
independently and critically assess the circumstances surrounding the suspected CRBSI 
event while remaining blinded to patient treatment assignment. 
 
All study subjects, including those who completed the study prior to implementation of 
the CAC process, with one or more positive blood cultures (other than for coagulase 
negative Staphylococcus, which requires a confirmatory culture) will be adjudicated for 
the presence of a CRBSI event by the CAC, which will remain blinded to treatment 
assignment. However, because the CAC determination is based data obtained from the 
investigative sites for suspected CRBSI, and the review cannot be initiated without blood 
culture results, it is imperative that the sites collected blood cultures when a CRBSI is 
suspected. 
 
The results of the CAC adjudication will not be provided back to the investigator/site. 
4.2         DISCUSSION OF STUDY DESIGN 
This randomized, double-blind, active-control, parallel-arm, multicenter study is designed 
to demonstrate whether the CLS Neutrolin® will reduce the occurrence of CRBSI. Safety 
and efficacy information, including maintenance of catheter patency and catheter loss, as 
well as adverse event occurrence will be evaluated against the active control heparin, 
which is the current standard CLS in United States clinical practice.  All subjects will 
receive standard of care therapy consistent with current clinical practice guidelines and 
best practices. 
The population chosen for this study will be representative of the general HD patient 
population using CVCs as their vascular access. 
Further discussion of the study design is located within Section 5. 
 


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5.0         SELECTION OF STUDY POPULATION 
This study will enroll subjects with End Stage Renal Disease who are receiving HD 
treatment using a permanent cuffed tunneled silicone or polyurethane HD catheter as 
their vascular access. The specific inclusion and exclusion criteria for enrolling subjects 
into this study are described in the following sections.  
5.1         INCLUSION CRITERIA 
Potential study subjects must satisfy the following criteria to be enrolled into the study:  
All subjects 18 years or older (meeting the following inclusion criteria):  
1. Subject has ESRD and undergoes chronic HD at least two times per week 
 
2. Subject has a HD catheter that has demonstrated the ability to achieve a 
minimum blood flow of at least 250 mL/min for at least two consecutive 
dialysis sessions to enable successful HD 
 
3. The HD central venous catheter is placed in a jugular or subclavian vein, with 
the tip of the catheter typically sitting at a junction of superior vena cava and 
right atrium  
 
4. The subject is not expected to expire within 180 days 
 
5. The subject is likely to require the use of a CVC for at least 60 days 
 
6. The subject (or the legal guardian) understands the nature of the study and 
provides written informed consent prior to the study enrollment 
 
7. The subject is willing to comply with specified follow-up evaluations and 
prescribed dialysis therapy and 
 
8. The subject is receiving adequate hemodialysis as assessed by the 
investigators and based on a single pool Kt/V measurement > 1.2 (within the 
last 30 days). 
 
9. All females of childbearing potential must have a negative pregnancy test at 
the screening visit (i.e., subject is not pregnant). Females of childbearing 
potential must agree to use an acceptable method of contraception for the 
duration of the study. Reliable forms of birth control are defined as:,  
• Abstinence as documented in the medical records and CRF. 
• Depo-Provera, or other hormonal contraceptive (oral, implant, 
ring, patch) for the duration of the study.  (NOTE: The subject 
must have used the chosen method of birth control for at least 1 
month/cycle prior to enrollment into the study). 
• Double barrier method (spermicidal jelly or foam with condoms or 
diaphragm. 


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Subjects that would not be required to use the required birth control 
methods are those who are:  
• Post-menopausal, defined as: 
o 12 months of spontaneous amenorrhea or 
o 6 months of spontaneous amenorrhea with serum FSH 
levels > 40 mIU/mL or 
• Surgically sterilized (i.e., previous tubal ligation or hysterectomy). 
5.2         EXCLUSION CRITERIA 
Subjects who meet any of the following criteria may not be enrolled into the study: 
 
1. 
Subjects who received antibiotics within the last 14 days 
 
2. 
Visible evidence of compromised skin integrity is present at the catheter 
exit site or evidence of a catheter exit site infection 
 
3. 
Subject has received any thrombolytic treatment (i.e., tPA – Cathflo®) in 
their current catheter within 30 days of randomization 
 
4. 
Fill volume of HD catheter is unknown or cannot be determined 
 
5. 
Subjects using any type of antimicrobial-coated or heparin-coated catheter 
 
6. 
Documented chronic bleeding diathesis, active or recurrent bleeding 
within 1 month prior to randomization 
 
7. 
Documented history of an atrial thrombus or known hypercoagulable state 
 
8. 
Subjects with open, non-healing skin ulcers 
 
9. 
Current requirement for systemic immunosuppression that would increase 
risk of infection; such as: 
a) Steroid dose higher than 10 times the physiologic dose (>50 mg 
Prednisone/day) 
b) Methotrexate dose sufficiently high to suppress WBC below 5,000 
c) Biologic immunomodulators (anti-TNF, anti-CD4, etc) within 1 
month 
d) Azathioprine dose greater than 2.5 mg/kg/day (175 mg for average 
adult) 
e) Calcineurin inhibitors:  
• 
cyclosporine dose greater than 8 mg/kg (560 mg for average 
adult) 
• 
tacrolimus dose greater than 0.4 mg/kg (30 mg for average adult) 
f) Sirolimus dose greater than 10 mg daily for average adult 
 


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10. 
Active malignancy requiring or anticipated to require chemotherapy likely 
to cause leukopenia and/or immunosuppression 
 
11. 
Known allergy or absolute contraindication to citrate, taurolidine or 
heparin or a history of heparin-induced thrombocytopenia 
 
12. 
Unstable malignancy 
 
13. 
Cirrhosis with encephalopathy 
 
14. 
Subject is currently taking another medication with known systemic drug 
interaction with citrate, taurolidine, or heparin 
 
15. 
Subject is currently enrolled in another investigational device and/or drug 
trial or has participated in another investigational device and/or drug trial 
within 30 days prior to enrollment 
 
16. 
Subject is anticipated to receive a renal transplant within 90 days (subjects 
can be on the transplant list, but a subject with a known or anticipated 
transplant date within the next 90 days should be excluded) 
 
17. 
Any other medical condition which renders the subject unable to or 
unlikely to complete the study, or which would interfere with optimal 
participation in the study or produce significant risk to the subject. 
 
Subjects who are screened, but are deemed to not meet eligibility criteria may be re-
screened one time if subject circumstances have changed or a new catheter has been 
placed, and the subject is now expected to be eligible (e.g., course of antibiotic therapy is 
completed more than 14 days from re-screening date).   Re-screened subjects must first 
be approved by the medical monitor.  Subject must be off of systemic antibiotics for at 
least 14 days to be eligible for re-screening, and must meet all other entry criteria on the 
re-screening date to be eligible.  If the medical monitor approves a re-screening, the 
subject will be assigned a new subject number.  Subjects who have been randomized and 
received at least 1 dose of investigational product cannot be re-entered into the study at a 
later point. 
 
5.3  
STUDY COMPLETION, EARLY WITHDRAWAL, NEW CATHETER 
PLACEMENT 
 
5.3.1 Study Completion 
A subject is considered as completing the study if at least one of the following conditions 
is met: 
• All assessments through study closure;  
• CRBSI meeting primary endpoint definition; 
• Catheter removal; 


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• Death; 
• Transfer to a non-study site; or  
• Termination of dialysis. 
5.3.2 Early Withdrawal from Treatment  
A subject should discontinue study treatment for any of the following reasons: 
1. The investigator believes that for the subject’s best interest; or 
2. For safety reasons (e.g., an adverse event) the subject should stop treatment; 
or  
3. Subject’s request/withdrawal of consent 
The subject, if agreeable, will continue to be monitored for safety parameters for 28 days 
following the last removal of the investigational product. At the end of the 28 day period 
after withdrawal (+7 days as needed for scheduling), subject should return to the site for a 
final safety visit, as outlined in 7.1.6. 
CorMedix reserves the right to close the investigational site, withdraw a subject 
(discontinue provision of blinded investigational product treatment), or terminate the 
study at any time (see Section 11.8). 
5.3.3  Interruption of investigational product dosing 
Randomized Investigational Product should be administered at all visits starting from day 
1 (date of randomization) through study completion unless contraindicated per 
investigator judgment.  Additionally, there may be cases where the subject cannot attend 
the study center for a regularly scheduled dialysis visit (e.g. hospitalization, travel out of 
town), requiring an investigational product interruption.  If more than 3 consecutive doses 
are missed, the study site must contact the medical monitor to review the circumstances 
of the interruption and assess if any additional actions are required.   
If an investigational product interruption occurs, the subject should resume randomized 
investigational product dosing as soon as possible.  The Investigational Product 
administration interruption of more than 3 consecutive doses should be clearly noted 
within the source documents and in two study records – (1) on the investigational product  
drug dosing CRF, and (2) on the interruption of investigational product CRF at the next 
monthly visit.  


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6.0          STUDY TREATMENTS 
6.1         IDENTITY OF INVESTIGATIONAL PRODUCTS  
Neutrolin® is a unique formulation of taurolidine 1.35%, citrate 3.5%, and heparin 4,000 
USP Units/4mL (1,000 USP Units/mL). Neutrolin® CLS and heparin CLS will be 
packaged in identical vials. The catheter lock solution is to be instilled in catheters using 
a volume matching the fill volume of the hemodialysis catheter, which typically varies 
from 3.6-5.0 mL.  
 
Vials should be stored at controlled room temperature between 15 and 25° C, and should 
not be frozen.  All vials are single use only, and any leftover solution should be discarded 
according to the institution’s procedures for disposal of biohazardous waste. 
6.2         BLINDING  
The Neutrolin® lock solution will match the control lock solution with respect to volume, 
color, viscosity, and smell and will be packaged in identical containers (at an off-site, 
central facility). 
The label will remain affixed to the investigational product container and will contain all 
identifying information except for the identity of the drug contained therein (e.g., active 
investigational product or active control).  
The blind should not be broken until all subjects have completed the study and the 
database is finalized. The blind should only be broken if specific emergency treatment 
would be dictated by knowing the treatment status of an individual subject. In such cases, 
a system will be in place for revealing assigned treatment. The blind should not be 
broken without consultation with the Medical Monitor. The date and reason for the 
unblinding must be documented.  
6.3         TREATMENTS TO BE ADMINISTERED  
Neutrolin® or active control (heparin, 1,000 USP Units/mL) will be used as a CLS as 
follows: 
1. Flush each lumen with 10 mL of saline. 
2. Withdraw CLS from the vial using a 3 mL or smaller syringe (to ensure 
accurate volume). Use one syringe for each lumen. 
3. Instill CLS into the access device in a quantity sufficient to fill the catheter 
lumen. Consult the manufacturer’s instructions for specific fill volume. CLS 
is intended to remain inside the access device until the next hemodialysis 
treatment. 
4. Prior to initiation of the next hemodialysis treatment, CLS should be 
withdrawn from the catheter and discarded according to the institution’s 
biohazardous waste policy. 
 
Day 1 (day of randomization): Following HD treatment, Neutrolin® or heparin control 
solution will be instilled.  


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Subsequent dialysis sessions: the lock solution will be removed from the HD catheter (if 
possible) prior to the initiation of dialysis.  At the end of dialysis, Neutrolin® lock 
solution or heparin control will be instilled as described above. 
6.4         METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUP  
Central randomization will be used for this study.  Subjects will be assigned in a 1:1 ratio 
using permuted blocks without additional stratification. 
 
6.5         SELECTION OF NEUTROLIN® COMPOSITION AND CONTROL 
Neutrolin® is available in Europe and the Middle East with a choice of two 
concentrations of heparin.  For this study, the Neutrolin® formulation was selected to 
match the heparin content of standard care in the United States. 
The active control in this trial is heparin 4,000 USP Units/4mL (1,000 USP Units/mL).  
Although there is no uniform standard, 1,000 USP Units/mL heparin is used in most HD 
CVCs. [17, 41].  
6.6         SELECTION AND TIMING OF THE CATHETER LOCK SOLUTION  
As noted above, subjects will be randomly assigned in a double-blind fashion either to 
Neutrolin® or control group.  Given that Neutrolin® and heparin are used as CLS, they 
will be instilled in both limbs of the subject’s HD catheter at the completion of each 
dialysis session. 
The Neutrolin® or control lock solution will be removed prior to each dialysis treatment, 
and instilled as a fresh lock solution following each dialysis treatment. 
6.7         PRIOR AND CONCOMITANT THERAPY/PROCEDURES 
Prior and concomitant medications and procedures are recorded throughout the study, 
including 30 days prior to randomization, in the corresponding CRF. As part of routine 
medical care, the study nurse should inquire about any new medications and procedures 
at every routine dialysis visit.  
Systemic antibiotic treatment (oral or parenteral) during the study is permitted if required 
for the treatment of infections documented not to be CRBSI (e.g., pneumonia, urinary 
tract infection, etc.).  Blood cultures should be taken prior to the administration of any 
systemic antibiotic or antifungal treatments, unless there is a documented microbiological 
cause other than CRBSI. Systemic antibiotic treatment is permitted as part of standard of 
care for suspicion of CRBSI once blood cultures are collected. 
Randomized investigational product instillation in the HD catheter may continue while 
receiving systemic antibiotics and after completion of the antibiotic regimen.  
Investigational product does not need to be interrupted.  Use of antibiotic therapy will be 
collected in the CRF.  
All medications different from the investigational product (prescriptions or over-the-
counter medications) and procedures administered 30 days prior to randomization, and 


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during the course of the study until the final safety visit must be documented in the 
concomitant therapy section of the CRF.  
6.7.1       Prohibited Concomitant Medications 
The use of systemic antibiotics within 14 days prior to enrollment, as well as any 
thrombolytic treatment (i.e., tPA – Cathflo®) instilled in their current catheter within 30 
days of randomization is prohibited, as outlined in the exclusion criteria (Section 5.2). 
Current requirement for systemic immunosuppression that would increase risk of 
infection; such as those described in section 5.2 are also prohibited.  If a subject requires 
treatment with a systemic immunosuppressant at doses higher than described in the 
exclusion criteria (Section 5.2; Exclusion Criteria 9) then the subject should be 
withdrawn from the study.  There are no other prohibited medications. 
6.8         STANDARD OF CARE FOR PREVENTION OF CRBSI 
In determining an appropriate standard of care, careful consideration was given to current 
practice guidelines, clinical practice standards of care, and scientific evidence in support 
of particular treatments.  Guidelines established by KDOQI and the CDC will be used in 
this trial as implemented by the site [2, 42]. 
The definition of standard of care for this study is as follows: 
1. All catheter and exit site care to be performed only by dialysis staff and 
subjects trained to do so; 
2. Conduct all catheter procedures following CDC best practices and/or facility 
standard operating procedures; 
3. Asepsis will be maintained through preexisting protocol at the study site. For 
example, use 2% Chlorhexidine in 70% ethanol or acceptable alternative for 
cutaneous antisepsis unless the subject has a history of sensitivity, in which 
case Chlorhexidine aqueous or 70% ethanol should be used; 
4. Use only sterile gauze or sterile semi-permeable transparent dressings to cover 
the catheter site. 
6.9      STANDARD OF CARE FOR HEMODIALYSIS 
All subjects will be provided with standard of care HD treatment according to the 
prescribing physician’s prescription and current standards of care for each dialysis 
facility.  However, this prescription must be intended to provide the subject with a 
spKt/V of at least 1.2. 
The protocol will allow for only the use of a permanent, cuffed, tunneled silicone or 
polyurethane HD catheter. 
6.10        TREATMENT COMPLIANCE  
Every effort will be made by the site personnel to ensure that subjects receive catheter 
lock instillations per protocol and return for scheduled visits. Each dose of blinded 
investigational product will be administered on the day dictated by the subject’s dialysis 
schedule (refer to Schedule of Assessments table).  


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6.11        INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the clinical investigator to ensure that all investigational product 
received at the site will be inventoried and accounted for throughout the study and the 
result recorded in the drug accountability form maintained in the Regulatory Binder. The 
study staff must be instructed to return all original containers to the investigator site 
secure drug storage area, whether empty or containing investigational product. 
Investigational product returned by study staff will be stored and disposed of according to 
the sponsor’s instructions. Contents of the investigational product containers must not be 
combined. The investigational product accountability will be verified by the sponsor or 
sponsor designee during on-site monitoring visits. Investigational product will be stored 
in a limited access area or in a locked cabinet under appropriate environmental 
conditions. Investigational product will be stored at room temperature. 
The investigator agrees not to supply the investigational product to any person other than 
sub-investigators, designated staff, and the subjects participating in the study. 
Investigational product may not be relabeled or reassigned for use by other subjects 
except under special circumstances approved by the sponsor. 
The investigator will retain and store all containers, which are full, empty, or contain 
unused investigational product, until these containers are inventoried by the sponsor or 
sponsor’s designee. The sponsor or the sponsor’s designee will provide instructions, 
which the investigator agrees to follow to return or dispose of all containers, whether 
empty or containing investigational product. The investigator agrees neither to dispense 
the investigational product from, nor store it at, any site other than the study sites agreed 
upon with the sponsor. 
 
 


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7.0          EFFECTIVENESS AND SAFETY VARIABLES 
7.1         SCHEDULE OF ASSESSMENTS 
The schedule of study visits and assessments is displayed in the following Schedule of 
Assessments Table: 
 
 
 


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Table 2.  Study Flow Chart 
Screening 
Baseline 
Visit 
Routine 
Dialysis 
Visits 
 
Monthly 
Assessmentsc 
Per 
protocol 
(when 
CRBSI 
suspected)b 
Final Safety 
Visit 
 
Study Assessments 
Day -14 
to 0a 
Day 1 
Dialysis visits 
after day 1, 
though study 
completion 
Every 4 weeks 
(+/- 5 days) 
 
28 (+7) days      
following the 
removal of last 
IP dose 
Informed consent 
X 
 
 
 
 
 
Assess inclusion/exclusion criteria 
X 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Investigational product 
Administration 
 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
 
Medical and surgical history 
(including vascular access status) 
X 
 
 
 
Focused 
 
Medication history 
X 
 
 
 
 
 
Physical exam 
X 
 
 
 
Focused 
X 
Vital signs (Temp, Pulse, 
Respiratory Rate) 
X 
X 
X 
X 
X 
X 
Blood pressure (pre-and post-
dialysis)l 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
Weight (pre-and post-dialysis) j 
X 
 
X 
X 
 
X 
Blood Culturesd 
 
 
 
 
X 
 
Serum pregnancy teste 
X 
 
 
X 
 
X 
Blood glucose, leukocyte count, 
CRP, and procalcitonin 
 
 
 
 
X 
 
Hematology f 
X 
 
 
X 
 
X 
Blood chemistryg (including 
adjusted serum calcium and 
albumin) 
X 
 
 
X 
 
X 
spKt/V 
X 
 
 
X 
 
 
Dialysis prescription parameters j 
X 
X 
X 
X 
 
 
Dialyzer Blood Flow j 
X 
X 
X 
X 
 
 
Treatment Time j 
X 
X 
X 
X 
 
 
Interventionsh 
X 
X 
X 
X 
X 
X 
Assessment of Skin around 
catheteri 
X 
X 
X 
X 
X 
X 
Adverse & clinical endpoint events 
 
X 
X 
X 
X 
X 
Concomitant medicationk 
X 
X 
X 
X 
 
X 
Verify compliance with study 
product administration 
 
 
 
X 
 
 
a   Some historical data earlier than Day -14 may be needed 
b  Document primary endpoint 
c     Visit to occur every 4 weeks concurrently with one of the dialysis treatment visits for the duration of subject participation in the 


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7.1.1       Screening Visit (Day-14 to Day 0) 
 
The screening period starts when the subject signs the informed consent document. 
Subjects who are screened for eligibility but are not enrolled in the trial must be entered 
on the Screening Log, indicating the reason(s) for exclusion. The following procedures 
will be performed within the 14 day period preceding randomization: 
• Informed consent 
• Review of inclusion and exclusion criteria  
• Demographics (including age, sex, race) 
• Physical examination and vital signs (NOTE: a physical examination conducted 
by the investigator within the past 30 days can be an applicable physical 
examination for study purposes) 
• Blood pressure (pre- dialysis if performed at a dialysis session) 
• Weight (pre-and post-dialysis, in kg) 
• Medical and surgical history  
• Height 
• Concomitant medications and medication history 
• Blood sample for clinical laboratory assessments: 
o Hematology 
o Blood chemistry and liver function 
o Serum pregnancy test (women of childbearing potential) 
• Record blood flow (Qb) data for last 2 dialysis treatments for current catheters.  If 
catheter has been in place for < 14 days, document at least 1 Qb from an available 
dialysis treatment 
• Document HD prescription 
• Document spKt/V (within the last 30 days) 
• Obtain dialysis duration time for last 2 dialysis treatments.  If catheter has been in 
place for < 14 days, document dialysis duration time from all available dialysis 
treatments 
study. 
d Blood cultures must be drawn if CRBSI is suspected 
e Applies only to female subjects of child-bearing potential 
f   Hematology panel: complete blood count (CBC) with differential, platelets, and reticulocyte count (%) 
g  Blood chemistry panel: sodium, potassium, chloride, blood urea nitrogen (BUN), serum creatinine, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase, bilirubin, adjusted serum calcium, serum albumin, carbon dioxide, 
and glucose 
h   Use of tPA or other thrombolytic treatments 
i    Assess skin around catheter for signs and symptoms of breakdown, infection (e.g. erythema, edema, induration, or discharge), and 
bruising 
j Parameters determined at each dialysis session 
k Concomitant medications taken during the 30 days prior to randomization and used any time through the final study visit should be 
recorded in the  concomitant medications  CRF.  As part of routine medical care, the study nurse should inquire about any new 
medications at every routine dialysis visit. 
l  Blood pressure for Screening and Final Safety Visits should be taken only pre-dialysis (not post-dialysis), if visit occurs during 
dialysis session.  For the CRBSI assessment, it should be taken at the time of blood culture collection. For all other Assessments, 
blood pressure should be taken pre- and post-dialysis. 


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• Assess skin around catheter for signs and symptoms of breakdown, infection (e.g., 
erythema, edema, induration, or discharge), and bruising 
• Document catheter interventions (e.g., use of tPA) used within 30 days prior to 
screening (current HD catheter). 
 
7.1.2       Baseline Visit (Day 1, Day of Randomization) 
The following assessments are to be conducted: 
• Confirm inclusion and exclusion criteria (see Section 5) 
• Vital signs (before dialysis treatment) 
• Blood pressure (pre and post dialysis) 
• Randomization 
• Assess skin around catheter for signs and symptoms of breakdown, infection (e.g. 
erythema, edema, induration, or discharge), and bruising 
• Administer and document dialysis treatment per dialysis prescription parameters  
• Record mean Qb 
• Following dialysis, record actual dialysis treatment time 
• Adverse and clinical endpoint event assessment 
• Concomitant medications (taken in the 30 days prior to randomization) 
• Interventions – record use of thrombolytic therapy if required (NOTE: tPA use 
within 30 days prior to randomization is an exclusion) 
• Investigational product administration – instill CLS upon discontinuation of the 
dialysis procedure using the procedure described in Section 6.3. 
All subjects will receive standard of care HD treatment and catheter care as noted in 
Section 6.8. 
7.1.3       Routine Dialysis Visits Until Study Completion 
Visits conducted two to three times weekly on regularly scheduled dialysis visit days 
from study day 1 to study completion: 
• Vital signs (before dialysis treatment) 
• Blood pressure (pre and post dialysis) 
• Weight (pre and post dialysis) 
• Review of concomitant medications 
• Assess skin around catheter for signs and symptoms of breakdown, infection (e.g. 
erythema, edema, induration, or discharge), and bruising 
• Remove study product from the catheter  
• Administer and document dialysis treatment per dialysis prescription parameters  
• Record mean Qb 
• Following dialysis, record actual dialysis treatment time 
• Adverse and clinical endpoint event assessment 
• Interventions – record use of thrombolytic therapy if required  
• Investigational product administration – instill CLS after dialysis procedure using 
standard protocol. 


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7.1.4       Subject Assessment and Management if CRBSI Suspected 
Infection monitoring will be done prior to and during all dialysis sessions. Sites are 
expected to collect data relating to a possible CRBSI occurring at their own facility, but 
also if the subject is assessed by another facility. If the subject demonstrates clinical signs 
or symptoms compatible with bacteremia, including any one of the following: change in 
body temperature, fever, observed rigors; or any two of the following: hypotension, 
tachycardia, increased respiratory rate, or an obvious change in mental status; or on any 
other clinical sign or symptom consistent with an infection. Assessment of a CRBSI 
should also occur under the following circumstances: the prescription of systemic 
antibiotic or antifungal therapy unless there is a documented microbiological source other 
than CRBSI, and at the time of catheter removal unless the subject is receiving systemic 
antibiotic or antifungal therapy or has received such therapy in the previous week. 
 
Blood cultures for the assessment of a CRBSI should be obtained following the 
procedure documented below. Additionally, vital signs, blood glucose, CRP, 
procalcitonin, and leukocyte count should be obtained as part of the CRBSI assessment.   
 
Blood cultures must be taken from two sites to enhance the validity of the culture testing 
results. One aerobic and 1 anaerobic blood culture bottle should be taken from each site. 
 
If the subject has clinical symptoms, while on or off dialysis, blood cultures will be 
obtained using peripheral venipuncture from a source not intended for future vascular 
access, and the venous or arterial hub of the HD CVC (or the venous or arterial dialysis 
circuit blood line if on dialysis). If a peripheral site is not available, as soon as the patient 
is evaluated, blood cultures can be obtained from both the venous and arterial hubs of the 
HD CVC (or the dialysis circuit blood lines if on dialysis), before the study subject 
receives antibiotics.  Ten to twenty mL of blood should be collected, without discarding 
any of the CLS.  Site of blood withdrawal (peripheral veinipuncture or catheter hub or 
dialysis circuit blood line) should be recorded in the CFR.  
Blood cultures should be obtained using the following procedure:  
• Wash hands and use appropriate personal protective equipment, including gloves 
• Clean the arterial port with an alcohol prep pad, allow to dry, and avoid touching 
the arterial port after cleaning 
• Two Bact/Alert system blood culture bottles should be used – 1 for the aerobic 
culture, and 1 for the anaerobic culture for each site of blood sample collection 
(CVC/dialysis circuit or peripheral site) 
o Verify that the flip-off caps on the bottles are intact and aseptically 
remove the cap 
o Clean each bottle with an alcohol prep pad 
• Collect specimen in the aerobic bottle first 
o Hold bottle upright and ensure that the bottle remains upright at all times 
to prevent back flow of culture media into the dialysis arterial line 
o Peel open the BD Vacutainer Safety-Lok Blood collection Set and thread 
the luer end of the tubing into the vacutainer holder 


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o Insert safety-lok blood collection set, with vacutainer attached into the 
arterial port 
o Push and hold vacutainer holder over the top of the vial to puncture the 
septum 
• Remove holder from the vial and immediately push and hold vacutainer over the 
second Bact/Alert system blood culture bottle for the anaerobic culture 
• When the second bottle is filled, withdraw the vacutainer from the bottle. 
• The safety-lok needle should be discarded in a biohazardous sharps container 
• Attach the printed labels with patient identifier to the blood culture bottles on the 
designated area, but do not cover the barcode on the bottle 
• Prepare blood culture bottles for shipment to the laboratory. 
• Do not refrigerate or freeze the bottles. 
 
The following assessments are to be conducted when a CRBSI is suspected: 
• Assessment of CRBSI signs and symptoms 
• Vital signs 
• Blood pressure 
• Assessment for alternate sources of infection 
• Focused physical examination (can be performed by appropriately delegated 
study personnel) 
• Blood cultures – Aerobic and anaerobic cultures to be collected as noted above 
• Blood glucose, CRP, procalcitonin, and leukocyte count 
• Assess skin around catheter for signs and symptoms of breakdown, infection (e.g., 
erythema, edema, induration, or discharge), and bruising, and obtain 
microbiological cultures if any catheter site exudate 
• Document catheter interventions (e.g., use of tPA) used within 30 days. 
 
If a study subject presents to an Emergency Department (ED), urgent care center, or other 
treatment facility, the PI will coordinate the evaluation of the subject with the treating 
physician at the facility whenever possible.  A review of the hospital records (complete 
history, physical examination, and progress and discharge notes) will be performed and 
recorded by the site on the corresponding CRF (e.g., Adverse Event and Concomitant 
Medication). A CVC and/or peripheral blood cultures will be obtained and the results 
should be entered on the local lab CRF in Medidata/Rave  Any other clinically-indicated 
testing will be done to rule out other potential causes of bacteremia. 
If a study subject receives Emergency Department or inpatient care, the subject or family 
members should inform the ED or inpatient attending physician that he/she is 
participating in a study and request that the Study Physician (or designee) be informed 
and ALL records (including microbiology reports) from the ED or inpatient visit be sent 
to the Study Physician.  The Study Physician (or designee) will provide any Study related 
information requested by the ED or inpatient physician and will review all records, when 
received.  


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7.1.5       Monthly Assessments (+/- 5 days) 
The following assessments are to be conducted every 4 weeks (i.e. monthly), and will be 
conducted as a part of one of the regularly scheduled dialysis treatment visits that occur 3 
times weekly: 
• Weight (pre-and post-dialysis, in kg) 
• Vital signs (before dialysis treatment; monthly assessment is concurrently 
collected at dialysis treatment visit) 
• Blood pressure (pre and post dialysis) 
• Blood sample for clinical laboratory assessments: 
o Hematology 
o Blood chemistry and liver function 
o Serum pregnancy test for women of childbearing potential 
• Verify compliance with study product administration 
• Verify and document dialysis prescription parameters 
• Dialyzer blood flow 
• Actual treatment duration  
• Interventions 
• Assess skin around catheter for signs and symptoms of breakdown, infection (e.g. 
erythema, edema, induration, or discharge), and bruising 
• spKt/V 
• Concomitant medications 
• Adverse and clinical endpoint event assessment (concurrently collected at dialysis 
treatment visit). 
 
7.1.6       Final Safety Visit (28 days, + 7 days after  removal of last dose of 
investigational product) 
This visit would be completed 28 days after the removal of the investigational product 
from the HD catheter at the scheduled final safety visit for each subject.  Subjects will 
return to a standard of care CLS to be instilled into the HD catheter after the completion 
of dialysis at this visit. If there is any reason why the subject cannot attend this visit, then 
the subject assessment should be done in the dialysis unit. There is a +7-day window to 
allow convenient scheduling. 
The following assessments are to be conducted: 
• Physical Exam (NOTE: a physical examination may be conducted by an 
appropriately delegated sub-investigator or medically qualified personnel) 
• Vital signs  
• Blood pressure (pre and post dialysis) 
• Weight (pre- and post-dialysis, in kg) 
• Blood sample for clinical laboratory assessments 
o Hematology 


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o Blood chemistry  
• Serum Pregnancy test 
• Concomitant medications taken through the final study visit 
• Assess skin around catheter for signs and symptoms of breakdown, infection (e.g. 
erythema, edema, induration, or discharge), and bruising 
• Adverse and clinical endpoint event assessments 
• Interventions – record use of thrombolytic therapy if required. 
 
7.1.7       Early Withdrawal Visit for Last Observation 
If the subject withdraws early, a visit should be completed at the PI institution whenever 
possible. If there is any reason why the subject cannot attend this visit, then the subject 
assessment should be done in the dialysis unit.  If the subject has transferred to another 
unit, the subject should be contacted by telephone in order to obtain the informational 
components of the visit assessments and every effort should be made to collect the 
appropriate blood samples. There is a 7-day window allowed in order to allow convenient 
scheduling. 
The following assessments are to be conducted: 
• Physical Exam (NOTE: a physical examination conducted by the an appropriately 
delegated sub-investigator or medically qualified personnel) 
• Vital signs 
• Blood pressure (pre and post dialysis) 
• Weight (pre- and post-dialysis, in kg) 
• Blood sample for clinical laboratory assessments 
o Hematology 
o Blood chemistry  
• Concomitant medications 
• Assess skin around catheter for signs and symptoms of breakdown, infection (e.g. 
erythema, edema, induration, or discharge), and bruising 
• Adverse and clinical endpoint event assessments. 
In the event of early withdrawal, the HD catheter should be locked using another non-
investigational therapy.  The subject, if agreeable, will continue to be monitored for 
safety parameters for 28 days following the last removal of the investigation product. At 
the end of the 28-day period after withdrawal (+7 days as needed for scheduling), subject 
should return to the site for a final safety visit, as outlined in 7.1.6.  
7.2         SCREENING/BASELINE ASSESSMENTS 
7.2.1    Subject Demographics 
The following demographic information will be collected at the screening visit and 
recorded in the CRF: 
• Month, date, and year of birth 
• Sex 


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• Race 
• Height (cm) 
• Weight (kg). 
Weight will be recorded in regular clothing without jacket, coat, or shoes.  Weight will 
also be collected at monthly visits and recorded in the CRF. 
7.2.2       Medical and Surgical History 
A relevant medical and surgical history will be obtained at the screening visit. The 
history will be reviewed to assess study eligibility and to provide an overview of the 
subject’s medical history and current status. The history will be obtained, and 
subsequently coded using MeDRA terms. 
In addition, details of the type of HD catheter will be recorded in the CRF.  This will 
include the following: 
• Name of tunneled silicone or polyurethane HD catheter, if available 
• Manufacturer 
• Fill volume per lumen. 
7.3         EFFECTIVENESS MEASUREMENTS 
Effectiveness assessments are based on the hypotheses that Neutrolin® is superior to 
heparin and will decrease the risk of CRBSI. CRBSI is the primary endpoint for this trial.   
For the purposes of this study, once the subject has been randomized and has received at 
least one instillation of the assigned lock solution, all episodes that satisfy the definitions 
in section 7.3.1.1 will be considered definite episodes of CRBSI.  Once the infection is 
confirmed as a CRBSI, the subject will be considered to have satisfied the infection 
endpoint and will be considered to have completed the study.  The subject will receive 
standard of care therapy for CRBSI and the decision as to removal of the catheter will be 
left to the PI, although KDOQI guidelines should be followed.  The use of an antibiotic 
CLS to treat the catheter following a documented episode of CRBSI will be discouraged. 
Should a subject receive treatment with an antibiotic CLS following confirmation of one 
positive blood culture, this subject would be discontinued from the study. Documentation 
of the reason(s) for removal or retention of the catheter following an episode of CRBSI 
will be recorded in the case report forms.  
Blood flow will be monitored during each dialysis session to ensure adequate blood flow 
is present for successful dialysis. 
 
7.3.1       Primary Effectiveness Endpoint (CRBSI) 
The primary endpoint is the occurrence of CRBSI. The primary hypothesis is that 
Neutrolin® is superior to the active comparator heparin, and will significantly decrease 
the risk of CRBSI. 
 
 
 


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7.3.1.1       Definition of CRBSI 
CRBSI is defined for this trial as follows: CRBSI requires that the same organism is 
grown from at least one blood culture from: 
• a peripheral site or bloodline sample 
and 
• either the arterial or venous catheter hub (or the venous or arterial dialysis circuit 
blood lines if on dialysis).     
In the event that a peripheral sample is obtained, the cephalic vein will be avoided for 
preservation of future vascular access. 
Blood cultures must be taken from two sites to enhance the validity of the culture testing 
results. One aerobic and 1 anaerobic blood culture bottle should be taken from each site. 
 
If the subject has clinical symptoms, while on or off dialysis, blood cultures will be 
obtained using peripheral venipuncture from a source not intended for future vascular 
access, and the venous or arterial hub of the HD CVC (or the venous or arterial dialysis 
circuit blood line if on dialysis). If a peripheral site is not available, as soon as the patient 
is evaluated, blood cultures can be obtained from both the venous and arterial hubs of the 
HD CVC (or the dialysis circuit blood lines if on dialysis), preferably before the study 
subject receives antibiotics.  Ten to twenty mL of blood should be collected, without 
discarding any of the CLS.   
 
Necessary clinical indication for suspicion of infection includes the following: 
 
One of the following symptoms: 
• Fever (defined as ≥37.8° C)  
or 
• Rigors, defined as shivering from a feeling of being cold, often 
with copious sweating, as documented by a medical professional 
 
OR two or more of the following symptoms:  
 
• Tachycardia defined as a heart rate greater than 100 beats per 
minute  
• Tachypnea, as defined as a RR greater than 24 breaths per minute 
• Low blood pressure as defined as a systolic blood pressure less 
than 90, as measured by a clinician (RN or MD) with a BP cuff, or 
a decrease in blood pressure greater than 30 mmHg 
• An obvious change in mental status from previously documented 
baseline   
 
All attempts will be made to document as many signs and/or symptoms as possible at the 
time of suspected CRBSI.   
 


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An investigator may choose to obtain blood cultures on other suspicions of CRBSI, but 
the CRBSI case definition requires the clinical indication for suspicion of infection 
criteria listed above in addition to the blood culture criteria listed above. No other 
alternate source of infection should be identified by clinically indicated testing as noted 
in Section 7.1.4. 
 
7.3.1.2 Clinical Adjudication Committee 
  
While sites will seek to identify that a CRBSI is present and will be responsible for 
collecting the clinical data and blood cultures as outlined in the protocol, each case will 
be reviewed by a Clinical Adjudication Committee (CAC) for the final assessment of 
CRBSI status.  The CAC is a multi-disciplinary committee of specialists who will review 
both the clinical documentation as well as the blood culture results to determine if the 
case is a CRBSI.  However, because the CAC determination is based on data obtained 
from the clinical sites, and the review cannot be initiated without blood culture results, it 
is imperative that the sites follow the protocol definition of CRBSI, and collect blood 
cultures when a CRBSI is suspected. 
7.4         SAFETY MEASUREMENTS  
Safety parameters will include AEs, clinical laboratory evaluations, vital signs, and 
physical exam findings. 
 
7.4.1       Adverse Events 
An AE is any unfavorable or unintended sign, symptom, or disease temporally associated 
with the use of the investigational drug whether or not considered related to the 
investigational drug. Collection of AE data will begin after the subject has signed the 
informed consent document and end 28 days after removal of the last dose of IP.  
Adverse events may include: 
 
• Objective signs observed by the PI or study personnel 
• Subjective or objective signs/symptoms 
• Concomitant disease or accidents 
• Clinically relevant adverse changes in laboratory parameters observed in a subject 
in the course of a clinical study 
• Pre-existing conditions that worsen in severity or frequency or have new 
signs/symptoms associated with them. 
Other findings related to out-of-range laboratory values, ECGs, vital signs, etc., 
considered not clinically significant are not to be recorded in the AE CRF page. 
 
Treatment-emergent AEs (TEAE) will be summarized in tables in the final study report. 
A treatment-emergent adverse event is an AE that starts or worsens after the subject’s 
first administration of investigational product. 
 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal 


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relationship with this treatment. An AE can therefore be any unfavorable and unintended 
change in structure, function, signs, or symptoms temporally associated with the use of a 
medicinal product, whether or not related to the product.  Worsening of a pre-existing 
condition is also considered an AE, as is the discovery of an abnormal finding during a 
physical examination that was not included in the medical history.  
Where there is deterioration in the condition for which the investigational drug is being 
used, there may be uncertainty as to whether this is normal disease progression or an AE 
related to the investigational drug administration.  If it is felt the investigational drug may 
have contributed to the deterioration, then this must be treated as an AE related to the 
investigational drug administration. 
Causality Assessment of AEs 
For all AEs, the PI will provide an assessment of causal relationship to the investigational 
drug. The causality assessment must be recorded in the AE CRF.  
 
Adverse events will be considered investigational drug related if classified by the PI as 
possible, probable, or definite. For clarification, those AEs that occur after enrollment, 
but prior to the first administration of investigational product will be deemed not to be 
related to the investigational product. Association of AEs to the investigational drug will 
be made using the following definitions: 
 
• Probably Not:  The temporal association, subject history, or clinical condition is 
such that the investigational drug is not likely to have had an association with the 
observed event 
• Possible:  The event: a) follows a reasonable temporal association with the 
investigational drug, but b) could have been produced by the subject’s clinical 
condition or other therapy 
• Probable:  The event: a) follows a reasonable temporal association with the 
investigational drug, b) abates upon discontinuation of investigational drug, and c) 
cannot be reasonably explained by the subject’s clinical condition or other therapy 
• Definite:  The event: a) follows a reasonable temporal association with the 
investigational drug, b) abates upon discontinuation of investigational drug, c) 
cannot be reasonably explained by the subject’s clinical condition or other 
therapy, and d) reappears on re-exposure to the investigational drug. 
 
AE SEVERITY ASSESSMENTS 
The PI will provide an assessment of the severity of each adverse reaction by recording a 
severity rating in the AE CRF.  Signs and symptoms will be graded by the PI as mild, 
moderate, severe, or life threatening according to the following definitions: 
 
• Mild:  Causing no limitation of usual activity; Events are usually transient and 
easily tolerated, requiring no special treatment and causing no disruption of the 
subject’s normal daily activities 
 


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• Moderate:  Causing some limitations of usual activities; Events introduce a low 
level of inconvenience or concern to the subject and may interfere with daily 
activities, but are usually improved by simple therapeutic measures.  Moderate 
experiences may cause some interference with functioning 
• Severe:  Causing inability to carry out usual activities; Events interrupt the 
subject’s normal daily activities and generally require systemic drug therapy or 
other treatment. They are usually incapacitating 
• Life-threatening:   Subject was at immediate risk of death from the event.  
ASSESSMENT OF AE OUTCOME 
The following definitions of AE outcomes will be used: 
• Recovered/Resolved 
• Recovered/Resolved with Sequelae 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Fatal 
• Unknown. 
 
CLINICAL FINDINGS 
Any significant clinical findings in the final examination, including clinically significant 
laboratory abnormalities at the end of the subject’s participation in the study, will be 
followed until the condition returns to pre-study status or can be explained as not being 
related to investigational drug. This also applies to all AEs that continue at the Final 
Safety Visit. Any treatment-emergent adverse event (TEAE) or SAE that occurs prior to 
the Final Safety Visit or within 28 days after removal of investigational product will be 
followed until event resolution, or until, in the opinion of the PI, becomes stable.   
 
SERIOUS ADVERSE EVENTS (SAES) 
The PI or other study personnel must immediately (within 24 hours of notification) 
inform the Sponsor/CRO of all SAEs that occur in study subjects. 
 
A SAE is any AE that meets at least one of following criteria: 
 
• 
Is fatal 
• 
Is life-threatening, meaning the subject was, in the view of the PI, at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a reaction 
that, had it occurred in a more serious form or progressed, might have caused 
death 
• 
Is a persistent or significant disability, incapacity, or substantial disruption of the 
ability to conduct normal life functions 
• 
Requires or prolongs inpatient hospitalization. Inpatient hospitalization will be 
considered a hospitalization that is longer than 24 hours, or a hospitalization that 
requires an intervention to treat emergent symptomatology (non-diagnostic) 
• 
Is a congenital anomaly or birth defect. 


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A SAE may also include events that are medically significant in the PI’s judgment 
including medically significant laboratory abnormalities. Other important medical events 
may be considered SAEs when, based upon appropriate medical judgment, they may 
jeopardize the subjects and may require medical or surgical interventions to prevent one 
of the outcomes as listed as above in this definition.  For example, an important medical 
event may not be immediately life-threatening or result in death or hospitalization but 
may require intervention to avoid death or life-threatening conditions.  In general, 
medically significant events are those which require medical/surgical intervention to 
prevent one of the outcomes listed above. 
REPORTING OF SAES 
All SAEs will be collected starting the day of Informed Consent signature until 28 days 
following removal of investigational product.  All SAEs and deaths due to any cause that 
occur, are to be reported.  SAEs are to be reported whether or not expected and regardless 
of relationship to investigational product, and must be reported to the Sponsor 
immediately upon discovery, by entering the SAE into the electronic clinical trial data 
system (Medidata/Rave), and by using an SAE reporting form provided by the Sponsor, 
and, if necessary, by telephone to the study Medical Monitor. Any additional SAE 
information and supporting documentation will be faxed to the safety hotline.  
 
The Medical Monitor will advise the PI regarding the nature of any further information or 
documentation that is required. The PI should provide the following documentation at the 
time of notification or as they become available: 
• SAE reporting form  
• Admission notes 
• Progress Notes, including consults (e.g. infectious disease) 
• Concomitant and support medication pages 
• Relevant diagnostic reports (including Microbiology reports) 
• Relevant laboratory reports 
• Hospital discharge summary  
 
Notification must include the PI’s assessment as to whether the event was or was not 
related to the use of the investigational product. The contact information for the Medical 
Monitor is provided in the Regulatory Binder at each study site, in the Contacts section 
and in the SAE section.  In addition, the Sponsor’s medical representative’s contact 
information is also provided in the Binder. 
 
All SAEs must be followed until the event resolves or, in the opinion of the PI, becomes 
stable.  The Sponsor will report any serious, unexpected and drug-related AEs to 
applicable regulatory agencies and make these reports available to the clinical sites.  
 
The PI must also promptly inform the governing IRB of the SAE and/or unanticipated 
problems involving risk to human subjects or others per the governing IRB’s 
requirements and retain a copy of the submission and responses in the clinical site’s 
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7.4.2   Pregnancies 
Pregnancy is not considered an AE.  However, subject pregnancy must be reported by the 
investigational staff within 24 hours of their knowledge of the event using the pregnancy 
notification form. Any subject found to be pregnant during Screening will not be 
randomized into the study.  The PI must promptly discontinue investigational product 
administration for any subject who is found to be pregnant during the study 
(randomization through Final Safety Visit) and notify the Medical Monitor 
immediately.   Any subject found to be pregnant during the study will be withdrawn from 
the study.  Any subject who is found to be pregnant during the study will be asked to 
confirm their consent to allow their treating physician to provide CorMedix with follow-
up information on the pregnancy itself and the pregnancy outcome (e.g. miscarriage, 
elective termination, live birth).  
7.4.3   Clinical Laboratory Evaluations 
Blood samples for central clinical laboratory evaluations will be assessed at specified 
intervals as outlined in the Schedule of Assessments table. The investigator will also 
review standard of care monthly local laboratory evaluations, and report any Adverse 
Events per Good Clinical Practice.  The investigator must review the per protocol central 
laboratory report in a timely manner, document this review by initialing/signing and 
dating the lab report, and record any clinically relevant changes occurring during the 
study in the AE section of the CRF.  
Clinical laboratory evaluations will include the following tests (at various times, detailed 
above): 
• Hematology: CBC with differential, platelets, and reticulocyte count (%) 
• Blood chemistry: calcium, albumin, sodium, potassium, chloride, carbon dioxide, 
BUN, serum creatinine, and glucose 
• Liver function: serum albumin, total protein, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), alkaline phosphatase and bilirubin 
• Serum pregnancy test (women of childbearing potential).  
 
7.4.4   Vital Signs 
Sitting systolic and diastolic blood pressure, temperature, pulse rate, and respiratory rate 
will be assessed at each visit designated within the protocol schedule with a completely 
automated device consisting of an inflatable cuff and an oscillatory detection system. 
Temperature will also be recorded. 
7.4.5   Physical Examination  
A complete physical examination will be performed at baseline and at the study 
completion visit to identify any changes that occur during the trial. Any abnormal 
findings will be recorded in the CRF. An assessment of skin around the catheter should 
be noted on the Physical Examination CRF. Any clinically significant abnormalities 
present at baseline will be reported as medical history and any clinically significant 
abnormalities that are develop during the study will be reported as AEs. 


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7.5   APPROPRIATENESS OF MEASUREMENTS 
All measurements will be performed using standard methods that are generally 
recognized as being reliable, accurate, and relevant. Blood cultures are an established 
method to assess infections in the medical community. All laboratory measures and 
dialysis procedures outlined in this protocol are well established and consistent with the 
current standard of care. 


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8.0       DATA QUALITY ASSURANCE 
According to the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), CorMedix 
delegates to the CRO the responsibility for implementing and maintaining quality 
assurance and quality control systems with written SOPs.  
Quality control will be applied to each stage of data handling.  
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
• Selection of qualified investigators and appropriate study centers 
• Investigator meeting(s) and review of protocol procedures and CRF completion 
with the investigator and associated personnel before enrolling any subjects and 
during the study as needed 
• Written instructions will be provided for collection, preparation, and shipment of 
laboratory samples, if appropriate 
• Central laboratories for clinical laboratory parameters 
• Site Initiation visit 
• Early site visits post-enrollment 
• Routine on-site monitoring visits 
• Review of CRFs for accuracy and completeness, resolution of discrepancies with 
the investigator or designee, as appropriate 
• Ongoing site communication and training  
• Data management quality control checks 
• Continuous data acquisition and cleaning 
• Internal review of data 
• Quality control check of the final clinical study report. 
 
In addition, CorMedix and the CRO Clinical Quality Assurance Department may conduct 
periodic audits of the study processes at the study site, central laboratories, or other 
vendors. Audits may also be conducted on the clinical database and final clinical study 
report. When audits are conducted, access must be authorized for all study related 
documents including medical history and concomitant medication documentation to 
authorized representatives of CorMedix or the CRO and regulatory authorities. 
8.1     MONITORING 
The site monitor will perform on-site monitoring visits as frequently as necessary. The 
monitor will record dates of the visits in a study center visit log that will be kept at the 
site. The first post-initiation visit will usually be made as soon as possible after 
enrollment has begun. Subsequent visits are made as needed per the monitoring plan. At 
these visits, the monitor will compare the data entered into the CRF with the hospital or 
clinic records (source documents). The nature and location of all source documents will 
be identified to ensure that all sources of original data required to complete the CRF are 
known to the CRO site monitor and investigational staff and are accessible for 
verification by the site monitor. If electronic records are maintained at the investigational 


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site, the method of verification must be discussed with the investigational staff. At a 
minimum, source documentation must be available to substantiate: subject identification, 
eligibility, and participation; proper informed consent procedures; dates of visits; 
adherence to protocol procedures; records of safety and effectiveness parameters; 
adequate reporting and follow-up of AEs; administration of concomitant medication; 
drug 
receipt/dispensing/return 
records; 
investigational 
product 
administration 
information; and date of subject completion, discontinuation from treatment, or 
withdrawal from the study, and the reason if appropriate. Specific items required as 
source documents will be reviewed with the investigator before the study. 
If data are recorded directly into the CRF, at a minimum there should be an entry in the 
medical record that each of the assessments was done, and by whom and the date it was 
done.  
Direct access to source documentation (medical records) must be allowed for the purpose 
of verifying that the data recorded in the CRF are consistent with the original source data. 
Findings from this review of CRF and source documents will be discussed with the 
investigational staff. CorMedix expects that, during monitoring visits, the relevant 
investigational staff will be available, the source documentation will be available, and a 
suitable environment will be provided for review of study-related documents. The 
monitor will meet with the investigator on a regular basis during the study to provide 
feedback on the study conduct.  
8.2      DATA MANAGEMENT AND CODING 
Data generated within this clinical trial will be handled according to the relevant SOPs of 
the data management and biostatistics departments of the CRO. Adverse events will be 
coded using the most recent version of the Medical Dictionary for Regulatory Activities 
(MedDRA). Concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary.  
8.3     QUALITY ASSURANCE AUDIT 
Representatives of the sponsor or sponsor’s delegate may visit the site to carry out an 
audit of the study in compliance with regulatory guidelines and company policy. These 
audits will require access to all study records, including source documents, for inspection 
and comparison with the CRF. Subject privacy must, however, be respected. 
Similar auditing procedures may also be conducted by agents of any regulatory body 
reviewing the results of this study in support of a regulatory submission. The investigator 
should immediately notify CorMedix if they have been contacted by a regulatory agency 
concerning an upcoming inspection. 


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9.0     STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
9.1     DETERMINATION OF SAMPLE SIZE 
This trial has been designed to achieve 80% power for the comparison between treatment 
arms subject to the following specifications: testing will be conducted at a 2-sided overall 
5% alpha level, Neutrolin® is associated with a 55% reduction in the risk (i.e., incidence) 
of CRBSI relative to the control arm, and one interim analysis will be performed at the 
midpoint of the trial with adjustment of the alpha level using the method of Pocock. 
Fifty-six CRBSI events in total will be needed to achieve the desired power, and the 
event rates will be monitored over the course of the trial to determine the times of the 
interim and final statistical analyses. It is expected that approximately 900 subjects will 
be randomized for this trial. 
9.2    INTERIM ANALYSIS 
A DSMB will meet periodically to review the accumulating study data.  The primary 
purpose of these reviews is to monitor safety and data quality.    
Additionally, the DSMB will oversee interim analyses for efficacy and for futility that 
will be performed when 28 CAC-adjudicated CRBSI events (1/2 of the total number of 
56 events) have occurred. If statistical significance is obtained for the primary efficacy 
endpoint at this time, the recommendation will be to stop the study early for efficacy. If 
the futility analysis indicates that continuing the study would be futile, the 
recommendation will be to stop the study early for futility. In either case, the DSMB will 
report its recommendation only to the CorMedix Executive Committee, which will make 
the final decision as to whether or not to stop the study in consultation with the FDA.  
9.3   ANALYSIS POPULATIONS 
9.3.1   Randomized Population 
The Randomized Population will include all subjects randomized. Subjects will be 
analyzed according to their allocated group determined by randomization. 
9.3.2   Full Analysis Population 
Subjects will be included in the Full Analysis Population according to the ITT principle 
for the primary and secondary analyses. The Full Analysis Population will include all 
subjects randomized and receiving one or more doses of study treatment. Subjects will be 
analyzed according to their allocated group determined by randomization. 
9.3.3    Safety Population 
The safety population will include all subjects taking at least one dose of study 
medication. Subjects will be analyzed according to the treatment they actually received.  
It is expected that the Safety Population will be identical to the Full Analysis Population. 
 


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9.4   SUBJECT DISPOSITION 
The total number of subjects screened, randomized, completed, and discontinued from 
the study will be summarized by treatment group and overall. The reason for termination 
for all subjects who discontinued will be summarized by treatment group and overall. A 
listing of subjects who discontinued from the study by reason for termination will also be 
presented. 
A table summarizing the analysis populations will be presented, with the number of 
randomized subjects as well as frequencies of exclusion from the respective analysis 
populations. 
9.5   SUBJECT CHARACTERISTICS 
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group for all subjects randomized.  
Baseline characteristics will include a summary of the following: 
• Subject demographics including age, sex, race 
• Baseline disease characteristics 
• Pre-existing medical conditions 
• Prior therapies. 
9.6    COMPLIANCE AND DURATION OF EXPOSURE 
The compliance and duration of drug or control exposure will be presented by treatment 
group. The number and percent of subjects who received drug or control at all visits will 
be presented to summarize compliance and duration of exposure. 
9.7    ANALYSIS OF PRIMARY ENDPOINT 
The time to CRBSI will be compared between the treatment arms using a log-rank test at 
an overall 2-sided 5% alpha level.  The null hypothesis is that there is no difference in the 
risk of CRBSI over time between the two treatment groups.  Subjects will be treated as 
censored in this analysis if the catheter is removed for reasons other than CRBSI (e.g., 
catheter removed because no longer required) or follow-up is completed in the absence of 
CRBSI. Because an interim analysis for efficacy will be performed, the method of 
Pocock will be used to control the overall alpha level. Therefore, the nominal 
significance level at the interim and final statistical analyses for the primary efficacy 
endpoint will be 0.0294.   
 
The primary analysis will be based upon the Full Analysis Population.  While testing will 
be based upon the log-rank test, the estimated treatment effect will be the incidence of 
CRBSI calculated as the number of subjects with a CRBSI episode divided by the 
number of years of follow-up over subjects (follow-up will be based upon the same time 
as used for the log-rank test).  The rate will be presented as the event rate per 1,000 days 
with 95% confidence interval for the comparison of rates between the treatment arms. 
This confidence interval will be derived assuming that the number of days until CRBSI 


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follows an exponential distribution.  The primary analysis will be repeated using all 
randomized subjects with available data. 
 
In addition, a sensitivity analysis will be performed in which cases considered to be 
indeterminate by the Clinical Adjudication Committee are treated as CRBSI events.  
 
9.7.1    Analysis of the Secondary Endpoints 
Similar methods of analysis will be used to estimate the overall rate of catheter loss for 
any reason and the rate of loss of catheter patency. Loss of catheter patency is defined as 
required use of a tissue plasminogen activating factor (tPA) or removal of catheter due to 
dysfunction. The fixed sequence testing procedure will be used for the comparison of the 
two treatments with respect to the effectiveness endpoints. Therefore, the analysis 
comparing the two treatments for catheter loss for any reason will be formally conducted 
only if the analysis for the primary effectiveness endpoint yields a statistically significant 
result favoring Neutrolin®, and the analysis comparing the two treatments for loss of 
patency will be formally conducted only if the analysis for catheter loss for any reason 
also yields a statistically significant result favoring Neutrolin®.  
The reason for catheter loss will be summarized by treatment group.  In addition to basic 
descriptive statistics, the rates per 1000 days of follow-up will be presented. 
9.8   SAFETY 
All safety analyses will be performed on the safety population, unless otherwise stated.  
Routine statistical testing will not be performed. 
9.8.1    Adverse Events 
AEs will be coded using the MedDRA. Adverse events are defined as treatment emergent 
if they start or worsen after a subject's first administration of study CLS. All AEs, 
including treatment emergent AEs (TEAEs), will be summarized by body system, 
preferred term, and treatment group, with the number of subjects and percentage 
reporting the event. A similar summary will be produced for SAEs, TEAEs leading to 
termination, severe TEAEs, and TEAEs with a relationship to the investigational product. 
Frequency (%) of TEAEs will be calculated for each body system, by preferred term, by 
treatment group. The severity of the TEAEs and the relationship to study medication will 
be summarized for each body system and preferred term by treatment group. 
Withdrawals due to TEAEs will be summarized for each body system and preferred term 
by treatment group. 
9.8.2    Clinical Laboratory Tests 
Descriptive statistics will be calculated for clinical laboratory tests (hematology, serum 
chemistry) at applicable visits. Where applicable, changes from baseline will be 
summarized across treatment groups. The number and percentage of subjects with 
abnormal laboratory results will be provided.  
 
 


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9.8.3   Vital Signs, Physical Findings and Other Safety Evaluations 
Vital signs and physical examination data will be summarized descriptively by treatment 
group. Changes in vital signs parameters from baseline will be summarized across 
treatment groups at each applicable post-randomization visit. 


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10.0   ETHICS 
10.1   INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW 
BOARD 
The investigator will provide the CRO with documentation of IRB approval of the 
protocol and informed consent before the study may begin at the study site(s). The 
investigator will supply documentation to the CRO of required IRB’s annual renewal of 
the protocol, and any approvals of revisions to the informed consent document or 
amendments to the protocol.  
The investigator will report promptly to the IRB any new information that may adversely 
affect the safety of subjects or the conduct of the trial. Similarly, the investigator will 
submit written summaries of the trial status to the IRB annually, or more frequently if 
requested by the IRB. Upon completion of the trial, the investigator will provide the IRB 
with a brief report of the outcome of the trial, if required. 
10.2    ETHICAL CONDUCT OF THE STUDY 
This study will be conducted and the informed consent will be obtained according to the 
ethical principles that have their origin in the Declaration of Helsinki (2004), the ICH 
Harmonized Tripartite Guideline for GCP (1997), the US Code of Federal Regulations 
(CFR) Title 21 parts 50, 56, and 312, and the applicable drug and data protection laws 
and regulations of the countries where the study will be conducted.  
10.3   SUBJECT INFORMATION AND CONSENT 
The informed consent form will be used to explain the risks and benefits of study 
participation to the subject in simple terms before the subject will be entered into the 
study. The informed consent form contains a statement that the consent is freely given, 
that the subject is aware of the risks and benefits of entering the study, and that the 
subject is free to withdraw from the study at any time. Written consent must be given by 
the subject and/or legal representative, after the receipt of detailed information on the 
study. 
The investigator is responsible for ensuring that informed consent is obtained from each 
subject or legal representative and for obtaining the appropriate signatures and dates on 
the informed consent document prior to the performance of any protocol procedures and 
prior to the administration of study medication. The investigator will provide each subject 
with a copy of the signed and dated consent form and will document in the subject’s 
source notes that informed consent was given. 


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11     STUDY ADMINISTRATION 
11.1   PROTOCOL MODIFICATIONS 
Neither the investigator nor CorMedix will modify this protocol without a formal 
amendment. All protocol amendments must be issued by CorMedix and signed and dated 
by the investigator. Protocol amendments must not be implemented without prior IRB 
approval, or when the relevant competent authority has raised any grounds for non-
acceptance, except when necessary to eliminate immediate hazards to the subjects, in 
which case the amendment must be promptly submitted to the IRB and relevant 
competent authority. When the change(s) involves only logistic or administrative aspects 
of the study, the IRB (and IEC where required) only needs to be notified. 
In situations requiring a departure from the protocol, the investigator or other physician in 
attendance will contact the CRO medical monitor (see contact information on the 
protocol cover page). If possible, this contact will be made before implementing any 
departure from the protocol. In all cases, contact with the CRO must be made as soon as 
possible in order to discuss the situation and agree on an appropriate course of action. 
The data recorded in the CRF and source document will reflect any departure from the 
protocol, and the source documents will describe this departure and the circumstances 
requiring it. 
11.2    REGULATORY APPROVAL AND NOTIFICATION 
This protocol and any amendment(s) must be submitted to the appropriate regulatory 
authorities in each respective country, if applicable. A study may not be initiated until all 
local regulatory requirements are met. 
All investigators must certify that they will comply with all relevant IND and GCP 
regulatory requirements. 
11.3    REQUIRED PRESTUDY DOCUMENTATION 
The following documents must be provided to the CRO before shipment of 
investigational product or control solutions to the investigational site: 
• protocol and amendment(s), if any, signed and dated by the investigator 
• a copy of the dated and signed written IRB approval of the protocol, amendments, 
informed consent form, any recruiting materials, and if applicable, subject 
compensation programs. This approval must clearly identify the specific protocol 
by title and number and must be signed by the chairman or authorized designee 
• name and address of the IRB including a current list of the IRB members and 
their function, with a statement that it is organized and operates according to GCP 
and the applicable laws and regulations. If accompanied by a letter of explanation 
from the IRB, a general statement may be substituted for this list. If an 
investigator or a member of the investigational staff is a member of the IRB, 
documentation must be obtained to state that this person did not participate in the 
deliberations or in the vote/opinion on the study 
• regulatory authority approval signed and dated or notification, if applicable 


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• statement of investigator, if applicable 
• documentation of investigator qualifications (e.g., curriculum vitae) 
• completed investigator financial disclosure form from the investigator 
• signed and dated clinical trial agreement, which includes the financial agreement 
• any other documentation required by local regulations. 
 
The following documents must be provided to the sponsor before enrollment of the first 
subject: 
• completed investigator financial disclosure forms from all sub-investigators 
• documentation of sub-investigator qualifications (e.g., curriculum vitae) 
• photocopy of the site signature log, describing delegation of roles and 
responsibilities at the start of the study 
• name and address of any local laboratory conducting tests for the study, and a 
dated copy of current laboratory normal ranges for these tests 
• local laboratory documentation demonstrating competence and test reliability 
(e.g., accreditation/license), if applicable. 
11.4    SUBJECT IDENTIFICATION REGISTER AND SUBJECT SCREENING 
LOG 
The investigator agrees to complete a subject identification register to permit easy 
identification of each subject during and after the study. This document will be reviewed 
by the sponsor site contact for completeness. 
The subject identification register will be treated as confidential and will be filed by the 
investigator in the trial center file. To ensure subject confidentiality, no copy will be 
made. All reports and communications relating to the study will identify subjects by 
initials and assigned number only.  
The investigator must also complete a subject screening log, which reports on all subjects 
who were seen to determine eligibility for inclusion in the study. 
11.5    CASE REPORT FORM COMPLETION 
Case report forms are provided for each subject in an electronic format. 
Electronic Data Capture (EDC) will be used for this study. The majority of the study data 
will be transcribed by study personnel from the source documents onto a CRF and 
transmitted in a secure manner to the sponsor. Worksheets may be provided for the 
capture of some data for easier transfer to the CRF. The electronic file will be considered 
as the case report form. 
All data relating to the study must be recorded in the CRF prepared by the sponsor. Data 
must be entered into CRFs in English. The CRFs are to be completed at the time or near 
the time of the subject’s visit, with the exception of results of tests performed outside the 
investigator’s office or clinic, so that they always reflect the latest observations on the 
subjects participating in the study. For tests performed outside the investigator’s office or 
clinic, CRFs are to be completed upon receipt of test results. 


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Every effort should be made to ensure that all subjective measurements (e.g., pain scale 
information or other questionnaires) to be recorded in the CRF are completed by the same 
individual who made the initial baseline determinations. The investigator must verify that 
all data entries in the CRFs are accurate and correct. 
All CRF entries, corrections, and alterations must be made by the investigator or other 
authorized study-site personnel. 
11.6    RECORD RETENTION 
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all 
CRFs and all source documents that support the data collected from each subject, as well 
as all study documents as specified in ICH/GCP Section 8, Essential Documents for the 
Conduct of a Clinical Trial, and all study documents as specified by the applicable 
regulatory requirement(s). The investigator/institution will take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor 
to inform the investigator/institution as to when these documents no longer need to be 
retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who 
will accept the responsibility. CorMedix must be notified in writing of the name and 
address of the new custodian. Under no circumstance shall the investigator relocate or 
dispose of any study documents before having obtained written approval from  
For case report forms completed on carbonless (NCR) paper, one copy is to be retained in 
the archives of CorMedix from the country in which the study is performed. A second 
copy must be archived by the investigator. 
If it becomes necessary for CorMedix or the appropriate regulatory authority to review 
any documentation relating to this study, the investigator must permit access to such 
reports. 
11.7    STUDY COMPLETION 
The final data from the center will be sent to CorMedix or designee no more than two 
weeks following completion of the final subject visit at that center. Continuation of this 
study beyond this time must be agreed upon by both the investigator and sponsor and 
may be implemented without amendment to the protocol. 
11.8    STUDY TERMINATION 
CorMedix reserves the right to close the investigational site or terminate the study at any 
time. Investigational sites will be closed upon study completion. An investigational site is 


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considered closed when all required documents and study supplies have been collected 
and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.  
Reasons for the early closure of an investigational site by CorMedix or investigator, or 
termination of a study by CorMedix may include but are not limited to: 
• failure of the investigator to comply with the protocol, CorMedix procedures, or 
GCP guidelines 
• safety concerns 
• sufficient data suggesting lack of efficacy after conduct of interim analysis 
• sufficient data suggesting efficacy after conduct of interim analysis 
• inadequate recruitment of subjects by the investigator. 
11.9    USE OF INFORMATION AND PUBLICATION 
All information, including but not limited to information regarding the CRO or CorMedix 
operations (e.g., patent application, formulas, manufacturing processes, basic scientific 
data, prior clinical data, and formulation information) supplied by CorMedix to the 
investigator and not previously published, and any data generated as a result of this study, 
are considered confidential and remains the sole property of CorMedix. The investigator 
agrees to maintain this information in confidence and use this information only to 
accomplish this study, and will not use it for other purposes without CorMedix prior 
written consent. 
The investigator understands that the information developed in the clinical study will be 
used by CorMedix in connection with the continued development of Neutrolin®, and thus 
may be disclosed as required to other clinical investigators or regulatory agencies. To 
permit the information derived from the clinical studies to be used, the investigator is 
obligated to provide CorMedix with all data obtained in the study. 
The results of the study will be reported in a clinical study report and will contain all data 
from all investigational sites. Any work created in connection with performance of the 
study and contained in the data that can benefit from copyright protection (except any 
publication by the investigator as provided for below) shall be the property of CorMedix 
as author and owner of copyright in such work. 
Sponsor shall have the right to publish such data and information without approval from 
the investigator. If an investigator wishes to publish information from the study, a copy of 
the manuscript must be provided to CorMedix for review at least 60 days before 
submission for publication or presentation. Expedited reviews will be arranged for 
abstracts, poster presentations, or other materials. If requested by CorMedix in writing, 
the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific 
integrity or regulatory compliance, CorMedix will review these issues with the 
investigator. CorMedix will not mandate modifications to scientific content and does not 
have the right to suppress information. The investigator will recognize the integrity of a 
multicenter study by not publishing data derived from the individual site until the 


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combined results from the completed study have been published in full, within 12 months 
after conclusion, abandonment, or termination of the study at all sites, or CorMedix 
confirms there will be no multicenter study publication. Authorship of publications 
resulting from this study will be based on generally accepted criteria for major medical 
journals. 
11.10    PRIVACY OF PERSONAL DATA 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the effectiveness, safety, quality, 
and utility of the investigational product(s) used in this study. 
These data must be collected and processed with adequate precautions to ensure 
confidentiality and compliance with applicable data privacy protection laws and 
regulations. 
CorMedix ensures that the personal data will be: 
• Processed fairly and lawfully 
• Collected for specified, explicit, and legitimate purposes and not further processed 
in a way incompatible with these purposes 
• Adequate, relevant, and not excessive in relation to said purposes 
• Accurate and, where necessary, kept current. 
Explicit consent for the processing of personal data will be obtained from the 
participating subject (or his/her legally acceptable representative) before collection of 
data. Such consent should also address the transfer of the data to other entities and to 
other countries. 
The subject has the right to request through the investigator access to his/her personal 
data and the right to request rectification of any data that are not correct or complete. 
Reasonable steps should be taken to respond to such a request, taking into consideration 
the nature of the request, the conditions of the study, and the applicable laws and 
regulations. 
Appropriate technical and organizational measures to protect the personal data against 
unauthorized disclosures or access, accidental or unlawful destruction, or accidental loss 
or alteration must be put in place. Sponsor personnel whose responsibilities require 
access to personal data agree to keep the identity of study subjects confidential. 
 


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12       REFERENCES 
 
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Solomon, L., et al. (2012).  Observational study of a need for thrombolytic 
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from: 
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Lok, C.E., et al., Trisodium citrate 4%--an alternative to heparin capping of 
haemodialysis catheters. Nephrol Dial Transplant, 2007. 22(2): p. 477-83. 
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Macrae, J.M., et al., Citrate 4% versus heparin and the reduction of thrombosis 
study (CHARTS). Clin J Am Soc Nephrol, 2008. 3(2): p. 369-74. 
31. 
Quarello, F. and G. Forneris, Prevention of hemodialysis catheter-related 
bloodstream infection using an antimicrobial lock. Blood Purif, 2002. 20(1): p. 
87-92. 
32. 
Hung, A.M. and T. Alp Ikizler, Hemodialysis central venous catheters as a 
source of inflammation and its implications. Semin Dial, 2008. 21(5): p. 401-4. 
33. 
Allon, M., Prophylaxis against dialysis catheter-related bacteremia with a novel 
antimicrobial lock solution. Clin Infect Dis, 2003. 36(12): p. 1539-44. 
34. 
Solomon, L.R., Cheesbrough, J.C., Bhargava, R., Mitsides, N., Heap, M., Green, 
G., Diggle P.  Observational Study of Need for Thrombolytic Therapy and 
Incidence of Bacteraemia using Taurolidine-Citrate-Heparin, Taurolidine-Citrate 
and Heparin Catheter Locks in Patients Treated with Haemodialysis.  Semin 
Dial,  2012.  25(2):233-238. 
35. 
Knight, B.I., et al., Peritoneal absorption of the antibacterial and antiendotoxin 
taurolin in peritonitis. Br J Clin Pharmacol, 1981. 12(5): p. 695-9. 
36.    Cooper, M.S. and N.J. Gittoes, Diagnosis and management of hypocalcaemia. 
BMJ, 2008. 336(7656): p. 1298-302. 


CorMedix Inc 
Protocol Number: LOCK-IT-100  
Confidential 
October 06, 2017 (Version 8) 
 
 
 
Page 67 of 67 
37. 
Simon, A., et al., Taurolidine-citrate lock solution (TauroLock) significantly 
reduces CVAD-associated grampositive infections in pediatric cancer patients. 
BMC Infect Dis, 2008. 8: p. 102. 
38. 
Gong, L., et al., The pharmacokinetics of taurolidine metabolites in healthy 
volunteers. J Clin Pharmacol, 2007. 47(6): p. 697-703. 
39. 
Lok, C.E., et al., Hemodialysis infection prevention with polysporin ointment. J 
Am Soc Nephrol, 2003. 14(1): p. 169-79. 
40. 
Thomas, C.M., et al., Concentration of heparin-locking solution and risk of 
central venous hemodialysis catheter malfunction. ASAIO J, 2007. 53(4): p. 485-
8. 
41. 
O’Grady NP, A.M., Dellinger EP, et al, Guidelines for the Prevention of 
Intravascular Catheter-Related Infections. Morbidity and Mortality Weekly 
Report, 2002. 51(RR-10): p. 1-29. 
42. 
KDOQI, Clinical practice guidelines for hemodialysis adequacy, update 2006. 
Am J Kidney Dis, 2006. 48 Suppl 1: p. S28-32. 

SAP_001.pdf: 
 
 
 
Study Assessing Safety & Effectiveness of 
a Catheter Lock Solution in Dialysis 
Patients to Prevent Bloodstream 
Infection 
 
Document Date: January 29, 2018 
 
NCT02651428 
 


Statistical Analysis Plan 
 
A Phase 3, prospective, multicenter, double-blind, randomized, active control study to demonstrate the 
safety and effectiveness of Neutrolin® in preventing catheter-related bloodstream infections in subjects 
receiving hemodialysis therapy as treatment for end stage renal disease 
LOCK-IT-100 
 
 
Sponsored by: 
CorMedix Inc. 
 
January 29, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, 
this document is to be treated as confidential and restricted to its intended use. This material is the 
property of CorMedix Inc. and must not be disclosed or used except as authorized in writing by 
CorMedix Inc. 


Page 2 of 13 
 
Table of Contents
1 
Study Description ............................................................................................................. 3 
1.1 Objectives ...................................................................................................................................... 3 
1.2 Study Design ................................................................................................................................. 3 
1.3 Method of Assigning Subjects to Treatment Groups .................................................................... 3 
1.4 Blinding.... ..................................................................................................................................... 3 
1.5 Sample Size ................................................................................................................................... 4 
2 
Statistical Methods ........................................................................................................... 4 
2.1 Analysis Populations ..................................................................................................................... 4 
2.2 Study Drug Dosing and Compliance ............................................................................................. 4 
2.3 Study Endpoints ............................................................................................................................ 4 
2.4 Statistical Assessment of the Trial Objectives .............................................................................. 5 
2.4.1 
Primary Endpoint Analysis ......................................................................................................... 5 
2.4.2 
Secondary Endpoint Analyses ..................................................................................................... 5 
2.5 Study Day and Visit Windows ...................................................................................................... 6 
2.6 Handling of Missing Data ............................................................................................................. 7 
2.7 Safety Analyses ............................................................................................................................. 7 
2.8 Interim Analysis ............................................................................................................................ 7 
3 
Summary Tables Listings and Figures ............................................................................. 7 
3.1 General Conventions ..................................................................................................................... 7 
3.2 Subject Disposition and Treatment ............................................................................................... 8 
3.3 Violations of Inclusion/Exclusion Criteria .................................................................................... 8 
3.4 Study Treatment ............................................................................................................................ 8 
3.5 Demographics and Baseline Characteristics ................................................................................. 9 
3.5.1 
Medical History ........................................................................................................................... 9 
3.6 Clinical Data .................................................................................................................................. 9 
3.6.1 
Concomitant Medications ............................................................................................................ 9 
3.7 Analysis of Efficacy Endpoints ..................................................................................................... 9 
3.7.1 
CRBSI ......................................................................................................................................... 9 
3.7.2 
Primary Efficacy Analysis ......................................................................................................... 10 
3.7.3 
Secondary Efficacy Analyses .................................................................................................... 10 
3.7.4 
Additional Analyses .................................................................................................................. 10 
3.8 Analysis of Safety Endpoints ...................................................................................................... 10 
3.8.1 
Brief Summary of Treatment Emergent Adverse Events (TEAEs) ........................................... 10 
3.8.2 
TEAEs by System Organ Class and Preferred Term ................................................................. 11 
3.8.3 
Clinical Laboratory Tests .......................................................................................................... 11 
3.8.4 
Vital Signs ................................................................................................................................. 11 
3.8.5 
Other Safety Analyses ............................................................................................................... 11 
4             Changes to the Protocol-Specified Analyses ................................................................. 11 
5 
References ...................................................................................................................... 12 
 
 
 


Page 3 of 13 
 
1 Study Description 
This study has been implemented to evaluate the efficacy and safety of Neutrolin® as a catheter lock 
solution (CLS) when used for the prevention of catheter-related bloodstream infection (CRBSI) in 
patients receiving hemodialysis (HD) for the treatment of End Stage Renal Disease (ESRD).   
1.1 Objectives 
The primary objective of this study is to demonstrate the efficacy and safety of Neutrolin® as a catheter 
lock solution (CLS) for prevention of catheter-related bloodstream infection (CRBSI) in subjects 
receiving hemodialysis (HD) for the treatment of End Stage Renal Disease (ESRD) when compared with 
heparin 4,000 USP Units/4 mL (1,000 USP Units/mL). The study will demonstrate whether Neutrolin® is 
superior to the active control heparin in reducing the incidence of CRBSI.  
1.2 Study Design 
This is a randomized, double-blind, active control, parallel-arm, multicenter study. Approximately 900 
subjects will be randomized in a 1:1 ratio to receive either Neutrolin® or the active control heparin 
(Heparin sodium USP 1,000 units/mL, Benzyl alcohol 9.45 mg/mL and Sodium chloride 9.0 mg/mL) as a 
CLS. Neutrolin® or heparin will be instilled into central venous HD catheters at the discontinuation of all 
dialysis sessions and will be withdrawn prior to the initiation of the next dialysis session. All subjects will 
receive standard of care consistent with clinical practice guidelines recommended by the Kidney Disease 
Outcomes Quality Initiative (KDOQI) for the placement, care and use of central venous catheters (CVC) 
for HD therapy. 
The primary endpoint is the presence or absence of a CRBSI (analysis will be made using the time to 
CRBSI). Subjects are to be followed from randomization (HD catheter will be in place prior to 
randomization) until occurrence of CRBSI, catheter removal, or the end of the study, whichever occurs 
first. The study has been designed to continue until approximately 56 subjects have experienced a CRBSI. 
It is expected that some subjects may be treated for 2 years or more.   
1.3  Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized in a 1:1 ratio to receive either Neutrolin® or the active control heparin (1,000 
USP units/mL) as a CLS.   Permuted block randomization (centralized) will be utilized without additional 
stratification.  
1.4 Blinding 
This is a double-blind study.  The sponsor, subjects and investigator staff will not have access to 
unblinded data (with the exception of sponsor staff required to be unblinded as needed to make safety 
reports to regulatory agencies) until the study is unblinded for the final study analysis. Prior to the final 
study analysis, the DSMB will have access to unblinded data as needed for their review.  To maintain the 
double-blind nature of this study, the DSMB reports will be prepared by an independent statistical group 
that will not otherwise be involved with the study.   


Page 4 of 13 
 
1.5 Sample Size 
This trial has been designed to achieve 80% power for the comparison between treatment arms subject to 
the following specifications: testing will be conducted at a 2-sided overall 5% alpha level using the log-
rank test, Neutrolin is associated with a 55% reduction in the risk of CRBSI relative to the control arm, a 
1 to 1 ratio will be used for the allocation of subjects to treatment arms, and one interim analysis will be 
performed at the midpoint of the trial with adjustment of the alpha level using the method of Pocock. 
Fifty-six CRBSI events in total will be needed to achieve the desired power. The interim analysis will be 
conducted based on the first 28 CRBSIs. The total sample size is expected to be approximately 900 
subjects.   
2 Statistical Methods 
2.1 Analysis Populations 
Three analysis populations will be defined.  These populations are 
 
Randomized Population – all subjects randomized. Subjects will be analyzed according to their 
allocated group determined by randomization.   
 
Full Analysis Population – all subjects randomized and receiving one or more doses of study 
medication. This population has been designed to be consistent with the intent-to-treat principle 
as the decision to begin treatment in this double-blind trial could not be influenced by knowledge 
of the assigned treatment (ICH-E9). Subjects will be analyzed according to their allocated group 
determined by randomization. 
 
Safety Population – all subjects taking at least one dose of study medication. Subjects will be 
analyzed according to the treatment they actually received. It is expected that the Safety 
Population will be identical to the Full Analysis Population. 
2.2 Study Drug Dosing and Compliance 
Study drug dosing will be assessed by calculating the duration of exposure, i.e., the length of time each 
subject received study drug, the total number of times drug was administered, the total number of vials 
administered, and the average dose. Study drug compliance will be assessed by calculating, at the subject 
level, the percentage of dialysis sessions at the study site at which the correct dosing was administered.  
2.3 Study Endpoints 
Primary Endpoint 
CRBSI defined as one positive blood culture (other than for coagulase negative Staphylococcus, which 
requires a confirmatory culture) from: 
1. a peripheral site or blood line sample or 
2. either the arterial or venous catheter hub (or the venous or arterial dialysis circuit blood lines if 
on dialysis)  
in a patient with no other apparent source of bloodstream infection other than the hemodialysis catheter, 
as assessed by the Clinical Adjudication Committee (CAC). 


Page 5 of 13 
 
Secondary Endpoints 
 
Catheter Removal: Catheter removal for any reason during the follow-up period of the trial. 
 
Loss of Catheter Patency: Loss of catheter patency is defined as required use of a tissue 
plasminogen activating factor (tPA) or removal of the catheter because of dysfunction during 
the follow-up period of the trial. 
2.4 Statistical Assessment of the Trial Objectives 
2.4.1 Primary Endpoint Analysis 
The primary analysis will be conducted using a log-rank test for the time to CRBSI at an overall 2-sided 
5% alpha level.  The null hypothesis is that there is no difference in the hazard rates of CRBSI over time 
between the two treatments. The time until CRBSI will be calculated as the number of days post 
randomization until the occurrence of a CAC-adjudicated CRBSI or the subject is censored. Subjects 
without a CRBSI will be treated as censored in this analysis if the catheter is removed for reasons other 
than CRBSI (e.g., catheter removed because no longer required) or follow-up is completed in the absence 
of CRBSI. Because an interim analysis for efficacy will be performed, the method of Pocock will be used 
to control the overall alpha level. Therefore, the nominal significance level at the interim and final 
statistical analyses for the primary efficacy endpoint will be 0.0294.  
The primary analysis will be based upon the Full Analysis Population. While testing will be based upon 
the log-rank test, the estimated treatment effect will be the difference between treatment groups in the 
incidence rate of CRBSI, calculated as the number of subjects with a CRBSI divided by the number of 
catheter-days of follow-up over subjects (follow-up will be based upon the same time as used for the log-
rank test). The rates will be presented as the event rates per 1000 catheter-days with a 95% confidence 
interval for the purpose of comparison of rates between the treatments. This confidence interval will be 
derived assuming that the number of catheter-days until CRBSI follows an exponential distribution.  
In the primary analysis of the primary endpoint, cases considered to be indeterminate by the CAC will be 
excluded. A sensitivity analysis will be performed in which cases considered to be indeterminate will be 
treated as CRBSI events. 
2.4.2 Secondary Endpoint Analyses 
Time until catheter removal for any reason and time to loss of catheter patency will be analyzed using 
similar methods as for the primary analysis in the Full Analysis Population. Loss of catheter patency is 
defined as required use of a tissue plasminogen activating factor (tPA) or removal of the catheter due to 
dysfunction. For these endpoints, subjects will be considered censored as of their final clinical assessment 
if the event of interest is not observed. Otherwise, the event time will be the number of catheter-days 
between randomization and the event. The fixed sequence testing procedure will be used for the 
comparison of the two treatments with respect to the efficacy endpoints. Therefore, the analysis 
comparing the two treatments for catheter removal for any reason will be formally conducted only if the 
analysis for the primary effectiveness endpoint yields a statistically significant result favoring 
Neutrolin®, and the analysis comparing the two treatments for loss of patency will be formally conducted 
only if the analysis for catheter loss for any reason also yields a statistically significant result favoring 
Neutrolin®.  


Page 6 of 13 
 
In addition to basic descriptive statistics, the rates per 1000 catheter-days of follow-up will be presented 
for both endpoints. Also, the reason for catheter loss will be summarized by treatment group. 
2.5 Study Day and Visit Windows 
Study day is defined as  
 
Study Day  =  event date-randomization date +1 (on or after the day of randomization) 
 
                      event date-randomization date (before the day of randomization) 
 
 
The following data will be collected at each dialysis session (2 or 3 times per week) until study 
completion: 
 
weight 
 
vital signs (temperature, blood pressure, pulse, respiratory rate) 
 
exit site assessment 
 
mean blood flow (Qb) 
 
adverse event assessment 
 
interventions such as thrombolytic therapy 
 
CRBSI assessment 
 
concomitant medications 
 
The following data will be collected monthly: 
 
weight 
 
vital signs 
 
hematology 
 
chemistry 
 
dialysis treatment adequacy assessment - Single pool Kt/V (Sp Kt/V) 
 
concomitant medications 
 
For descriptive analyses that may require the assignment of visits to months (e.g., hematology graphs), 
assessments will be assigned to analysis months (every 4 weeks) based upon the date the assessment took 
place regardless of the CRF page completed.  Assessments will be mapped to visits as outlined in  
Table 1.  Should more than one assessment exist within a given visit window the value closest to the 
scheduled visit should be used (choose the later visit if equally close).  For data collected at each dialysis 
visit, analysis windows will not be assigned, and the nominal visits (week/day) will be used for data 
display. 
 
Table 1 Monthly Visit Windows 
Visit 
Start of Window 
End of Window 
Baseline 
Date of informed consent 
0 
Month 1 
1 
41 
Month 2 
42 
69 


Page 7 of 13 
 
Month m 
m*28-14 
m*28+13 
 
For subjects where the reference date is missing, the study day will also be missing. 
2.6 Handling of Missing Data 
The primary and secondary analyses have been designed to characterize the risk of various events for the 
time period each subject has his or her first on study catheter.  In this framework, missing data will exist if 
a subject discontinues follow-up for these events while the study is ongoing and the initial catheter is still 
in place. The statistical technique that will be used in the primary statistical analysis to deal with missing 
data is to treat the subject as censored at the time the catheter is removed for reasons other than CRBSI or 
follow-up is prematurely discontinued. This method will be appropriate if the reason for discontinuing 
follow-up is not related to a change in the subject that would be predictive of an increased risk of a 
CRBSI. 
To explore the reasons for missing data and to assess any bias associated with premature discontinuation, 
all reasons for subjects terminating study follow-up will be summarized by treatment arm.   
A sensitivity analysis will be performed in which cases considered to be indeterminate by the Clinical 
Adjudication Committee are treated as CRBSI events. 
2.7 Safety Analyses 
Statistical analyses will be descriptive in nature and testing for statistical significance will not be routinely 
applied. Safety analyses will be based upon the clinical database only.  Events recorded in the safety 
database will be reconciled with the clinical database prior to database lock.  
2.8 Interim Analysis 
A DSMB will meet periodically to review the accumulating study data. The primary purpose of these 
reviews is to monitor safety and data quality.  
Additionally, the DSMB will oversee interim analyses for efficacy and for futility that will be performed 
when 28 CAC-adjudicated CRBSI events (1/2 of the required total number of 56 events) have occurred. If 
statistical significance is obtained for the primary efficacy endpoint at this time, the recommendation will 
be to stop the study early for efficacy. If the futility analysis indicates that continuing the study would be 
futile, the recommendation will be to stop the study early for futility. In either case, the DSMB will report 
its recommendation only to the CorMedix Executive Committee, which will make the final decision as to 
whether or not to stop the study in consultation with the FDA. 
3 Summary Tables Listings and Figures 
3.1 General Conventions 
Unless otherwise stated, summary statistics including the number of subjects (n), mean, standard 
deviation, median, minimum and maximum will be presented for continuous variables.  Minimum and 
maximum values will be presented to the same decimal precision as the raw values, the mean and median 


Page 8 of 13 
 
values to one more, and the standard deviation, to two more decimal places than the raw values.  For 
categorical variables, per category, the absolute counts (n) and percentages (%) of subjects with data, and 
if appropriate, the number of subjects with missing data, will be presented.  Percentages will be presented 
to one decimal place. 
For efficacy and safety analyses, age will be calculated relative to the date of randomization. 
For adverse events reported on a per-subject basis, medical history and concomitant medications, the 
denominator for the percentage calculation will be the number of subjects in the analysis population and 
in the subgroup of interest at risk in each treatment arm.   
All p-values will be rounded to 4 decimal places.  If a p-value is less than 0.0001 it will be displayed as 
“< 0.0001”. 
All non-efficacy summary tables will use either the Randomized Population or the Safety Population. All 
efficacy summary tables will use the Full Analysis Population unless specified otherwise.  Summaries 
will be provided by treatment group.  
Not all data collected (e.g., vital signs at each dialysis visit) will be summarized or listed.  All such data 
will be included in the appropriate analysis file for display and summarization as needed during the 
preparation of the clinical study report (i.e., ad hoc displays). 
3.2 Subject Disposition and Treatment 
The total number of subjects screened, randomized, completed, discontinued from the study, and in each 
analysis population will be summarized by treatment group and overall. The reason for termination for all 
subjects who discontinued will be summarized by treatment group and overall. A listing of subjects who 
discontinued from the study by reason for termination will also be presented.  
 
Subjects randomized but not included in a given analysis population will be summarized by analysis 
population and the reason for exclusion will be presented.   
3.3 Violations of Inclusion/Exclusion Criteria 
Subjects enrolled in the trial without meeting the inclusion/exclusion criteria will be summarized for the 
Randomized Population with the following information: treatment assigned and inclusion/exclusion 
criteria violated. 
3.4 Study Treatment  
The following information will be presented by treatment arm and overall: 
 
duration of exposure 
 
total number of times drug administered 
 
total number of vials administered 
 
average dose  
 
compliance (100*No. of dialysis sessions at study site at which the correct dosing was 
administered/total number of dialysis sessions at study site) 


Page 9 of 13 
 
 
dose interruptions: percentage of months with dose interruptions and percentage of months with 
more than 3 consecutive missed doses.  
3.5 Demographics and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented by treatment group 
and overall for the Randomized Population. No statistical testing will be performed. Baseline 
characteristics will include summaries of the following: 
 
 
Subject demographics including age, sex, and race 
 
Baseline disease characteristics 
 
Pre-existing medical conditions 
 
Prior therapies 
3.5.1 Medical History 
Medical history will be descriptively summarized based upon the MedDRA system organ class (SOC) 
and preferred term by treatment and overall for the Safety Population.  Data summaries will be sorted by 
the overall frequency of reporting within SOC. 
3.6 Clinical Data 
3.6.1 Concomitant Medications 
Concomitant medications will be descriptively summarized based upon the coded values (WHO) by 
treatment for the Safety Population.  Data summaries will be sorted by the overall frequency of recorded 
use. Medications with end dates prior to dosing will not be included in these summaries. A table of 
medications used prior to dosing (including routine medications given with HD) will also be provided.   
3.7 Analysis of Efficacy Endpoints 
3.7.1 CRBSI 
The clinical criteria associated with CRBSI will be summarized by treatment group.  This summary will 
consist of the number and percent of subjects with each of the following 
 
Fever (defined as ≥37.8° C)  
 
Rigors, defined as shivering from a feeling of being cold, often with copious 
sweating, as documented by a medical professional 
 
Tachycardia, defined as a heart rate greater than 100 beats per minute  
 
Tachypnea, defined as a RR greater than 24 breaths per minute 
 
Low blood pressure, defined as a systolic blood pressure less than 90, as 
measured by a clinician (RN or MD) with a BP cuff, or a decrease in blood 
pressure greater than 30 mmHg 
 
An obvious change in mental status from previously documented baseline   
 
A listing of this information will also be provided. 


Page 10 of 13 
 
3.7.2 Primary Efficacy Analysis 
The number of subjects in each treatment arm will be summarized in the Full Analysis Population using 
the following categories:  
 
Occurrence of CAC-adjudicated CRBSI,  
 
Subject followed without occurrence of CAC-adjudicated CRBSI at the time the study 
was closed to further follow-up, or 
 
Subject was censored (provide count for each reason censored) for other reasons. 
The p-value for the log-rank comparison, hazard ratio (HR) with 95% confidence interval (active/control), 
and the incidence of CRBSI with 95% CI for each treatment group will be presented. The log-rank test 
will be performed using PROC LIFETEST in SAS. The HR and confidence interval will be calculated 
using PROC PHREG in SAS with only treatment in the MODEL statement and study day as the response 
variable.   
Kaplan-Meier curves will be displayed by treatment group for the time until CRBSI (implemented using 
PROC LIFETEST). 
3.7.3 Secondary Efficacy Analyses 
The analyses of the time until catheter removal for any reason and of time until loss of catheter patency 
will be based on the Full Analysis Population using the log-rank comparison, hazard ratio with 95% 
confidence interval (active/control), and incidence of the event of interest with 95% CI.  For these 
endpoints, subjects will be considered censored as of their final clinical assessment if the event of interest 
is not observed.  Otherwise, the event time will be the number of days between randomization and the 
event. 
3.7.4 Additional Analyses 
The HR for the primary analysis and relative risk for the incidence rates (along with 95% CIs for both) 
will be presented (tabular summary and graphically using a forest plot) for subgroups formed by the 
following variables (at baseline): 
 
age (< 65, ≥ 65 and ≥ 75 years of age)  
 
race  
 
sex 
 
diabetes 
 
months receiving dialysis (≤12 months vs. > 12 months)  
 
port location, and 
 
catheter type 
3.8 Analysis of Safety Endpoints 
All of the tables described in the following are to be conducted using the Safety Population. 
3.8.1 Brief Summary of Treatment Emergent Adverse Events (TEAEs) 
Adverse events are defined as treatment emergent if they start or worsen after a subject's first  
administration of study CLS. A brief  summary of TEAEs, serious TEAEs, TEAEs leading to death, 


Page 11 of 13 
 
TEAEs leading to drug discontinuation, TEAEs leading to study discontinuation, study drug-related 
TEAEs, and serious study drug-related TEAEs will be presented by treatment arm and overall. The total 
number of TEAEs and the number and percentage of subjects with at least one TEAE will be presented 
summarized by severity and by relationship to study drug for each treatment arm and overall.  This 
information will also be listed. 
3.8.2 TEAEs by System Organ Class and Preferred Term 
The number and percentage of subjects reporting TEAEs will be tabulated by preferred term and system 
organ class (SOC) for each treatment group.  TEAEs will be classified by SOC and preferred term using 
the Medical Dictionary for Regulatory Activities (MedDRA). Similar summaries will be produced for 
SAEs, TEAEs leading to termination, severe TEAEs, and TEAEs with a relationship to the investigational 
product. 
 
TEAEs will also be summarized by SOC, preferred term, and severity and by SOC, preferred term and 
relationship to study medication.  In the event of multiple occurrences of AEs with the same 
SOC/preferred term in one subject, the AE will be counted once as the occurrence with the highest 
severity or closest relationship for the summaries by severity and relationship, respectively.    
3.8.3 Clinical Laboratory Tests 
Descriptive statistics will be calculated for clinical laboratory tests (hematology, serum chemistry) at 
applicable visits. Where applicable, changes from baseline will be summarized by treatment group.  
3.8.4 Vital Signs  
Vital signs, actual values and changes from baseline, will be summarized by treatment group for the 
monthly visit (note, data summaries for each dialysis visit will not be produced) using descriptive 
statistics.  
3.8.5 Other Safety Analyses 
Dialyzer blood flow, time between end of last medication and start of treatment, and spKt/V will be 
summarized by treatment arm using descriptive statistics for a summary of previous dialysis treatment. 
Dialyzer blood flow, ESA Dose, IV Iron Dose, and Heparin will be summarized by treatment arm and 
visit using descriptive statistics for dialysis sessions. 
3.8.5.1 Pregnancy 
Pregnancies will be summarized by treatment arm.  Outcomes will be listed for each pregnancy. 
 
4 Changes to the Protocol-Specified Analyses 
The definition of the primary endpoint was revised from the protocol, as per agreement with the FDA. It 
reflects use of a Clinical Adjudication Committee. 


Page 12 of 13 
 
The protocol stated that the number and percentage of subjects who received drug or control at all visits 
will be presented to summarize compliance and duration of exposure, but this will not be done.  
The protocol stated that the primary analysis of the primary endpoint would be repeated using all 
randomized subjects with available data, but this will not be done. 
The protocol stated that physical examination data will be summarized descriptively by treatment group, 
but this will not be done. 
The protocol stated that changes in vital signs parameters from baseline will be summarized across 
treatment groups at each applicable post-randomization visit, but this will be done only for the monthly 
visits.  
The protocol stated that the number and percentage of subjects with abnormal laboratory results will be 
provided, but this will not be done. 
5 References 
Pocock, S.J., Group sequential methods in the design and analysis of clinical trials. Biometrika, 1977. 64: 
191-199. 
 
 
 


Page 13 of 13 
 
 
 


Addendum to Statistical Analysis Plan 
 
A Phase 3, prospective, multicenter, double-blind, randomized, active control study to demonstrate the 
safety and effectiveness of Neutrolin® in preventing catheter-related bloodstream infections in subjects 
receiving hemodialysis therapy as treatment for end stage renal disease 
LOCK-IT-100 
 
 
Sponsored by: 
CorMedix Inc. 
 
November 10, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
Part or all of the information in this statistical analysis plan addendum may be unpublished material. 
Accordingly, this document is to be treated as confidential and restricted to its intended use. This material 
is the property of CorMedix Inc. and must not be disclosed or used except as authorized in writing by 
CorMedix Inc. 


Page 2 of 6 
 
Table of Contents
  1.0 
Introduction.......................................................................................................................3 
  1.1 
   Efficacy Analyses..........................................................................................................................3 
  1.2 
   Safety Analyses.............................................................................................................................5  
  1.3 
   Other Analyses..............................................................................................................................5  
 
 
 


Page 3 of 6 
 
1.0 Introduction 
The planned interim analysis of the study was conducted, and the study was stopped at the 
recommendation of the Data Safety Monitoring Board because of the demonstration of efficacy based on 
the primary endpoint. The interim analysis was conducted, as planned, based on data through the date of 
occurrence of the 28th Clinical Adjudication Committee (CAC)-adjudicated catheter-related blood stream 
infection (CRBSI) (03 December 2017). While the data for the interim analysis were being source 
verified and cleaned, the study continued and more data were accrued. The purpose of this addendum to 
the Statistical Analysis Plan (SAP) is to describe (1) planned efficacy analyses of the three efficacy 
endpoints based on all of the efficacy data through the last patient’s last visit (LPLV), (2) planned safety 
analyses of all of the safety data through the LPLV, and (3) other analyses.  
1.1   Efficacy Analyses 
Primary Endpoint 
The primary endpoint is catheter-related blood stream infection (CRBSI), defined as one positive blood 
culture (other than for coagulase negative Staphylococcus, which requires a confirmatory culture) from: 
1. a peripheral site or blood line sample or 
2. either the arterial or venous catheter hub (or the venous or arterial dialysis circuit blood lines if 
on dialysis)  
in a patient with no other apparent source of bloodstream infection other than the hemodialysis catheter, as 
assessed by the Clinical Adjudication Committee (CAC). 
The primary analysis of the primary endpoint was performed at the interim analysis, and it resulted in a 
positive outcome and the stopping of the study. This analysis of this endpoint represents the final formal 
analysis for this endpoint. Nevertheless, in order to summarize all of the available information on this 
endpoint, the analysis of the primary endpoint will be repeated using all of the data through the LPLV. 
The p-value from this analysis will be reported to provide a measure of the strength of evidence of 
efficacy from the study but it will not represent a second test of the null hypothesis for this endpoint. As 
for the interim analysis, the analysis of the primary endpoint based on all of the data through the LPLV 
will be conducted based on the Full Analysis Population using the Kaplan-Meier method. The time until 
CRBSI will be calculated as the number of days post randomization until the occurrence of a CAC-
adjudicated CRBSI. A patient will be considered to have a CRBSI event if there is a CAC-determined 
CRBSI. If there is no such CRBSI, the patient will be censored at the earliest of the following dates: 
 
1. Date of catheter removal, if any 
2. Date of study completion, if any 
3. Date of last study drug dose plus 3 days 
 
Three days was added to the date of last study drug dose because the study drug would be withdrawn at 
the next dialysis session, which would typically be about three days later.  
In this analysis of the primary endpoint, cases adjudicated as indeterminate by the CAC will not be 
considered to be CRBSI cases. A sensitivity analysis will be performed in which cases adjudicated as 


Page 4 of 6 
 
indeterminate will be considered to be CRBSI cases. Subgroup analyses of the primary analysis of the 
primary endpoint will be conducted as described in the Statistical Analysis Plan. These analyses will be 
performed based (1) on all of the efficacy data through the data cutoff date for the interim analysis and 
also (2) on all of the efficacy data through the LPLV. 
Secondary Endpoints 
The secondary endpoints are as follows: 
• 
Catheter Removal: Defined as catheter removal for any reason during the follow-up period of 
the trial. 
• 
Loss of Catheter Patency:  Defined as required use of a tissue plasminogen activating factor 
(tPA) or removal of the catheter because of dysfunction during the follow-up period of the 
trial. 
Analyses of these endpoints were conducted and provided to the Data Safety Monitoring Board at the 
time of the interim analysis. Unlike the primary endpoint, however, the primary analyses of these 
endpoints will be based on data through the LPLV.  
Time until catheter removal for any reason and time to loss of catheter patency will be analyzed based on 
the Full Analysis Population using the Kaplan-Meier method as for the primary endpoint.  
A patient will be considered to have had loss of catheter patency if either of the following conditions are 
met: 
1. If the reason for study completion is specified as “Catheter Removal (not due to CRBSI)” and the 
reason (for catheter removal) is indicated as being “Catheter Malfunction/Dysfunction – Loss of 
patency” or 
2. If the Reported Name of Drug Med or Therapy (Preferred) is “Alteplase” and the item “For tPA 
usage, if the usage was directly related to a loss of patency” is indicated as “Yes”. 
The time of the event will be the number of days between randomization and the event. (If both of the 
above conditions are met, the date of occurrence of the earlier condition will be used.) If there is no such 
loss of catheter patency, the patient will be censored at the earliest of the following dates: 
1. Date of catheter removal, if any 
2. Date of study completion, if any 
3. Date of last study drug dose plus 3 days 
A patient will be considered to have had a catheter removal if there is a date of catheter removal. If a 
patient does not have a date of catheter removal, the patient will be considered censored at the earliest of 
the following dates: 
1. Date of study completion, if any 
2. Date of last study drug dose plus 3 days 
The time to the event will be the number of days between randomization and the event.  


Page 5 of 6 
 
1.2 Safety Analyses 
Analyses of safety were conducted and provided to the Data Safety Monitoring Board at the time of the 
interim analysis. The primary analyses of safety, however, will be based on data through the LPLV. These 
analyses will be conducted as described in the Statistical Analysis Plan. 
1.3 Other Analyses 
Data for subject disposition, demographics and baseline characteristics, and study treatment will be 
analyzed as described in the Statistical Analysis Plan. Analyses will be performed based (1) on all of the 
data through the data cutoff date for the interim analysis and also (2) on all of the data through the LPLV.  


Page 6 of 6 
 
Approval Sheet 
 
Product: 
Neutrolin®  
Protocol Number: 
LOCK-IT-100 
Date: 
November 10, 2018 
 
 
The individuals signing below have reviewed and approve this addendum to the statistical analysis plan.  
 
 
 
 
Roger B. Johnson, Ph.D. 
Director, Biostatistics 
Biostatistical Consulting Inc. 
 
Date 
 
 
 
 
 
 
Eugene C. Poggio, Ph.D. 
Chief Biostatistician 
Biostatistical Consulting Inc. 
 
Date 
 
 
 
 
 
 
Liz Masson 
Executive Vice President/Head, Clinical Operations 
CorMedix 
 
Date 
 
 
 
 
 
 
 
 
11 Nov 2018