A Prospective, Randomized, Multi-Center, Open-Label, Cross-Over Study of Lokelma to Control Interdialytic Hyperkalemia Following Augmentation of Dialysate Potassium
Phase: PHASE4
Conditions: Hyperkalemia
Sponsor: NephroNet, Inc.

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date 28 April 2022 
1 (76) 
 
 
Drug Substance 
sodium zirconium cyclosilicate (added to 
dialysate) 
Study Number 
NN-007 (ADAPT) 
Company Reference 
D9480C00024 
Version 
4.0 (Amendment 2) 
Date 
28 April 2022 
A Prospective, RanDomized, Multi-Center, Open-Label, Cross-Over Study of 
Sodium Zirconium Cyclosilicate to Control Interdialytic HyperkalemiA 
Following Augmentation of Dialysate Potassium: Efficacy to Reduce the 
Incidence of Post-Dialysis Atrial Fibrillation and Clinically SignificanT 
Cardiac Arrhythmias - ADAPT Trial 
Sponsor:   
NephroNet Inc. 
575 Professional Drive, Suite 260 
Atlanta, GA 30046 
 
Contact: James Tumlin, MD 
Cell: 770-490-9203 
Email: JamesTumlinMD@nephronet.com  
 
 
This document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to the Company and opportunity to redact. 

ESR Protocol 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date: 28 April 2022 
2 (76) 
VERSION HISTORY 
 
Version 1.0, 11 November 2021 
Superseded by Version 2.0, February 2022. Note: This version was not submitted to the 
Institutional Review Board. 
Version 2.0, 16 February 2022 
Initial creation with Piccolo Testing System Update 
Version 3.0 (Amendment 1), 06 April 2022 
• Clarifications and/or minor changes made to the following: 
Ø Study Objective and Outcome Measures 
Ø Inclusion/Exclusion Criteria 
Ø Schedule of Assessments 
Ø LINQ Insertable Cardiac Monitor 
Ø Blood Draws and Standard of Care Laboratory Testing 
Ø Investigational Product (removal of 10 gram packet)  
Ø Administrative Updates  
Version 4.0 (Amendment 2), 28 April 2022 
• Clarifications and/or minor changes made to the following: 
Ø Safety Objectives 
Ø Exclusion Criteria 
Ø Schedule of Assessments and Footnotes 
Ø Assignment of Subject Numbering 
Ø Blood Draws and Standard of Care Laboratory Testing 
Ø Administrative Updates  
 

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date 28 April 2022 
3 (76) 
 
PROTOCOL SYNOPSIS 
 
A Prospective, RanDomized, Multi-Center, Open-Label, Cross-Over Study 
of Sodium Zirconium Cyclosilicate to Control Interdialytic HyperkalemiA 
Following Augmentation of Dialysate Potassium: Efficacy to Reduce the 
Incidence of Post-Dialysis Atrial Fibrillation and Clinically SignificanT 
Cardiac Arrhythmias - ADAPT Trial 
 
 
National Coordinating Investigator:  
James A. Tumlin, MD 
Professor of Medicine, Emory University School of Medicine, Atlanta 
President, NephroNet Inc. 
Nephrologist, Georgia Nephrology, LLC 
575 Professional Drive Suite 260 
Atlanta GA, 30046 
Tel: 770-490-9203 
E-mail: JamesTumlinMD@nephronet.com 
 
Study site(s) and number of subjects planned 
Planned number of sites: Approximately 10 - 12 
Planned number of patients randomized: 88 
Average number of patients randomized per site: approximately 9  
(No minimum or maximum number of enrolled subjects will be specified.) 
 
 

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date: 28 April 2022 
4 (76) 
 
Study design 
This is a prospective, open-labelled, randomized, 2x2 cross-over design study of 88 patients 
with end stage renal disease (ESRD) receiving routine out-patient dialysis using a standard 2.0 
potassium ion (K+)/2.5 calcium ion (Ca++) dialysate bath. The overall aim of the study is to 
determine whether converting stable hemodialysis patients from a “standard” 2.0 K+/2.5 Ca++ 
dialysate (without Lokelma) to a 3.0 K+/2.5 Ca++ mEq dialysate supplemented with the orally 
administered potassium binder sodium zirconium cyclosilicate (Lokelmaâ) to treat inter-
dialytic hyperkalemia will reduce the incidence and duration of post-dialysis atrial fibrillation. 
Following screening, eligible subjects will undergo placement of an implantable cardiac loop 
recorder (LINQ device) to monitor for the development of atrial fibrillation or any clinically 
significant cardiac arrhythmias [CSCA]). After a two-week recovery period (to allow the patient 
to heal from cardiac loop recorder placement), patients will be randomized (1:1 ratio) to one of 
two treatment sequences: 
• Sequence A: standard 2.0 K+/2.5 Ca++ dialysate with no Lokelma supplementation for 
two (2) months, followed by a cross-over to experimental 3.0 K+/2.5 Ca++ dialysate with 
Lokelma supplementation (on off-dialysis days) for two (2) months;  
Or 
• Sequence B: experimental 3.0 K+/2.5 Ca++ dialysate with Lokelma supplementation (on 
off-dialysis days) for two (2) months, followed by standard 2.0 K+/2.5 Ca++ dialysate 
with no Lokelma supplementation for two (2) months. 
Each two-month treatment period (both 2.0 K+/2.5 Ca++ dialysate and 3.0 K+/2.5 Ca++ 
dialysate with Lokelma sequences) will be preceded by a two-week run-in period, to 
allow the patient to adapt to the new dialysate bath.  
While receiving the higher K+ dialysate, patient will be treated on off-dialysis days (4 
days/week) with Lokelma, titrated to maintain K+ between 4.0 and 5.5 mEq/L. Refer to 
section 7.2 for the initial dose and frequency details. 
Throughout both treatment phases, patients will undergo continuous cardiac monitoring using 
the programmable Medtronic Reveal LINQ ICM device to detect the development of atrial 
fibrillation or CSCA (i.e., pre-defined event of bradycardia, ventricular tachycardia, or 
asystole). The incidence of atrial fibrillation and CSCA events occurring during the two 
treatments (experimental vs standard) will be compared. 
 
 

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date: 28 April 2022 
5 (76) 
 
Study Objectives 
Primary Efficacy Objective: Atrial Fibrillation Rates 
Primary Outcome Measure: 
To demonstrate whether increasing the K+ concentration 
in a standard hemodialysis bath from 2.0 K+/2.5 Ca++ to a 
3.0 K+/2.5 Ca++ composition with SZC will reduce the 
incidence of atrial fibrillation events [1].  
Ø Frequency of atrial fibrillation events [1] 
occurring during the 8-week Treatment 
Phase-1 and the 8-week Treatment 
Phase-2 dialysate cross-over periods. 
Secondary Efficacy Objective #1: Clinically 
Significant Cardiac Arrhythmia Rates 
Secondary Outcome Measures: 
To determine whether the incidence and duration of post-
dialysis CSCAs (defined as bradycardia, ventricular 
tachycardia and/or asystole [4]) observed during 
experimental treatment [2] will be reduced compared to 
standard treatment [3]. 
Ø Frequency of CSCAs (bradycardia, 
ventricular tachycardia and/or asystole) 
during the 8-week Treatment Phase-1 
and the 8-week Treatment Phase-2 
dialysate cross-over periods. 
Ø Total duration of CSCAs (bradycardia, 
ventricular tachycardia and/or asystole) 
during the 8-week Treatment Phase-1 
and the 8-week Treatment Phase-2 
dialysate cross-over period. 
Secondary Efficacy Objective #2: Events Outside the 
Optimal K+ “Window” 
Secondary Outcome Measure: 
To determine whether the addition of oral sodium 
zirconium cyclosilicate (Lokelmaâ) during the 2-month 
treatment phase with the 3.0 K+/2.5 Ca++ dialysate bath 
will reduce the risk of weeks outside the “K+ safety range” 
of 4.0 to 5.5 mEq/L compared to the 2-month treatment 
phase with the 2.0 K+/2.5 Ca++ dialysate bath.  
 
Ø Whether or not K+ outside of the 4.0 to 
5.5 mEq/L safety range ( a yes/no binary 
outcome). 
The risk of weekly events of pre-dialysis 
K+ or the risk of post-dialysis K+ falling 
outside the “K+ safety range” will be 
compared between the two dialysate 
groups. 
Safety Objective #1: Lokelma Induced Hypokalemia 
Safety Outcome Measure: 
To evaluate whether the use of Lokelma during periods 
when patients are  receiving a 3.0 K+/2.5 Ca++ bath is 
associated with hypokalemic events defined as K+ <3.5 
mEq/L. 
Ø Total number of hypokalemic events 
defined as Piccolo Point of Care Testing 
(POCT) or laboratory-measured K+ of < 
3.5 mEq/L. 
Safety Objective #2: Incidence of Dialysis-related 
Hypokalemia, Hypomagnesemia, Hypophosphatemia, 
or Low Calcium 
Safety Outcome Measure: 

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date: 28 April 2022 
6 (76) 
To determine the levels of K+, Mg++, calcium and PO4 
during dialysis (measured promptly prior to the 
termination of dialysis) during experimental treatment [2] 
compared to standard treatment [3]. 
Note: Each electrolyte is its own ”safety” objective 
independently. 
 
Ø Number of events (measured promptly 
prior to the termination of dialysis) 
where a Piccolo POCT measurement of 
K+ is < 3.5 mEq/L OR Ca++ is < 7.0 
mEq/L, OR Mg++ is < 2.0 mg/dl OR a 
PO4 level is <3.0 mEq/L.  
All episodes where a specific electrolyte 
falls below the above listed threshold 
will be considered an “event” for that 
electrolyte. 
The 
total 
number 
of 
“events” will be recorded during the 8-
week Treatment Phase-1 and the 8-week 
Treatment Phase-2 cross-over periods. 
Safety Objective #3: Adverse Experiences 
Safety Outcome Measure: 
To evaluate the safety and tolerability of the experimental 
treatment [2] compared to standard treatment [3] based on 
the frequency of reported adverse experiences. 
Ø Frequencies 
of 
AEs, 
SAEs, 
and 
withdrawals due to AEs, with focus on 
treatment-related events. 
Exploratory Objectives: 
Exploratory Outcome Measures: 
1) To evaluate the relationship between protein-bound 
uremic toxins (PBUTs) and atrial fibrillation rates.  
PBUTs such indoxyl sulfate (IS) and p-Cresol sulfate 
(PCS) can induce atrial fibrillation (Aoki et al. 2015; Tang 
et al. 2015). 
Ø Correlation between PBUTs (IS, PCS, 
and ADMA) and the frequency of atrial 
fibrillation events. 
2) To determine whether the levels of K+, Mg++, calcium 
and PO4 (measured promptly prior to the termination of 
dialysis) correlate with the incidence of clinical events, 
including intradialytic hypotension, muscle cramping, 
and cardiac events (defined as atrial fibrillation, 
bradycardia, ventricular tachycardia, and asystole). We 
will also evaluate whether the 3.0 K+ dialysate reduces the 
rates of these clinical events.   
Ø Correlation between electrolyte levels 
and 
clinical 
events 
(intradialytic 
hypotension, muscle cramping, and 
cardiac events). 
Ø Correlation between electrolytes falling 
below threshold levels (Ca++ < 7.0 
mEq/L, PO4 levels <3.0 mEq/L, Mg++< 
2.0 mg/dl, and K+ of < 3.5 mEq/L) and 
cardiac 
events 
(defined 
as 
atrial 
fibrillation, 
bradycardia, 
ventricular 
tachycardia, or asystole). 
Abbreviations: ADMA=asymmetric dimethylarginine; AE=adverse event; CSCA=clinically significant cardiac 
arrhythmia; IS=indoxyl sulfate; PBUT= protein-bound uremic toxin; PCS=p-Cresol sulfate; SAE=serious adverse 
event 
[1] Atrial fibrillation will be defined as irregular heart rhythms and irregular R-R intervals in the absence of 
definable P waves for a minimum of 6 minutes. Each atrial fibrillation event will be adjudicated and validated as 
a true atrial fibrillation event by a central cardiologist who is blinded to dialysate K+ content. 
[2] Experimental treatment (8 weeks): hemodialysis using 3.0K+/2.5 Ca++ dialysate bath, with sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation on off-treatment days 
[3] Standard treatment (8 weeks): hemodialysis using 2.0K+/2.5 Ca++ dialysate bath, without sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation 
[4] CSCA events are defined as follows: 
§ 
Bradycardia: Heart rate of £ 40 beats per minute (BPM) for a minimum duration of 6 seconds. 

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date: 28 April 2022 
7 (76) 
§ 
Ventricular Tachycardia: Regular tachy-arrhythmia of ³ 130 BPM for a minimum duration of 30 seconds  
§ 
Asystole: Absence of detectable ventricular conduction for a minimum of 3 seconds 
Target subject population 
The ADAPT trial will enroll adult ESRD patients receiving hemodialysis for at least 3 months, 
who have shown reasonable compliance with dialysis sessions and medications, and had two 
(2) pre-dialysis K+ measurements between 5.1 and 6.5 mEq/L following a long dialytic 
“weekend”. Patients with a history of paroxysmal episodes of  atrial  fibrillation (excluding 
chronic atrial fibrillation) will be preferentially recruited. Patients with known left ventricular 
hypertrophy (LVH) and prior history of intra-dialytic cramping will also be identified, 
approached, and recruited for study participation. 
Patient receiving peritoneal or home hemodialysis, or hemodialysis via a tunneled IVC catheter 
and with a known central stenosis of access extremity will be excluded from the study. Patients 
with the known placement of a dual or single chamber pacemaker or an automatic implantable 
cardiac defibrillator (AICD) will be ineligible for study participation.  
Duration of treatment 
Following the screening period’s two confirmatory pre-dialysis K+ measurements and after 
meeting study eligibility criteria, patients will be referred to the electrophysiology cardiologist 
of choice by the site principal investigator where a sub-cutaneous (SQ) continuous cardiac loop 
recorder will be placed in the left anterior chest wall. Patients will be allowed to accommodate 
to the loop recorder for 2-weeks before they are randomized (1:1 ratio) to one of two treatment 
sequences (Sequence A or B, as described above), and start study treatment with 2.0 K+/2.5Ca++ 
dialysate bath without potassium binder supplementation or 3.0 K+/2.5 Ca++ dialysate bath with 
Lokelma supplementation (taken on off-dialysis days). There will be a 2-week cardiac 
monitoring blanking period where patients will be allowed to accommodate to the higher K+ 
dialysate and the use of Lokelma. Any data recorded by the insertable loop recorder (ILR, LINQ 
device) during this time period will not be used for any endpoint analysis. During the next 8-
week treatment period (Phase I of the study), patients will undergo continuous cardiac 
monitoring by the ILR. At the end of Phase I, data will be downloaded from the ILR and a new 
2-week blanking period will begin where patients will “cross-over” to the alternative dialysate 
bath and will be allowed to equilibrate to the new dialysate. Patients dialyzed for 8 weeks using 
a 2.0 K+/2.5Ca++ bath (without potassium binder supplementation) during Phase I will be 
switched to the 3.0 K+/2.5 Ca++ bath with Lokelma supplementation, and vice versa. During the 
subsequent 8-week treatment period (Phase II of the study), patients will undergo continuous 
cardiac monitoring by the ILR. At the conclusion of Phase II, a new cardiac monitoring blanking 
period will begin and blood sampling will be stopped. The ILR will be removed by the affiliated 
electrophysiology cardiologist. This process may take an additional 2 weeks. Therefore, for 
each patient, the planned total study treatment duration will be 20 weeks, and the total study 
participation will be approximately 25 weeks. 

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date: 28 April 2022 
8 (76) 
Investigational product, dosage, and mode of administration 
The investigational product in this study is sodium zirconium cyclosilicate (Lokelmaâ), a 
potassium binder product for oral administration. Lokelmaâ for oral suspension will be supplied 
in 5.0 gram packets. 
Patients will use Lokelma supplementation on off-dialysis days (4 days/week) while receiving 
hemodialysis with 3.0 K+/2.5 Ca++ mEq dialysate bath. The individual starting dose will be 5.0 
grams, and may be titrated weekly in 5.0 gram increments up to 15.0 grams to maintain K+ 
between 4.0 and 5.5 mEq/L. 
Statistical methods 
Statistical Hypothesis 
The primary statistical hypothesis of the study is that the rate of atrial fibrillation events during 
hemodialysis using the 3.0 K+ dialysate bath supplemented with Lokelma is not equal to the 
rate of events incurred during hemodialysis using the 2.0 K+ dialysate bath. 
Sample Size Estimate 
The sample size estimation is based upon the primary statistical hypothesis and its details are 
separately documented. 
With >90% power to reject the primary hypothesis, 40 subjects would need to be randomized 
into one of two treatment sequences in the 2x2 cross-over study using the simulation study  with 
a 2-sided alpha of 0.05, assuming an event rate of 4.6 with the 2.0 K+ dialysate bath, an 
overdispersion parameter of 0.07 and a reduction of rate ratio of 25%. Accounting for an 
estimated 10% of randomized subjects not completing both study periods, 44 subjects per 
treatment sequence or 88 subjects in total will be randomized in the study. 
Analysis Populations 
§ All-participants Analysis Set: will consist of all participants who were screened for the 
study. 
§ Full Analysis Set (FAS): will include all randomized patients, with patients being analyzed 
as randomized. All efficacy endpoints will be analyzed using the FAS. 
§ Safety Analysis Set (SAS): will include all randomized participants who during the first 
treatment period (study Phase I): (i) received at least one dose of the study drug (Lokelma) 
during treatment with the 3.0 K+ dialysate bath; or (ii) completed Visit 2 during treatment 
with the 2.0 K+ dialysate bath. All safety endpoints will be analyzed using the SAS. 
Analysis of the Primary Variable 
The primary efficacy endpoint is the frequency of atrial fibrillation events occurring during the 
8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods. 
The primary analysis will test the null hypothesis that there is no difference in the rate of atrial 
fibrillation events between the 3.0K+ dialysate bath with Lokelma and the 2.0K+ dialysate bath 
without Lokelma, against the alternative hypothesis that there is a difference in the rate of atrial 
fibrillation events between the 3.0K+ dialysate bath with Lokelma and the 2.0K+ dialysate bath 

Clinical Study Protocol Synopsis 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date: 28 April 2022 
9 (76) 
without Lokelma. Statistical hypothesis testing will be completed at a 2-sided 0.05 significance 
level. 
A generalized linear model assuming the distribution of negative binomial will be used, with 
fixed effect terms for the treatment groups (3.0K+ dialysate bath with Lokelma and 2.0K+ 
dialysate bath without Lokelma), the study period, and log (the duration of period) as an offset 
variable. An independent working variance-covariance will be employed. Additional model 
terms may be included, details of which will be described in the SAP. The estimated risk ratio 
between groups and its 95% robust confidence interval (CI) will be displayed. The null 
hypothesis will be rejected if the p-value (based upon the Wald statistics) is less than 0.05. 
The primary analysis will not account for missing values. However, sensitivity analyses will be 
conducted using the pattern mixture model with multiple imputation (PM-MI) method. Details 
of the PM-MI method will be provided in the SAP. 
Interim Analysis 
No interim analysis is planned. 
Data Monitoring Committee 
Not applicable. 
 

Clinical Study Protocol 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date 28 April 2022 
10 (76) 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................... 3 
TABLE OF CONTENTS ....................................................................................... 10 
1. 
INTRODUCTION ................................................................................................. 17 
1.1 
Background and Rationale for Conducting the Study ........................................... 17 
1.1.1 
Background and Significance ................................................................................ 17 
1.2 
Rationale for Study Design, Doses, and Control Groups ...................................... 21 
1.3 
Benefit/risk and ethical assessment ........................................................................ 22 
1.4 
Study Design .......................................................................................................... 23 
2. 
STUDY OBJECTIVES .......................................................................................... 25 
2.1 
Primary Objective .................................................................................................. 25 
2.2 
Secondary Objectives ............................................................................................. 25 
2.3 
Safety Objectives ................................................................................................... 26 
2.4 
Exploratory Objectives .......................................................................................... 27 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 27 
3.1 
Inclusion Criteria .................................................................................................... 27 
3.2 
Exclusion Criteria .................................................................................................. 28 
3.3 
Subject Enrollment and Randomization ................................................................ 30 
3.4 
Procedures for Handling Incorrectly Enrolled or Randomized Subjects ............... 30 
3.5 
Methods for Assigning Treatment Groups ............................................................. 30 
3.6 
Methods for ensuring blinding ............................................................................... 31 
3.7 
Methods for unblinding .......................................................................................... 31 
3.8 
Restrictions ............................................................................................................. 31 
3.9 
Discontinuation of Investigational Product ............................................................ 31 
3.9.1 
Procedures for Discontinuation of a Patient from Investigational Product ........... 32 
3.10 
Criteria for Withdrawal .......................................................................................... 32 
3.10.1 
Screen failures ........................................................................................................ 32 
3.10.2 
Withdrawal of the informed consent ...................................................................... 33 

Clinical Study Protocol 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date 28 April 2022 
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3.11 
Discontinuation of the study .................................................................................. 33 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 33 
4.1 
Screening Period .................................................................................................... 39 
4.1.1 
Obtaining Written Informed Consent .................................................................... 39 
4.1.2 
Assignment of Unique Patient Enrollment Number .............................................. 39 
4.1.3 
Recording of Demographic Data ........................................................................... 39 
4.1.4 
Review of Medical/Surgical, Laboratory, and Medication History ....................... 39 
4.1.5 
Physical Exam ........................................................................................................ 40 
4.1.6 
Vital Sign Measurements and Weight ................................................................... 40 
4.1.7 
12-Lead Electrocardiogram (ECG) ........................................................................ 41 
4.1.8 
K+ and PO4 Piccolo POCT System Measurements (Weeks -4 and -3) .................. 41 
4.1.9 
Insertion of the Cardiac Loop Recorder (Week -2) ............................................... 42 
4.2 
Treatment period .................................................................................................... 45 
4.2.1 
Blood Draws (Weeks 3 to 10 and Weeks 13 to 20) ............................................... 45 
4.2.2 
Insertable Cardiac Loop Recordings (Weeks 3 to 10 and Weeks 13 to 20) .......... 46 
4.2.3 
Cross-Over (Week 11) ........................................................................................... 47 
4.3 
Follow-up period .................................................................................................... 47 
5. 
STUDY ASSESSMENTS ..................................................................................... 47 
5.1 
Efficacy Assessments ............................................................................................. 47 
5.1.1 
Atrial Fibrillation ................................................................................................... 47 
5.1.2 
Clinically Significant Cardiac Arrhythmias ........................................................... 48 
5.1.3 
Potassium Measurements ....................................................................................... 48 
5.1.4 
Correlations Between Laboratory Parameters and Clinical Events ....................... 48 
5.2 
Safety assessments ................................................................................................. 49 
5.2.1 
Laboratory safety assessments ............................................................................... 49 
5.2.2 
Physical examination ............................................................................................. 50 
5.2.3 
Cardiac Monitoring ................................................................................................ 50 
5.2.3.1 
12-lead ECG ........................................................................................................... 50 
5.2.4 
Vital signs .............................................................................................................. 50 
5.2.5 
Other safety assessments – Concomitant Medications .......................................... 50 
5.2.6 
Pregnancy Test for Females of Childbearing Potential ......................................... 50 
5.3 
Safety Protocols ..................................................................................................... 51 
5.3.1 
Safety Protocol for Patients with Piccolo POCT-Confirmed Hypokalemia 
or Hyperkalemia ..................................................................................................... 51 
5.3.2 
Safety Protocol for Patients with Intra-Dialytic Arrhythmias ............................... 51 
5.3.3 
Safety Protocol for Patients with Intra-Dialytic Hypotensive Events .................... 51 
5.3.4 
Safety Protocol for Patients with Intra-Dialytic Symptomatic Muscle 
Cramping ................................................................................................................ 52 
5.4 
Pharmacokinetics ................................................................................................... 52 
5.5 
Pharmacodynamics ................................................................................................ 52 
5.6 
Pharmacogenetics ................................................................................................... 52 

Clinical Study Protocol 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date 28 April 2022 
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5.7 
Biomarker Analysis ................................................................................................ 52 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 52 
6.1 
Definition of Adverse Events ................................................................................. 53 
6.2 
Definitions of Serious Adverse Event .................................................................... 53 
6.3 
Definition of Suspected Unexpected Serious Adverse Event (SUSAR) ............... 54 
6.4 
Recording of adverse events .................................................................................. 54 
6.4.1 
Time period for collection of adverse events ......................................................... 54 
6.4.2 
Follow-up of unresolved adverse events ................................................................ 54 
6.4.3 
Variables ................................................................................................................ 54 
6.4.4 
Causality collection ................................................................................................ 55 
6.4.5 
Adverse events based on signs and symptoms ....................................................... 55 
6.4.6 
Adverse events based on examinations and tests ................................................... 55 
6.5 
Reporting of serious adverse events to the IRB and/or the Regulatory 
Authority ................................................................................................................ 56 
6.6 
Reporting of Serious Adverse Events to Company ............................................... 56 
6.7 
Overdose ................................................................................................................ 57 
6.8 
Pregnancy ............................................................................................................... 57 
6.8.1 
Maternal exposure .................................................................................................. 57 
6.8.2 
Paternal exposure ................................................................................................... 58 
6.9 
Management of IP-related Toxicities / Dose Reductions ...................................... 58 
6.10 
Study Governance and Oversight .......................................................................... 58 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 58 
7.1 
Identity of Investigational Product(s) .................................................................... 58 
7.2 
Dose and Treatment Regimens .............................................................................. 59 
7.2.1 
Dosing Regimen ..................................................................................................... 59 
7.2.2 
Study Drug Dispensation and Instructions for Reconstitution and Dosing ........... 59 
7.3 
Labelling ................................................................................................................ 60 
7.4 
Storage ................................................................................................................... 60 
7.5 
Compliance ............................................................................................................ 60 
7.6 
Accountability ........................................................................................................ 60 
7.7 
Concomitant and Other Treatments ....................................................................... 60 
7.7.1 
Prohibited Treatment .............................................................................................. 60 
7.7.2 
Other concomitant treatment .................................................................................. 61 
7.8 
Post Study Access to Study Treatment .................................................................. 61 
8. 
STATISTICAL ANALYSES ................................................................................ 61 
8.1 
Statistical Considerations ....................................................................................... 61 

Clinical Study Protocol 
Drug Substance sodium zirconium cyclosilicate (added to dialysate)  
Study Code D9480C00024 
Version 4.0 
Date 28 April 2022 
13 (76) 
8.2 
Sample Size Estimate ............................................................................................. 61 
8.3 
Definitions of Analysis Sets and Analysis Periods ................................................ 62 
8.3.1 
All-participants Analysis Set ................................................................................. 62 
8.3.2 
Full Analysis Set .................................................................................................... 62 
8.3.3 
Safety Analysis Set ................................................................................................ 62 
8.4 
Outcome Measures for Analyses ........................................................................... 62 
8.4.1 
Primary Efficacy Endpoint: Frequency of Atrial Fibrillation Events .................... 62 
8.4.2 
Secondary Efficacy Endpoint #1: Frequency and duration of Clinically 
Significant Cardiac Arrhythmia Events ................................................................. 63 
8.4.3 
Secondary Efficacy Endpoint #2: Events Outside the Optimal K+ 
“Window” .............................................................................................................. 63 
8.4.4 
Exploratory Efficacy Endpoint #1:Relationship Between PBUTs and Atrial 
Fibrillation Rates .................................................................................................... 63 
8.4.5 
Exploratory Efficacy Endpoint #2: Correlation Between Electrolytes and 
Clinical Events ....................................................................................................... 63 
8.4.6 
Safety Endpoint #1: Lokelma Induced Hypokalemia ............................................ 63 
8.4.7 
Safety Endpoint #2: Incidence of Dialysis-related Hypokalemia, 
Hypomagnesemia, Hypophosphatemia, or  Low Calcium .................................... 64 
8.4.8 
Safety Endpoint #3: Adverse Experiences ............................................................. 64 
8.5 
Methods for statistical analyses ............................................................................. 64 
8.5.1 
General Considerations .......................................................................................... 64 
8.5.1.1 
COVID Considerations .......................................................................................... 65 
8.5.2 
Analysis of the Primary Variable ........................................................................... 65 
8.5.3 
Analysis of the Secondary Variables ..................................................................... 65 
8.5.4 
Analysis of the Exploratory Variables ................................................................... 66 
8.5.5 
Subgroup analysis .................................................................................................. 66 
8.5.6 
Safety Analyses ...................................................................................................... 66 
8.5.7 
Interim analysis ...................................................................................................... 67 
9. 
STUDY AND DATA MANAGEMENT ............................................................... 67 
9.1 
Training of study site personnel ............................................................................. 67 
9.2 
Monitoring of the study .......................................................................................... 68 
9.2.1 
Source data ............................................................................................................. 68 
9.2.2 
Research Agreement(s) .......................................................................................... 68 
9.2.3 
Archiving of study documents ............................................................................... 68 
9.2.4 
Deviation from the clinical study protocol ............................................................ 68 
9.3 
Study Timetable and End of Study ........................................................................ 69 
9.4 
Data Management .................................................................................................. 69 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 70 
10.1 
Ethical Conduct of the Study ................................................................................. 70 
10.2 
Patient Data Protection ........................................................................................... 70 

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10.3 
Ethics and Regulatory Review ............................................................................... 70 
10.3.1 
Ethics Review ........................................................................................................ 70 
10.3.2 
Regulatory Review ................................................................................................. 70 
10.4 
Informed consent .................................................................................................... 70 
10.5 
Changes to the protocol and informed consent form ............................................. 71 
10.6 
Audits and inspections ........................................................................................... 71 
11. 
LIST OF REFERENCES ....................................................................................... 71 
 
LIST OF TABLES 
Table 1 
Study Plan and Schedule of Assessments ................................................. 34 
Table 2 
Laboratory Safety Variables – Basic Metabolic Panel ............................. 49 
 
LIST OF FIGURES 
Figure 6 - Study Flow Chart ................................................................................................... 24 
Figure 7 - PiccoloXpress Chemistry Analyzer ....................... Error! Bookmark not defined. 
Figure 8 - LINQ Insertable Cardiac Monitor .......................................................................... 43 
Figure 9 - Cardiac Monitoring Data Flow .............................................................................. 44 
Figure 10 – Patient Assistant .................................................................................................. 46 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information .................................................................. 73 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ................................................................................. 75 
Appendix C 
Pharmacogenetics Research ..................................................................... 76 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADMA 
asymmetric dimethylarginine   
AE 
adverse event 
AICD 
automatic implantable cardiac defibrillator 
ALB 
Albumin 
BUN 
Blood urea nitrogen 
BPM 
beats per minute 
Ca±± 
Calcium 
CKD 
chronic kidney disease 
Clˉ 
Chloride 
CSCA 
clinically significant cardiac arrhythmia 
CSR 
Clinical Study Report 
CRE 
Creatinine 
CTCAE 
Common Terminology Criteria for Adverse Event 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
DNA 
deoxyribonucleic acid  
DOPPS 
Dialysis Outcomes and Practice Patterns Study  
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
Electrocardiogram 
eCRF 
electronic case report form  
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EP 
Electrophysiologist 
ESRD 
end-stage renal disease  
FAS 
Full Analysis Set  
GCP 
Good Clinical Practice 
GLU 
Glucose 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 

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Abbreviation or 
special term 
Explanation 
ILR 
insertable loop recorder 
IP 
Investigational Product  
IS 
indoxyl sulfate 
IVRS 
Interactive Voice Response System 
IRT 
Interactive Response Technology 
K± 
Potassium 
LIDI 
long inter-dialytic interval  
LIMS 
Laboratory information management system 
LSLV 
Last Subject Last Visit 
LVH 
left ventricular hypertrophy 
MID 
Monitoring in Dialysis (clinical trial acronym) 
Mg++ 
Magnesium 
Na± 
Sodium 
NCI 
National Cancer Institute 
OAE 
other significant adverse event 
PBUT 
protein-bound uremic toxin 
PCR 
polymerase chain reaction 
PCS 
p-Cresol sulfate 
PHOS 
Phosphorus 
PI 
Principal Investigator  
POCT 
Point of Care Testing 
PWd 
P-wave duration  
RA 
Research Agreement 
RSI 
Reference Safety Information – reference information for the expectedness of a 
serious adverse reaction to the IP 
SAE 
serious adverse event  
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set  
SCD 
sudden cardiac death  
SQ 
Subcutaneous 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 

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1. 
INTRODUCTION 
1.1 
Background and Rationale for Conducting the Study 
Patients with end-stage renal disease (ESRD) have significantly higher mortality rates compared 
to non-dialysis populations. Recent data from the United States Renal Data System (USRDS) 
database finds that the annualized death rates for all ESRD patients is approximately 23.7% 
with cardiac disease accounting for 40% of that number. Further analysis demonstrates that 
while the majority of ESRD patients have well defined risk factors for coronary disease, the 
cause of death is not due to atherosclerotic disease or myocardial infarction, but rather due to 
cardiac arrhythmias and sudden death. Moreover, these deaths parallel the weekly cycle of 
dialysis with the highest proportion occurring after the prolonged “dialysis weekend”. This 
observation suggests that dialysis itself may directly contribute to the development of 
dysrhythmias presumably through the need to clear excess volume and electrolytes. The 
standard practice dialyzing patients with 2.0 mEq/L K+ dialysate has been shown to slow atrial 
conduction rates and contribute to patient mortality. To further define the clinical risk factors 
that contribute to dialysis-associated arrhythmias, a growing number of studies have used 
continuous loop electrocardiogram (ECG) recorders which are subcutaneously implanted 
devices that have the capability for prolonged recordings of cardiac rhythms. These studies find 
that atrial fibrillation is the most common form of post-dialysis arrhythmia which can be 
observed in over 40% of dialysis patients for up to 12 hours after dialysis (Roy-Chaudhury et 
al. 2018). We propose that the use of a 3.0 mEq/L K+ dialysate with the addition of Lokelma to 
control interdialytic hyperkalemia will reduce the rates of post-dialysis atrial fibrillation 
compared to dialysis with a standard 2.0 mEq/L K+ dialysate. 
1.1.1 
Background and Significance 
Atrial fibrillation is the most common cardiac arrhythmia affecting about 2% of those aged < 
65 years and more than 9% among those over the age of 65 years or older in the United States 
(Mozaffarian et al. 2016). When compared to the general population, atrial fibrillation is even 
more prevalent with upwards to 20% of ESRD patients having been evaluated or treated for 
atrial fibrillation (Soliman et al. 2010). The increased incidence of atrial fibrillation is not 
limited to ESRD patients but has also been reported in patients with pre-dialysis chronic kidney 
disease (CKD). In a review of 62,459 patients with estimated glomerular filtration rate (eGFR) 
between 15-59 mL/min, Airy et al demonstrated that atrial fibrillation was present in up to 23% 
of patients with an all-cause mortality rate of 45% (Airy et al. 2018). These observations have 
led to the speculation that the actual delivery of dialysis contributes to the development of atrial 
fibrillation and other cardiac arrhythmias. To determine whether the electrolyte composition of 
dialysate was associated with the onset of cardiac sudden death, Pun and Middleton et al 
retrospectively performed a case-controlled analysis of over 17,000,000 dialysis sessions from 
the DaVita/Gambro database and examined the effect of dialysate potassium on sudden death 
rates. As shown in Figure 1, the incident rate of sudden cardiac arrhythmia was approximately 
40% whether the patient was dialyzed with a low (<2.0 K+) or standard (>2.0 K+) dialysate. 
However, sudden death rates continued to climb up approximately 57% when the low K+ 
dialysate was consistently used. In contrast, sudden death rates were the lowest among those 
patients whose pre-dialysis K+ was 5.0. Even when the pre-dialysis K+ was at 3.5 mEq/L, the 

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sudden death rate using a standard dialysate bath was approximately half the rate observed with 
low K+ dialysates, while arrhythmia rates continued to climb with the low K+ bath (Pun et al. 
2011). 
 
 
 
 
 
 
 
 
Figure 1 - Effect of Dialysate Potassium on the Incidence of Sudden Cardiac Arrhythmia  
Source: Pun et al. 2011 
This important paper suggests that a K+ of 5.0 mEq/L may be optimal for preventing dialysis- 
associated arrhythmias. The observation that differences in dialysate K+ levels markedly 
affected arrhythmia rates suggested that dialysis itself could be contributing to the markedly 
elevated sudden death rates among ESRD patients. To examine this question, Roy-Chaudhury 
and Tumlin et al. conducted the Monitoring in Dialysis (MID) Study in which 66 patients 
receiving outpatient hemodialysis underwent placement of the Reveal XT or Reveal LINQ 
(Medtronic, Minneapolis, MN) insertable cardiac monitoring device. This device allows for 
continuous and long-term detection of both atrial and ventricular arrhythmias before and after 
a dialysis for periods of up to 30 days. In this purely observational trial, participating patients 
were maintained on their standard dialysis prescription and the incident rates of atrial 
fibrillation, bradycardia, ventricular tachycardia, and asystole were monitored for 6 months. 
The study used a vigorous definition for atrial fibrillation requiring a minimum of a 6-minute 
duration to be considered clinically significant. As shown in Figure 2, 42% of patients 
experienced a clinically significant atrial fibrillation event during the 6 months of study. In 
addition, the rates of atrial fibrillation paralleled the “dialysis week”, showing the highest rates 
during dialysis, but also showing significantly increased event rates for up to 12 hours after 
completion of a dialysis session. Moreover, when the investigators examined the difference in 
arrhythmia rates between patients being dialyzed with a 2.0 K+ dialysate versus a 3.0 K+ bath, 
there was a statistically lower rate of arrhythmias among patients dialyzed with the 3.0 K+ bath 
(P<0.0015) (Roy-Chaudhury et al. 2018).  
 

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Figure 2 – Incidence of Clinically Significant Atrial Fibrillation in the MID Study  
Source: Roy-Chaudhury et al. 2018 
In a similar study, Sacher et al used an implantable loop recorder to extend the observations of 
Roy-Chaudry and Tumlin and determine clinical outcomes of patients with dialysis-associated 
arrhythmias. The incidence of specific arrhythmias was similar with 20% patients developing 
de novo atrial fibrillation or flutter with a nearly identical number developing bradycardia. Of 
the patients with bradycardia, 3 progressed to asystole and sudden death. An analysis of serum 
electrolytes at the time of the arrhythmia demonstrated that hyperkalemia was associated with 
conduction disorders while hypokalemia was associated with ventricular arrhythmias and atrial 
fibrillation (Sacher et al. 2018). More recently, Ohnishi et.al conducted a cohort study of 3967 
participants in the Dialysis Outcomes and Practice Patterns Study in Japan (DOPPS-Japan) and 
examined the long-term effects of post-dialysis hypokalemia on all-cause mortality and the 
incidence of cardiac mortality due to sudden death. As a part of the original observational 
protocol, participating patients had post-dialysis serum potassium (K+) measured every 4 
months. Patients were then divided into quartiles based upon the average post dialysis K+.  As 
can be seen in Figure 3, patients with low post-dialysis K+ (< 3.0 mEq/L) had significantly 
reduced survival with a hazard mortality of 1.89 (Ohnishi et al. 2019). These observations 
underscore the sensitivity of ESRD patients to electrolyte induced cardiac arrhythmia.  
Moreover, it points to the need to and the need to identify a “K+ safety range” and to 
individualize dialysate baths to achieve optimal before, after and during dialysis. 
 

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Figure 3 - Cumulative Survival by Post-dialysis K Group in the DOPPS-Japan Study 
Low group: baseline post-dialysis K<3.0mEq/L; Medium-low group: baseline post-dialysis K³3.0 to 3.5mEq/L; 
Medium-high group: post-dialysis K³3.5 to 4.0 mEq/L; High group: post-dialysis K³4.0 mEq/L. 
Source: Ohnishi et al. 2019 
The mechanisms by which K+ changes during dialysis induce cardiac arrhythmias is unknown, 
but changes in P wave conductivity is a known risk factor for atrial fibrillation. Two recent 
studies that examined the effect of changes in post-dialysis K+ have shown that P-wave duration 
(PWd) increased following dialysis, indicating a slowing in intra-atrial conduction velocity (see 
Figure 4). Moreover, the greater the change in K+ following dialysis correlates with an increase 
in P-wave velocity during a dialysis (Severi et al. 2010; Krijthe et al. 2013).  
 
 
 
 
 
 
 
 
 
 
 
 
Figure 4 – (A) Haemodialysis-induced changes in P-wave duration. (B) Scatter plot and 
regression line showing the correlation between P-wave duration and serum K+ 
concentration changes during haemodialysis sessions.  
Source: Severi et al. 2010 
Historically the K+ concentration in a standard dialysate bath has been between 2.0 and 3.0 
mEq/L, with the majority of dialysis sessions conducted with the 2.0 K+ bath. Many of the 
studies high-lighted here have raised the question of whether the potassium concentration of the 

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“standard dialysate bath” should be re-assessed. The consistent and legitimate concern for such 
a change has been the development of hyperkalemia during the inter-dialytic period. The recent 
approval of novel and effective oral K+ binders such at sodium zirconium cyclosilicate 
(Lokelmaâ) have provided a possible solution to the problem of inter-dialytic hyperkalemia. A 
recent study of 196 stable hemodialysis patients demonstrated that regular use of Lokelma on 
“off-dialysis days” is able to lower serum K+ levels on interdialytic days. As shown in Figure 
5, Lokelma was able to “optimize” pre-dialysis values to approximately 5.0 mEq/L (Fishbane 
et al. 2019). It is unclear whether this same effect could be accomplished using a higher (3.0 
K+) dialysate. We propose using Lokelma as a vehicle to allow for wide-spread use of higher 
dialysate baths which the hope that this maneuver would translate into lower rates of cardiac 
arrhythmias. 
 
 
 
 
 
 
 
 
 
 
Figure 5 - Mean Pre- and Post-dialysis K+ values with SZC vs Placebo 
Abbreviations: K=potassium; SZC=sodium zirconium cyclosilicate (Lokelmaâ) 
Source: Fishbane et al. 2019 
1.2 
Rationale for Study Design, Doses, and Control Groups 
Chronic outpatient hemodialysis patients have high rates of rapid changes in potassium and 
other electrolytes critical to the generation cardiac arrythmias. A growing body of data suggests 
that intra-dialytic K+ levels fall to level of 2.0 or lower and are a potential major contributor to 
the generation of atrial fibrillation, bradycardia, and other clinically significant arrhythmias. We 
propose that raising the dialysate bath to 3.0 K+ from current standard of care levels of 2.0 K+ 
will reduce levels of hypokalemia-induced arrhythmias. We further propose that the use of 
sodium zirconium cyclosilicate (Lokelmaâ) will ensure that secondary hyperkalemia is 
controlled following the introduction of the 3.0 K+ dialysate bath. 
This is a prospective, open-labelled, cross-over design study of 88 patients with ESRD receiving 
routine outpatient dialysis using a standard 2.0K+/2.5 Ca++ dialysate bath. NephroNet and the 

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study design team have chosen to use an open labelled design for the ADAPT trial due to the 
difficulty in attempting to “blind” a patient’s dialysis solution. Moreover, due to  the critical 
consequences of improper delivery of K+ to ESRD patients, we considered it unethical to 
attempt a blinded study on safety grounds.  
Patients will be monitored for the development of atrial fibrillation or clinically significant 
cardia arrhythmias (CSCA) using an implantable cardiac loop recorder (LINQ device). After 2 
months of treatment, all enrolled patients will be “crossed-over” from either a 2.0 K+ to a 3.0 
K+ dialysate bath or from a 3.0 K+ to a 2.0 K+ dialysate bath.  
The study design also includes several measures aimed to minimize the risk of adverse 
experiences. Because patients with persistently high serum K+ after the long dialysis weekend 
are not likely to tolerate the move to a  higher K+ dialysate, the enrollment criteria include a 
requirement for two (2) separate pre-dialysis measurements of serum K+ < 6.5  mEq/L. A two-
week recovery period will allow patients to heal from cardiac loop recorder insertion before 
randomization. In addition, each two-month treatment period (both sequences) will be preceded 
by a two-week accommodation period, to allow the patient to adapt to the new dialysate bath. 
While receiving the higher K+ dialysate, patients will be treated on off-dialysis days (4 
days/week) with oral Lokelma, to reduce interdialytic hyperkalemia. Lokelma will be titrated 
to maintain serum K+ levels within a safe range, between 4.0 and 5.5 mEq/L. 
1.3 
Benefit/risk and ethical assessment 
End stage renal disease (ESRD) patients have significantly higher mortality rates compared to 
non-dialysis populations. Recent data from the USRDS database finds that the annualize death 
rates for all ESRD patients is approximately 23.7% with cardiac disease accounting for 40% of 
that number. Further analysis demonstrates that while the majority of ESRD patients have well 
defined risk factors for coronary disease, the cause of death is not due to atherosclerotic disease 
or myocardial infarction, but rather due to cardiac arrhythmias and sudden death. Current 
estimates indicate that up to 35% of deaths among chronic ESRD patients are due to sudden 
cardiac death (SCD). Any maneuvers to reduce dialysis-related arrythmias has the potential to 
significantly reduce the cardiovascular mortality among ESRD patients. 
Potential benefits of study participation include: 
1) 
Reduction in overall SCD rates 
2) 
Potential for reduction in atrial fibrillation sequelae, including but not limited to embolic 
stroke, myocardial infarction, ischemic bowel disease, and acute critical limb ischemia 
Potential risks associated with study participation include: 
1) Excessive study treatment-associated hypokalemia, with potential exacerbation of 
arrhythmia 
2) Risk for hypokalemia-associated muscle weakness, with risk for fall, etc. 
3) Risk for local chest wall infection from insertion of the cardiac loop recorder device.  
The discussion of risks and benefits to participating in the ADAPT trial and its goal of fine-
tuning dialysate electrolyte composition highlights both the pressing need and difficulty of 
electrolyte management among ESRD populations. Based on available data (as presented in 

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Section 1.1) and the risk mitigation strategies incorporated in the study design, the benefit-risk 
assessment favours the initiation of the ADAPT trial. 
1.4 
Study Design  
This is a prospective, open-labelled, randomized, 2x2 cross-over design study of 88 patients 
with end stage renal disease (ESRD) receiving routine out-patient dialysis using a standard 2.0 
potassium ion (K+)/2.5 calcium ion (Ca++) dialysate bath. The overall aim of the study is to 
determine whether converting stable hemodialysis patients from a “standard” 2.0 K+/2.5 Ca++ 
dialysate to a 3.0 K+/2.5 Ca++ mEq dialysate supplemented with the orally administered 
potassium binder sodium zirconium cyclosilicate (Lokelmaâ) to treat inter-dialytic 
hyperkalemia will reduce the incidence and duration of post-dialysis atrial fibrillation. 
Following the screening period’s two confirmatory pre-dialysis K+ measurements and after 
meeting study eligibility criteria, subjects will undergo placement of an implantable cardiac 
loop recorder (LINQ device) to monitor for the development of atrial fibrillation or any CSCA). 
After a two-week recovery period (to allow the patient to heal from the cardiac loop recorder 
placement), patients will be randomized (1:1 ratio) to one of two treatment sequences: 
• Sequence A: standard 2.0 K+/2.5 Ca++ dialysate with no Lokelma supplementation for 
two (2) months, followed by a cross-over to experimental 3.0 K+/2.5 Ca++ dialysate with 
Lokelma (on off-dialysis days) for two (2) months;  
Or 
• Sequence B: experimental 3.0 K+/2.5 Ca++ dialysate with Lokelma supplementation (on 
off-dialysis days) for two (2) months, followed by standard 2.0 K+/2.5 Ca++ dialysate 
with no Lokelma supplementation for two (2) months. 
Each two-month treatment period (both 2.0 K+/2.5 Ca++ dialysate and 3.0 K+/2.5 Ca++ 
dialysate with Lokelma sequences) will be preceded by a two-week run-in period, to 
allow the patient to adapt to the new dialysate bath.  
While receiving the higher K+ dialysate, patient will be treated on off-dialysis days (4 
days/week) with Lokelma, titrated to maintain serum K+ between 4.0 and 5.5 mEq/L. 
Throughout both treatment phases, patients will undergo continuous cardiac monitoring using 
the programmable Medtronic Reveal LINQ ICM device to detect the development of atrial 
fibrillation or CSCA (i.e., pre-defined event of bradycardia, ventricular tachycardia, or 
asystole). The incidence of atrial fibrillation and CSCA events occurring during the two 
treatments (experimental vs standard) will be compared. 
 
 

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Figure 6 - Study Flow Chart 
 
 

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2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
Primary Objective: Atrial Fibrillation Rates 
Primary Outcome Measure: 
To 
demonstrate 
whether 
increasing 
the 
K+ 
concentration in a standard hemodialysis bath from 
2.0 K+/2.5 Ca++ to a 3.0 K+/2.5 Ca++ composition with 
SZC will reduce the incidence of atrial fibrillation 
events. [1]  
 
Ø Frequency of atrial fibrillation events [1] 
occurring during the 8-week Treatment 
Phase-1 and the 8-week Treatment Phase-2 
dialysate cross-over periods. 
 
 
Abbreviations: CSCA=clinically significant cardiac arrhythmia 
[1] Atrial fibrillation will be defined as irregular heart rhythms and irregular R-R intervals in the absence of 
definable P waves for a minimum of 6 minutes. Each atrial fibrillation event will be adjudicated and validated as a 
true atrial fibrillation event by a central cardiologist who is blinded to dialysate K+ content. 
[2] Experimental treatment (8 weeks): hemodialysis using 3.0K+/2.5 Ca++ dialysate bath, with sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation on off-treatment days 
[3] Standard treatment (8 weeks): hemodialysis using 2.0K+/2.5 Ca++ dialysate bath, without sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation 
2.2 
Secondary Objectives 
Secondary Efficacy Objective #1: Clinically 
Significant Cardiac Arrhythmia Rates 
Secondary Outcome Measure: 
To determine whether the incidence and duration of 
post-dialysis CSCAs (defined as bradycardia, 
ventricular tachycardia and/or asystole [1]) observed 
during experimental treatment [2] will be reduced 
compared to standard treatment. [3] 
 
Ø Frequency 
of 
CSCAs 
(bradycardia, 
ventricular tachycardia and/or asystole) [1] 
occurring during the 8-week Treatment 
Phase-1 and the 8-week Treatment Phase-2 
dialysate cross-over periods. 
Ø Total duration of CSCAs (bradycardia, 
ventricular tachycardia and/or asystole) [1] 
occurring during the 8-week Treatment 
Phase-1 and the 8-week Treatment Phase-2 
dialysate cross-over periods. 
Secondary Efficacy Objective #2: Events Outside 
the Optimal K+ “Window” 
Secondary Outcome Measure: 
To determine whether the addition of oral sodium 
zirconium cyclosilicate (Lokelmaâ) during the 2-
month treatment phase with the 3.0 K+/2.5 Ca++ 
dialysate bath will reduce risk of weeks outside the 
“K+ safety range” of 4.0 to 5.5 mEq/L compared to 
the 2-month treatment phase with the 2.0 K+/2.5 Ca++ 
dialysate bath.  
 
Ø Whether or not K+ outside of the 4.0 to 5.5 
mEq/L 
safety 
range 
(Yes/No 
binary 
outcome measure). 
The risk of weekly events of pre- dialysis 
K+ or the risk of post-dialysis K+ falling 
outside the “K+ safety range” will be  
compared between the two dialysate 
groups. 

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Abbreviations: CSCA=clinically significant cardiac arrhythmia 
[1] CSCA events are defined as follows: 
§ 
Bradycardia: Heart rate of £ 40 beats per minute (BPM) for a minimum duration of 6 seconds. 
§ 
Ventricular Tachycardia: Regular tachy-arrhythmia of ³ 130 BPM for a minimum duration of 30 seconds  
§ 
Asystole: Absence of detectable ventricular conduction for a minimum of 3 seconds 
[2] Experimental treatment (8 weeks): hemodialysis using 3.0K+/2.5 Ca++ dialysate bath, with sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation on off-treatment days 
[3] Standard treatment (8 weeks): hemodialysis using 2.0K+/2.5 Ca++ dialysate bath, without sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation  
2.3 
Safety Objectives 
Safety Objective #1: Lokelma-Induced 
Hypokalemia 
Safety Outcome Measure: 
To evaluate whether the use of oral sodium zirconium 
cyclosilicate (Lokelmaâ) during periods when 
patients are  receiving a 3.0 K+/2.5 Ca++ dialysate bath 
is associated with hypokalemic events defined as K+ 
<3.5 mEq/L. 
Ø Total number of hypokalemic events defined 
as Piccolo POCT or laboratory-measured K+ 
of < 3.5 mEq/L. 
Safety Objective #2: Incidence of Dialysis-related 
Hypokalemia, Hypomagnesemia, 
Hypophosphatemia, or  Low Calcium 
Safety Outcome Measure: 
To determine the levels of K+, Mg++, calcium and PO4 
during dialysis (measured promptly prior to the 
termination 
of 
dialysis) 
during 
experimental 
treatment [2] compared to standard treatment [3]. 
Note: Each electrolyte is its own ”safety” objective 
independently. 
Ø Number of events (measured promptly prior 
to the termination of dialysis) where a 
Piccolo POCT measurement of K+ is  < 3.5 
mEq/L OR Ca++ is < 7.0 mEq/L, OR Mg++ is 
< 2.0 mg/dl, OR a PO4 level is <3.0 mEq/L.  
All episodes where a specific electrolyte 
falls below the above listed threshold will be 
considered an “event” for that electrolyte. 
The total number of “events” will be 
recorded during the 8-week Treatment 
Phase-1 and the 8-week Treatment Phase-2 
cross-over periods. 
Safety Objective #3:  Adverse Experiences 
Safety Outcome Measure: 
To evaluate the safety and tolerability of the 
experimental treatment [2] compared to standard 
treatment [3] based on the frequency of reported 
adverse experiences. 
Ø Frequencies of AEs, SAEs, and withdrawals 
due to AEs, with focus on treatment-related 
events. 
Abbreviations: AE=adverse event; CSCA=clinically significant cardiac arrhythmia; SAE=serious adverse event 
[2] Experimental treatment (8 weeks): hemodialysis using 3.0K+/2.5 Ca++ dialysate bath, with sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation on off-treatment days 
[3] Standard treatment (8 weeks): hemodialysis using 2.0K+/2.5 Ca++ dialysate bath, without sodium zirconium 
cyclosilicate (Lokelmaâ) supplementation 
 

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2.4 
Exploratory Objectives   
Exploratory Objectives: 
Outcome Measures: 
1) To evaluate the relationship between protein-
bound uremic toxins (PBUTs) and atrial 
fibrillation rates.  
PBUTs such indoxyl sulfate (IS) and p-Cresol 
sulfate (PCS) can induce atrial fibrillation (Aoki 
et al. 2015; Tang et al. 2015). 
Ø Correlation between PBUTs (IS, PCS, and 
ADMA) and the frequency of atrial fibrillation 
events. 
2) To determine whether the levels of K+, Mg++, 
calcium and PO4 (measured promptly prior to 
the termination of dialysis) correlate with the 
incidence 
of 
clinical 
events, 
including 
intradialytic hypotension, muscle cramping, 
and cardiac events (defined as atrial fibrillation, 
bradycardia, 
ventricular 
tachycardia, 
and 
asystole). We will also evaluate whether the 3.0 
K+ dialysate reduces the rates of these clinical 
events.   
Ø Correlation between electrolyte levels and clinical 
events 
(intradialytic 
hypotension, 
muscle 
cramping, and cardiac events). 
Ø Correlation between electrolytes falling below 
threshold levels (Ca++ < 7.0 mEq/L, PO4 levels 
<3.0 mEq/L, Mg++< 2.0 mg/dl, and K+ of < 3.5 
mEq/L) and cardiac events (defined as atrial 
fibrillation, bradycardia, ventricular tachycardia, 
and asystole). 
Abbreviations: ADMA=asymmetric dimethylarginine; IS=indoxyl sulfate; PBUT=protein-bound uremic toxin; 
PCS= p-Cresol sulfate 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
All study participants will be recruited from specialist (nephrology) care clinics.  
Each subject must meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion Criteria 
For inclusion in the study subjects should fulfil the following criteria based on local regulations: 
1. 
Provision of informed consent prior to any study-specific procedures  
2. 
Female or male aged above 18 years 
3. 
Patients with ESRD receiving hemodialysis three times per week for a minimum of 
3 months 
4. 
Patients must have two (2) pre-dialysis K+ measurements between 5.1 and 6.5 mEq/L 
by Piccolo POCT following the long dialytic “weekends” (i.e., on two consecutive 
Mondays for patients on a Monday-Wednesday-Friday dialysis schedule or on two 
consecutive Tuesdays for patients on a Tuesday-Thursday-Saturday dialysis 
schedule) during screening, before insertion of the cardiac loop recorder. 
5. 
Female participants must be 1 year post-menopausal, surgically sterile, or using one 
highly effective form of birth control (defined as one that can achieve a failure rate 

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of less than 1% per year when used consistently and correctly.) They should have 
been stable on their chosen method of birth control for a minimum of 1 month before 
entering the study and willing to remain on the birth control until 4 weeks after the 
last dose. 
3.2 
Exclusion Criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
Exclusion Criteria Related to the Underlying Condition: 
1. 
Patients with a QTc(f) > 550 msec and/or Congenital long QT syndrome 
2. 
Patients with a Haemoglobin < 9 g/dl. 
3. 
Patients with any medical condition, including active, clinically significant infection 
or liver disease, that in the opinion of the investigator or Sponsor may pose a safety 
risk to a subject in this study, which may confound safety or efficacy assessment and 
jeopardize the quality of the data, or may interfere with study participation. 
4. 
Patient receiving peritoneal or home hemodialysis 
5. 
Patient receiving hemodialysis via a tunneled inferior vena cava (IVC) catheter and 
known central stenosis of access extremity 
6. 
Patient receiving outpatient hemodialysis for < 3 months 
7. 
Patient receiving outpatient hemodialysis for prolonged Acute Kidney Injury (AKI) 
and considered by the site Principal Investigator (PI) likely to achieve renal recovery 
within 6 months 
Note: Patients receiving out-patient hemodialysis for AKI for longer than 6 months 
with no demonstrable renal clearance can be screened for study participation. 
8. 
Patient currently receiving a 1.0 K+, 3.0 K+ dialysate bath and unwilling to convert to 
a 2.0 K+/2.5 Ca++ dialysate bath 
9. 
Subject unwilling to convert from a 2.0 K+ dialysate bath to a 3.0 K+ dialysate bath 
10. 
Two or more pre-dialysis K+ of < 5.1 or > 6.5 mEq/L measured by Piccolo POCT 
after the long dialytic “weekends” during screening 
Note: If one of the two screening pre-dialysis K+ levels is between 4.6 to 5.0 mEq/L 
or 6.6 to 7.0 mEq/L, the patient can undergo an additional whole blood Piccolo POCT 
K+ measurement. Patients who fail the third whole blood Piccolo POCT K+ 
measurement will be considered ineligible for study participation. Note: Screen 
failures can be re-screened once to confirm eligibility in the study. 
11. 
Any documented whole blood Piccolo POCT K+ measurement that falls below 4.6 
mEq/L or exceeds 7.0 mEq/l during the screening period 
12. 
Current use of a medication for treatment of hyperkalemia (e.g., Patiromer).  

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Note: If a medication for treatment of hyperkalemia is stopped prior to or after the 
consenting process, the subject will undergo a one week washout prior to the first 
whole blood Piccolo POCT K+ measurement. 
Exclusion Criteria Related to Other Medical Conditions and Treatments: 
13. 
Anticipated life expectancy of <6 months, as assessed by the site PI 
14. 
Chronic atrial fibrillation, defined as sustained atrial fibrillation of >3 months 
duration 
15. 
Development of atrial fibrillation requiring hospitalization, medical therapy, 
anticoagulation, or cardioversion during study pre-screening or screening period 
16. 
Patient with a known placement of a dual or single chamber pacemaker 
17. 
Patient with an automatic implantable cardiac defibrillator (AICD) 
18. 
Patient with a LINQ implanted cardiac loop recorder with less than 6 months of 
battery life. 
19. 
Current use of amiodarone or other anti-arrhythmic therapy.  
Note: Patients on such medications must undergo a two week washout prior to the 
first whole blood Piccolo POCT K+ measurement. 
20. 
Known history of cardiac arrhythmias due to prolonged QT syndrome  
21. 
Subject unwilling to receive an implanted LINQ cardiac loop recorder (unless 6 
months are remaining in their previously implanted device). 
22. 
Known active drug abuse 
23. 
Positive hepatitis C polymerase chain reaction (PCR) test with active viral 
deoxyribonucleic acid (DNA) shedding or chronic active hepatitis B as evidenced by 
detectable surface antigen from standard of care routine dialysis labs. 
Note: Patients with negative PCR DNA testing for either hepatitis B or C will be 
allowed to participate in the study. 
24. 
Known to have tested positive for human immunodeficiency virus (HIV) from 
standard of care routine dialysis labs. 
25. 
For women only: currently pregnant (confirmed with positive pregnancy test) or 
breastfeeding. 
26. 
Patients with known and/or active severe constipation, bowel obstruction or 
impaction, including abnormal post-operative bowel motility disorders or diabetic 
gastroparesis 
Exclusion Criteria Related to the Investigational Product (IP): 
27. 
Known hypersensitivity to sodium zirconium cyclosilicate (Lokelmaâ). 
Other/General Exclusion Criteria: 

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28. 
Previous randomization in the present study. Note: Screen failures can be re-screened 
once to confirm eligibility in the study. 
29. 
Participation in another interventional (non-observational) clinical study within 4 
weeks prior to enrollment in the present study 
Procedures for withdrawal of incorrectly enrolled subjects are provided in Section 3.4. 
3.3 
Subject Enrollment and Randomization 
Study participants will be recruited from each site’s current and actively managed dialysis 
population. ESRD patients on a three times weekly hemodialysis regimen will be identified 
through regular monthly rounding visits by the site PI / Delegated Staff and through interactions 
with the dialysis unit nursing staff. Patients with a known history of dialysis-associated atrial 
fibrillation will be sought out for participation in the study. Site PIs will attempt to enroll at 
least 25% of their patients with a known history of post-dialysis intermittent (but not chronic) 
atrial fibrillation. Prospective patients will be approached by the site PI or designated clinical 
research staff to obtain written informed consent before any study-specific screening procedures 
commence. A log of all patients who entered pre-study screening will be maintained by the site 
research team. 
Patients who meet all inclusion and none of the exclusion criteria will be randomized in a 1:1 
ratio to one of two treatment sequences, consistent with a two-period cross-over design. Central 
randomization via an interactive response technology (IRT) will be utilized; refer to Section 3.5 
for details. Randomization codes will be assigned strictly sequentially as patients become 
eligible for randomization.  
A total of 88 patients are planned to be randomized, accounting for an anticipated 10% drop-
out rate. Patients who discontinue or are withdrawn from the study post-randomization WILL 
NOT be  replaced (i.e., their randomization code cannot be reused). 
3.4 
Procedures for Handling Incorrectly Enrolled or Randomized 
Subjects 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be enrolled 
or receive study medication.  There can be no exceptions to this rule. Patients who are enrolled, 
but subsequently found not to meet all the eligibility criteria must not be randomized or initiated 
on treatment and must be withdrawn from the study. 
Where a subject does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the PI should inform the Sponsor immediately, and a discussion should 
occur between the Sponsor and the PI regarding whether to continue or discontinue the patient 
from treatment.  The Sponsor must ensure all decisions are appropriately documented. 
3.5 
Methods for Assigning Treatment Groups 
The study sponsor (NephroNet) will be responsible for preparing the randomization scheme. 
Permuted block randomization using 2x2 Latin Squares will be applied to ensure a balanced 
assignment (1:1 ratio) to the two treatment sequences in the study.  

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Patients who meet all inclusion and none of the exclusion criteria will be randomized to one of 
two treatment sequences, consistent with a two-period cross-over design: 
• Sequence A: standard 2.0 K+/2.5 Ca++ dialysate with no Lokelma supplementation for 
two (2) months, followed by a cross-over to experimental 3.0 K+/2.5 Ca++ dialysate with 
Lokelma supplementation (on off-dialysis days) for two (2) months;  
Or 
• Sequence B: experimental 3.0 K+/2.5 Ca++ dialysate with Lokelma supplementation (on 
off-dialysis days) for two (2) months, followed by standard 2.0 K+/2.5 Ca++ dialysate 
with no Lokelma supplementation for two (2) months. 
Central randomization via an interactive response technology (IRT) will be utilized. 
Randomization codes will be assigned strictly sequentially as patients become eligible for 
randomization. Randomization will occur by the site PI (or qualified designee) contacting the 
IRT and obtaining the randomization code and associated treatment sequence for each eligible 
patient. The original randomization notification will be filed as part of the source documents. 
Sites are expected to randomize approximately nine (9) patients on average (no minimum or 
maximum number of enrolled patients will be specified). 
3.6 
Methods for ensuring blinding 
Not applicable; this is an open label study. 
3.7 
Methods for unblinding  
Not applicable; this is an open label study. 
3.8 
Restrictions 
Apart from the limitations described in the exclusion criteria (see Section 3.2), there will be no 
restrictions affecting patients’ daily life activities associated with participation in the study. 
3.9 
Discontinuation of Investigational Product 
Patients may be discontinued from investigational product (IP) in the following situations: 
• Patient decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment; 
• Incorrectly randomized participant where violation of the inclusion/exclusion criteria would 
put the participant at undue risk; 
• Adverse event for which the investigator judges continued treatment may put the participant 
at undue risk; 
• Pregnancy; 
• Development of any of the following study-specific criteria for discontinuation: 
o Permanent atrial fibrillation, as determined by echocardiogram or cardiology 
assessment; 

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o Requiring for permanent placement of a cardiac pacemaker or AICD; 
o Refractory hyperkalemia (K+ > 6.5 mEq/L) while on 15 grams 4 days per week of 
Lokelma; 
o Hypokalemic event (defined as pre-dialysis K+ level of < 3.5 mEq/L): Patients 
experiencing a minimum of two (2) hypokalemic events while taking Lokelma will 
have their Lokelma adjusted or discontinued at the discretion of the site PI; 
o Renal transplant. 
• Severe non-compliance with the study protocol. 
Note: patients wishing to remain in the study on treatment despite developing an adverse event 
may do so at the site PI’s discretion, unless they remain hyperkalemic with K+ > 6.5 mEq/L 
after a long inter-dialytic interval (LIDI) for two (2) consecutive weeks. 
Regardless of the reason for discontinuation, all reasons for discontinuation of study treatment 
must be documented in the electronic case report form (eCRF). 
If the patient is discontinued from investigational product, the scheduled study visits, data 
collection and procedures should continue according to the study protocol until study 
completion, unless the patient withdraws consent for any further study procedures and follow-
up. The approach taken should be documented in the eCRF. 
3.9.1 
Procedures for Discontinuation of a Patient from Investigational Product  
At any time, patients are free to discontinue investigational product or withdraw from the study 
(i.e., investigational product and assessments – see Section 3.10), without prejudice to further 
treatment.  Patients deciding to discontinue the investigational product will be asked to: (i) 
provide the reason(s) for discontinuation, including the development of any adverse event(s) 
contributing to their decision; (ii) return to the clinic for the remaining study visit(s) and 
assessment(s); and (iii) return all unused study drug to the site. Adverse events will be followed 
up, as described in Section 6. 
The investigational product (Lokelma) can be discontinued abruptly (without the need for 
gradual treatment stepdown or tapering). Patients may be allowed to re-start the investigational 
product at the discretion of the site PI. 
Patient withdrawal from study is described in Section 3.10. 
3.10 
Criteria for Withdrawal  
Patients can decide to be discontinued from both investigational product and further study 
procedures/visits at any time (withdrawal of consent). 
3.10.1 
Screen failures  
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized. These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrollment’ (i.e., patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (not randomized 
patients). 

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3.10.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE. Regardless of the reason for withdrawal, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  
If a patient withdraws from participation in the study, his/her randomization code cannot be 
reused. Withdrawn randomized patients will not be replaced.  
Patients who withdraw consent prior to completion of the study, will have the option to either 
keep the ILR device implanted or have their ILR device removed by the affiliated 
electrophysiology cardiologist.   
3.11 
Discontinuation of the study 
The study may be stopped if, in the judgment of the Sponsor, trial participants are placed at 
undue risk because of clinically significant findings that: 
• meet individual stopping criteria or are otherwise considered significant  
• are assessed as causally related to study drug  
• are not considered to be consistent with continuation of the study. 
• Unscheduled ECG will be performed if a patient develops a suspected arrhythmia since 
date from the loop recorded will not be evaluated simultaneously. ECG will also be 
measured if S-K < 3.0. If an absolute QTc >550ms, or an increase in QTc interval > 60ms 
from baseline to more than 500ms is reached the subject will immediately receive 
appropriate medical intervention and be discontinued from the study drug treatment. The 
QTcF algorithm (QT interval corrected by the Fridericia method) is recommended. All 
patients meeting the QTc>500ms criterion will immediately have potassium assessed, if 
not already done within 1 hour of performing the ECG. 
Regardless of the reason for termination, all participant data available at the time of study 
stopping must be recorded in the eCRF. For patients still in the study at the time of study 
discontinuation, the reasons for discontinuation should be documented as “Study termination 
by the Sponsor”. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.  
4. 
STUDY PLAN AND TIMING OF PROCEDURES  
The Study Plan and schedule of assessments is provided in Table 1. 
Details of study assessments completed during the Screening, Treatment, and Follow-up periods 
are included in sections 4.1, 4.2, and 4.3.

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Table 1 
Study Plan and Schedule of Assessments 
Study Period / 
Visit 
Screening 
ILR 
Insertion by 
EP 
cardiologist 
Baseline/ 
Randomization 
New 
Dialysate 
Accommo-
dation 
Period 1 
Treatment 
Phase 1 
Cross-
over 
New 
Dialysate 
Accommo-
dation 
Period 2 
Treatment 
Phase 2 
ILR Removal 
by EP 
cardiologist 
End of Study 
Reference 
to 
Protocol 
Section 
Study Week (Wk) 
[*  , ** or  ***] 
-4 to -3** 
-2* 
1** 
1 & 2** 
3 to 10** 
11** 
11 & 12** 
13 to20** 
21-22* 
22-23*** 
Study Day (D) 
 
-28 to -15 
 
-14 
1 
1 to 14 
15 to 70 
71 
71 to 84 
85 to 140 
Between 
D141 and 
D155 
Within 1 to 
14 days 
after ILR 
Removal 
Day of the week 
 
 
M/T 
M/T 
M/T 
M/T 
M/T 
M/T 
 
 
 
Written informed 
consent  
X 
 
 
 
 
 
 
 
 
 
4.1.1 
Assignment of 
unique Screening 
Number 
X 
 
 
 
 
 
 
 
 
 
4.1.2 
Demographics  
X 
 
 
 
 
 
 
 
 
 
4.1.3 
Medical/surgical & 
Medication history 
X 
 
 
 
 
 
 
 
 
 
4.1.4 
Physical 
examination  
X 
 
 
 
 
 
 
 
 
 
4.1.5 
Vital signs and 
weight 
measurements  
X 
 
 
X 
X 
 
X 
X 
 
X 
4.1.6 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
5.2.3.1 
 K+ Piccolo POCT 
(pre-dialysis) [1] 
X 
 
 
X 
X 
 
X 
X 
 
 
4.1.7 
4.2.1 

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Table 1 
Study Plan and Schedule of Assessments 
Study Period / 
Visit 
Screening 
ILR 
Insertion by 
EP 
cardiologist 
Baseline/ 
Randomization 
New 
Dialysate 
Accommo-
dation 
Period 1 
Treatment 
Phase 1 
Cross-
over 
New 
Dialysate 
Accommo-
dation 
Period 2 
Treatment 
Phase 2 
ILR Removal 
by EP 
cardiologist 
End of Study 
Reference 
to 
Protocol 
Section 
Study Week (Wk) 
[*  , ** or  ***] 
-4 to -3** 
-2* 
1** 
1 & 2** 
3 to 10** 
11** 
11 & 12** 
13 to20** 
21-22* 
22-23*** 
Study Day (D) 
 
-28 to -15 
 
-14 
1 
1 to 14 
15 to 70 
71 
71 to 84 
85 to 140 
Between 
D141 and 
D155 
Within 1 to 
14 days 
after ILR 
Removal 
Inclusion/exclusion 
criteria 
X 
 
X 
 
 
 
 
 
 
 
3.1, 3.2 
Day of the Week 
 
 
M/T 
M/T 
M/T 
M/T 
M/T 
M/T 
 
 
 
ILR insertion [7] 
 
X 
 
 
 
 
 
 
 
 
4.1.9 
Randomization to 
one of two 
treatment 
sequences [6] 
 
 
X 
 
 
 
 
 
 
 
3.5 
Study drug 
dispensed/ 
returned on 3.0 
K+/2.5 Ca++ 
dialysate group 
 
 
 
X 
X 
 
X 
X 
 
 
7.2.2 
Cardiac Data Loop 
Recordings  
 
 
 
 
X 
 
 
X 
 
 
4.2.2 
K+, Ca++ and  
PO4 Piccolo POCT 
promptly before 
dialysis end) [2]  
 
 
 
X 
X 
 
X 
X 
 
 
4.2.1 

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Table 1 
Study Plan and Schedule of Assessments 
Study Period / 
Visit 
Screening 
ILR 
Insertion by 
EP 
cardiologist 
Baseline/ 
Randomization 
New 
Dialysate 
Accommo-
dation 
Period 1 
Treatment 
Phase 1 
Cross-
over 
New 
Dialysate 
Accommo-
dation 
Period 2 
Treatment 
Phase 2 
ILR Removal 
by EP 
cardiologist 
End of Study 
Reference 
to 
Protocol 
Section 
Study Week (Wk) 
[*  , ** or  ***] 
-4 to -3** 
-2* 
1** 
1 & 2** 
3 to 10** 
11** 
11 & 12** 
13 to20** 
21-22* 
22-23*** 
Study Day (D) 
 
-28 to -15 
 
-14 
1 
1 to 14 
15 to 70 
71 
71 to 84 
85 to 140 
Between 
D141 and 
D155 
Within 1 to 
14 days 
after ILR 
Removal 
Blood samples for 
PBUTs [3]  
 
 
 
 
X 
 
 
 
 
 
4.2.1 
Day of the Week 
 
 
M/T 
M/T 
M/T 
M/T 
M/T 
M/T 
 
 
 
Local laboratory 
Mg++ promptly 
before dialysis 
end) [4] 
   
 
 
X 
X 
 
X 
X 
 
 
4.2.1 
Adverse event 
recording & review 
[8]  
 
 
 
X 
X 
X 
X 
X 
X 
X 
6.4 
Serious Adverse 
event recording & 
review [9] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6.4 
Concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5.2.5, 7.7 
Local laboratory 
Mg++ promptly 
before dialysis 
end) for muscle 
cramping [5] 
   
 
 
X 
X 
 
X 
X 
 
 
4.2.1 

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Table 1 
Study Plan and Schedule of Assessments 
Study Period / 
Visit 
Screening 
ILR 
Insertion by 
EP 
cardiologist 
Baseline/ 
Randomization 
New 
Dialysate 
Accommo-
dation 
Period 1 
Treatment 
Phase 1 
Cross-
over 
New 
Dialysate 
Accommo-
dation 
Period 2 
Treatment 
Phase 2 
ILR Removal 
by EP 
cardiologist 
End of Study 
Reference 
to 
Protocol 
Section 
Study Week (Wk) 
[*  , ** or  ***] 
-4 to -3** 
-2* 
1** 
1 & 2** 
3 to 10** 
11** 
11 & 12** 
13 to20** 
21-22* 
22-23*** 
Study Day (D) 
 
-28 to -15 
 
-14 
1 
1 to 14 
15 to 70 
71 
71 to 84 
85 to 140 
Between 
D141 and 
D155 
Within 1 to 
14 days 
after ILR 
Removal 
Pregnancy Test 
for Females of 
Childbearing 
Potential 
X 
 
 
 
 
 
 
 
 
 
4.1.4. 
5.2.6 
 
Abbreviations: AE=adverse event; Ca=calcium; ECG=electrocardiogram; EP=electrophysiologist; ILR=insertable loop recorder; K=potassium; 
Mg++=magnesium; PBUTs=protein-bound uremic toxins [including p-Cresol sulfate [PCS], indoxyl sulfate, and asymmetric dimethylarginine [ADMA]); 
SAE=serious adverse event  
 
*Performed on any day. (Note: ILR placement needs to be one week prior to baseline, which starts on Mondays or Tuesdays after each long dialysis 
weekend.) 
 
**Performed weekly, on Mondays or Tuesdays after each long dialysis weekend. (Note: Screening ICF can be obtained on any dialysis day, but all other 
procedures need to be performed on Monday or Tuesdays after the long dialysis weekend. Additionally, consenting may be conducted several weeks prior to 
other study procedures depending on the need for a prohibited medication washout or whether the consenting process occurred on a day other than the 
Monday or Tuesday after the long dialysis weekend.) 
 
***Performed on any dialysis day 
 
 

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[1] K+ Piccolo POCT (utilizing full renal panel) are performed pre-dialysis, on a Monday or Tuesday after the long dialysis weekend, twice during the 
Screening period, and weekly during the treatment period (both 2-week accommodation periods and 8-week Treatment phases).  Note: K+ Piccolo POCT may 
be performed several weeks after consenting depending on the need for a prohibited medication washout or whether the consenting process occurred on a day 
other than the Monday or Tuesday after the long dialysis weekend. 
 
[2] During the treatment period (both 2-week accommodation periods and 8-week Treatment phases), a second Piccolo POCT is performed promptly before 
dialysis end and within 30 minutes prior to rinse back on Mondays or Tuesdays after each long dialysis weekend (i.e., weekly), to measure  K+ ,Ca++and PO4. 
 
[3] Applies only to the first twenty-five (25) patients randomized receiving standard treatment (hemodialysis using 2.0K+/2.5 Ca++ dialysate bath, without 
Lokelma supplementation) during Treatment Phase-1. Performed weekly, on Mondays or Tuesdays after each long dialysis weekend, promptly before dialysis 
end and within 30 minutes prior to rinse back. 
 
[4] Performed weekly, on Mondays or Tuesdays after each long dialysis weekend, promptly before dialysis end and within 30 minutes prior to rinse back. 
Mg++ levels will be determined by the local laboratory at each site.  
 
[5] Performed (if possible) upon symptomatic muscle cramping, promptly before dialysis end and within 30 minutes prior to rinse back. Mg++ levels will be 
determined by the local laboratory at each site. 
 
[6] Baseline/Randomization is conducted on Week 1 of the new Dialysate Accommodation Period 1. Crossover occurs on the same day as Week 11 of the 
new Dialysate Accommodate Period 2. Neither Baseline/Randomization nor Crossover will be considered a separate visit. 
 
[7] If ILR insertion is performed more than 30 days after the last K+ Piccolo POCT determination, please contact the sponsor who will determine if an 
additional K+ Piccolo POCT determination will be required prior to the baseline visit.  These will be handled on a case-by-case basis. 
 
[8] Adverse events will be collected from the time of first dose of Lokelmaâ, throughout the treatment and post-treatment follow-up period, up to the last study 
visit.  
 
[9] SAEs will be reported from the time the patient signed the Informed Consent Form. 

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4.1 
Screening Period 
The process for identifying prospective study patients (pre-screening) is described in Section 
3.3.  
Screening assessments will be carried out according to the schedule provided in Table 1. The 
following section details the screening activities, starting with the consent process. During 
screening, consenting patients will be assessed to ensure that they meet all eligibility criteria. 
Patients who do not meet these criteria must not be randomized in the study. 
4.1.1 
Obtaining Written Informed Consent 
Potential patients expressing a willingness to participate in the study will be interviewed by the 
Site PI or their qualified designee, and the study objectives, benefits and risks of participation, 
and study requirements will be thoroughly reviewed with the patient. The patient will be given 
a copy of the consent form to review, and adequate time will be provided to ask questions, 
discuss with family members, and decide about study participation. If the patient wishes to 
participate in the study, he/she will be required to provide written informed consent prior to any 
study-specific procedures commence. A copy of the signed consent form will be given to the 
patient and the original will be kept in the patient file with the source documents. 
Note: Consenting may be conducted several weeks prior to other study procedures depending 
on the need for a prohibited medication washout or whether the consenting process occurred on 
a day other than the Monday or Tuesday after the long dialysis weekend. 
4.1.2 
Assignment of Unique Patient Enrollment Number 
Consenting patients will be assigned a unique Patient Enrollment Number comprised by a 2-
digit site number, and a sequentially assigned 3-digit number starting with 001. For example, at 
site 01, the first enrolled patient will be assigned 01-001, the second patient 01-002, etc. If the 
second patient does not meet all the inclusion/exclusion criteria (e.g., the patient fails to meet 
the required K+ ranges), his/her Patient Enrollment Number will not be replaced, and the 3rd 
consenting patient will be assigned 01-003.  
Upon randomization, the patients will be assigned a sequential subject number of 01 through 
88. 
4.1.3 
Recording of Demographic Data 
Demographic data (date of birth, sex, self-reported race, and ethnicity) will be recorded at 
screening.  
4.1.4 
Review of Medical/Surgical, Laboratory, and Medication History 
Patient medical records and prior dialysis flow sheets will be reviewed to determine whether 
the patient meets all inclusion and none of the exclusion criteria. The review will include, but 
will not be limited to the following: 
1) Routine "standard of care" laboratory data for the 2 months prior to giving written 
informed consent.   

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2) Routine "standard of care" determinations of the ratio of urea clearance (K) multiplied 
by dialysis time (t) to the volume of water in the body (Kt/V) for the 2 months prior to 
giving written informed consent.   
3) Routine dialysis parameters, such as blood flow (Qb), dialysate flow (Qd), amount of 
fluid ultra-filtrated during dialysis (Delta UF) and post-dialysis exit weight for each of 
the 2 months prior to giving written informed consent.   
4) Evidence of past history of intermittent atrial fibrillation (patients with > 3 months of 
continuous atrial fibrillation will be considered ineligible for study participation).  
5) History of repeated muscle cramping (patients with such history will be identified and 
approached for study participation). 
6) Past echocardiograms, if available, completed within 6 months prior to giving written 
informed consent. If there is echocardiographic data available, the following will be 
recorded for assessing and adjudicating atrial fibrillation events and any clinically 
significant cardiac arrhythmias, as available: 
a) Left ventricular ejection fraction (LVEF) 
b) Presence of distinct wall motion defects 
c) Estimated left end-diastolic pressure 
d) Distinct valvular abnormalities 
e) E/A (ratio of peak velocity blood flow from left ventricular relaxation in 
early diastole [E wave] to peak velocity flow in late diastole caused by atrial 
contraction [A wave]) and E/e’ (ratio of transmitral early peak velocity [E] 
to early diastolic mitral annulus velocity [e']) 
f) Atrial cross-sectional diameter 
g) Right ventricular systolic pressure.  
7) Negative pregnancy test for females of childbearing potential to confirm eligibility. 
 
4.1.5 
Physical Exam  
A complete physical examination will be performed prior to the placement of the LINQ 
implantable recorder, with focus on general appearance, respiratory and cardiovascular systems, 
and lower extremities, and will include a limited neurological exam. 
4.1.6 
Vital Sign Measurements and Weight 
Measurement of vitals is standard of care throughout each dialysis session, and will include 
blood pressure, pulse, weight, and body temperature.  
Measurement of vitals and weight will be recorded post dialysis on Friday or Saturday prior to 
the long dialysis weekend and pre-dialysis on Monday or Tuesday after the long dialysis 
weekend.  

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4.1.7 
12-Lead Electrocardiogram (ECG) 
A standard 12-lead ECG recording will be performed and used for confirmation of eligibility. 
4.1.8 
K+ and PO4 Piccolo POCT System Measurements (Weeks -4 and -3)  
Patients will have blood draws completed prior to dialysis on two (2) separate occasions 
following the long dialytic “weekends” (i.e., on two consecutive Mondays for patients on a 
Monday-Wednesday-Friday dialysis schedule or on two consecutive Tuesdays for patients on a 
Tuesday-Thursday-Saturday dialysis schedule) during screening, before insertion of the cardiac 
loop recorder. Initial measurements of K+ levels will occur real-time, using the Piccolo POCT 
system. 
Patients with two (2) separate pre-dialysis Piccolo POCT measurements of K+ between 5.1 
and 6.5 mEq/L will be considered eligible for study participation and be allowed to proceed to 
placement of the implantable loop recorder. If one of the two screening pre-dialysis K+ levels 
is between 4.6 to 5.0 mEq/L or 6.6 to 7.0 mEq/L, the patient can undergo an additional whole 
blood Piccolo POCT K+ measurement. Patients who fail the third whole blood Piccolo POCT 
K+ measurement will be considered ineligible for study participation.  Screen failures can be 
re-screened once to confirm eligibility in the study. 
Note: K+ and PO4 Piccolo POCT may be performed several weeks after consenting depending 
on the need for a prohibited medication washout or whether the consenting process occurred on 
a day other than the Monday or Tuesday after the long dialysis weekend. 
In addition, PO4  will be measured by the Piccolo Xpress chemistry analyzer to determine 
incidence of hypophosphatemia (<3.0 mEq/L).  
Piccolo POCT System 
The Piccolo Xpress chemistry analyzer provides quantitative in-vitro determinations of 
clinical chemistry analytes in lithium-heparinized whole blood, heparinized plasma, or serum. 
The system consists of a portable analyzer and single-use disposable reagent discs. The 
analyzer (see figure below) contains the following features and components (see Figure 7 
below):  
 
• A variable-speed motor to spin the reagent disc 
• A photometer to measure analyte concentrations 
• two microprocessors to control testing and analytical functions 
• A thermal line printer to print out results 
• A WVGA color touchscreen for communicating with the analyzer 
• Optional data functions for more detailed analysis information 
 
 

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Figure 7 - Piccolo Xpress Chemistry Analyzer 
 
Each reagent disc is self-contained clear plastic, 8 cm in diameter and 2 cm thick, and containing 
an aqueous diluent in its center and dry reagent beads in cuvettes around its edge. All blood 
separation and sample diluent mixing is performed within the disc itself. 
To perform an analysis, the operator needs only to collect a blood sample (lithium-heparinized 
whole blood or plasma, ), place the sample in the reagent disc, put the disc into the analyzer 
drawer on the front of the analyzer, and input patient information. When analysis is finished, 
the results print automatically. 
Results are printed for inclusion within the patient's medical record. One Ethernet port and five 
USB ports are provided so data can be sent to an external printer, computer, memory stick, or 
laboratory information systems/electronic medical record systems (LIS/EMR). 
The entire analysis requires ~100 μL of sample and is capable of providing results in about 12 
minutes. 
Please refer to the Piccolo Xpress Chemistry System Operator’s Manual (provided separately 
from this protocol) for additional details on proper use and operation of the System. All System 
operators should familiarize themselves with the applicable sections in the operator’s manual 
prior to conducting testing to assure safe and effective use of the Piccolo POCT System.  
 
4.1.9 
Insertion of the Cardiac Loop Recorder (Week -2)  
Patients who have completed the screening assessments and are willing to proceed with study 
participation will be referred to a cardiac electrophysiologist (EP) or qualified implanter who is 

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trained and experienced in the placement of the LINQ device. It is anticipated that arranging for 
placement of the device (including scheduling and actual implantation) will take approximately 
1-2 weeks, but may take up to 30 days. Please contact the sponsor if ILR placement will take 
longer then 30 days after the last qualifying Piccolo POCT K+ System Measurements.  The 
sponsor will determine on a case-by-case basis if an additional Piccolo POCT K+ System 
Measurement is required prior to Baseline. 
LINQ Device Insertion 
As described in Section 8, patients with two (2) separate pre-dialysis Piccolo POCT 
measurements of K+ between 5.1 and 6.5 mEq/L will proceed to scheduling and placement of a 
LINQ cardiac loop recorder. The research staff will schedule placement of the LINQ device 
with a participating EP cardiologist or qualified implanter on an “off-dialysis” day. As shown 
in Figure 8, the Medtronic Reveal LINQTM implantable Loop recorder is a 1.7-inch-long 
rectangle shaped device that is placed subcutaneously (SQ) along the left parasternal border by 
a trained EP cardiologist or qualified implanter. This procedure requires only local anesthesia 
and is approximately 20 minutes in duration. Clinicians should follow the implant manuals 
when performing the Reveal LINQ implant.  
 
 
 
 
 
 
 
Figure 8 - LINQ Insertable Cardiac Monitor 
After the LINQ device is implanted, it should be programmed to the study required settings 
specified below. The patient ID should be entered and it should be the CareLink Clinic code, 
followed by the device serial number.  
It is recommended to choose “Cryptogenic Stroke” as the “Reason for Monitoring”. 
Programming Parameter 
Required Setting 
AT/AF Detection 
On 
Type 
AF Only 
AF Detection 
Balanced Sensitivity 
Ectopy Rejection 
Aggressive 
AT/AF Recording Threshold 
All Episodes 
Episode Priority 
Tachy, Pause, Brady 

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Tachy Detection 
On  
Tachy Interval 
130 bpm 
Tachy Duration 
16 beat 
Brady Detection 
On 
Brady Interval 
40 bpm 
Brady Duration 
4 beats 
Pause Detection 
On 
Pause Duration 
3 sec 
*Recommended to be programmed to nominal settings that are automatically programmed with 
“Cryptogenic Stroke” as “Reason for Monitoring” with adjustments to Tachy and Brady 
Intervals. 
Post-LINQ Device Insertion  
For 2 weeks after LINQ device insertion, patients will be given time to heal and adapt to the 
device. During this 2-week blanking period, the device will measure continuous cardiac data, 
but it will not be interrogated and will not be used for analysis. During this blanking period, 
Medtronic will train study staff on how to interrogate and transmit LINQ device data, which 
will be sent to the Medtronic Monitoring Service; refer to the data flow shown in Figure 9.   
After the 2-week ILR post-insertion recovery period, patients will be randomized to one of two 
treatment sequences, as described in Section 3.5. The day of randomization will be denoted as 
Study Day 1 and will also mark the start of Treatment Phase 1. 
Figure 9 - Cardiac Monitoring Data Flow 
1. Medtronic cardiac device is interrogated once a week in the dialysis clinic using the Patient Connector and the 
CareLink Express mobile app on a tablet. 
2. The app will confirm that the transmission was successful. 
 

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3. Transmission will be read and triaged by the Medtronic Monitoring Service and sent to study Cardiologist for 
initial review. 
4.2 
Treatment period 
Assessments during the treatment period will be carried out according to the schedule provided 
in Table 1. 
After completing the 2-week post-ILR insertion blanking period, patients will be switched to 
the dialysate arm that they had been allocated to through randomization. After a 2-week 
“accommodation” period to the new dialysate (Weeks 1 and 2), the cardiac monitoring blanking 
period will be complete, and patient’s ILRs will be interrogated weekly in order to download 
and transmit cardiac monitoring data. Patients will also undergo weekly Piccolo POCT blood 
draws initiated on Mondays or Tuesdays after their long dialysis weekends.  
4.2.1 
Blood Draws (Weeks 3 to 10 and Weeks 13 to 20)  
During both 8-week treatment phases, the first twenty-five (25) patients randomized receiving 
standard treatment (hemodialysis using 2.0K+/2.5 Ca++ dialysate bath, without Lokelma 
supplementation) will undergo blood collection for select chemistry tests and determination of 
protein-bound uremic toxins (PBUTs).  
Blood will be drawn as follows: 
1) A 4.0 ml Green Top tube will be drawn from the dialysis line after placement of the dialysis 
needles and BEFORE the initiation of dialysis. The Green Top tube will be in & out inverted 
3 times and then used for Piccolo POCT measurements of K+, Ca++and PO4, as described in 
Section 8.  This will be repeated promptly before the anticipated termination of the dialysis 
session and within 30 minutes prior to rinse back. 
2) Treatment Phase-1 only: Two 4.0 ml Purple Top tubes will be drawn from the first twenty-
five (25) patients receiving standard treatment (hemodialysis using 2.0K+/2.5 Ca++ dialysate 
bath, without Lokelma supplementation) by the same method (as described above) and 
centrifuged. Each tube of plasma (approximately 1ml after processing) will be transferred 
to a 1.0 ml O-Ring sealed cryovials (two cryovials pre-dialysis and two cryovials promptly 
before the anticipated termination of the dialysis session and within 30 minutes prior to rinse 
back)  and frozen at -80oC until analyzed for measurement of pre- and post-dialysis 
concentrations of the following PBUTs: p-Cresol sulfate (PCS), indoxyl sulfate, and 
asymmetric dimethylarginine (ADMA). Measurement of pre- and post-dialysis levels will 
be conducted by an outside vendor using gas chromatography-mass spectrometry (GC-MS) 
(Tsikas et al. 2003). 
3) 5) A 5.0 ml Yellow Top SST tube will be drawn from the dialysis line promptly before the 
anticipated termination of the dialysis session (and within 30 minutes prior to rinse back) 
will be sent to the local laboratory for routine measurement of Mg++ levels.  
4) A 2nd 4.0 ml Green Top tube will be drawn from the dialysis line promptly before the 
anticipated termination of the dialysis session (and within 30 minutes prior to rinse back) 
for Piccolo POCT measurement of post-dialysis electrolytes (K+, Ca++ and PO4), as 
described in Section 8. 

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5) A 5.0 ml Yellow Top SST tube will be drawn from the dialysis line promptly before the 
anticipated termination of the dialysis session (and within 30 minutes prior to rinse back) 
and will be sent to the local laboratory for routine measurement of Mg++ levels upon 
symptomatic muscle cramping (if possible).  
4.2.2 
Insertable Cardiac Loop Recordings (Weeks 3 to 10 and Weeks 13 to 20)  
ILR interrogation will be initiated at the end of each 2-week accommodation period (to the new 
dialysate) and will continue throughout the two 8-week treatment phases. Devices will not be 
interrogated during either 2-week accommodation periods (following randomization and cross-
over) and the data recorded during that time will not be used for analysis.  
Patients will undergo LINQ device interrogation on a weekly basis, on each Monday or Tuesday 
after their long “dialysis weekend” throughout the two 8-week treatment phases. Each download 
session will occur prior to the pre-dialysis vital signs and weight measurements using the Patient 
Connector and the CareLink Express mobile app on a tablet. This process is anticipated to take 
less than 5 minutes. Data will not be reviewed at the time of interrogation. 
Cardiac Data Monitoring  
ILR will be interrogated weekly following the long “dialysis weekend” using the Patient 
Connector and the CareLink Express mobile app on a tablet. Cardiac data will be managed via 
the CareLink network and reviewed by the Medtronic Monitoring Service, where clinically 
relevant cardiac data will be identified and prioritized based on clinically actionable events. If 
a patient’s arrhythmia meets any of the three CSCA categories, the principal study cardiologist 
and the site PI will be contacted to determine whether the patient requires further evaluation. 
Participating sites will receive copies of relevant cardiac events to enter into their patient’s 
medical records. 
Patients participating in the study may also receive a Patient Assistant, a hand-held, battery-
operated telemetry device that enables the patient to activate the recording of cardiac 
information in the LINQ device while experiencing or immediately after a symptomatic event 
(see Figure 10). During the monitoring period, patients will be instructed to mark their symptom 
when they sense a tachyarrhythmia, bradycardia, or irregular heart rate. These events will be 
reviewed during the weekly LINQ device data download in order to determine if the symptoms 
were associated with a cardiac event.  
 
 
 
 
 
 
 
Figure 10 – Patient Assistant 
 
 

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4.2.3 
Cross-Over (Week 11)  
At the end of the first treatment phase (Weeks 3 to 10) of the study, all blood draws will be 
stopped for 2 weeks. Cardiac loop recording devices will not be interrogated during this 2-week 
accommodation period, and the data recorded during that time will not be used for analysis. 
Patients who completed treatment with experimental 3.0 K+/2.5 Ca++ dialysate with Lokelma 
supplementation (on off-dialysis days) during Treatment Phase-1 will be crossed over to 
standard 2.0 K+/2.5 Ca++ dialysate with no Lokelma supplementation for Treatment Phase-2. 
Patients who completed treatment with standard 2.0 K+/2.5 Ca++ dialysate with no Lokelma 
supplementation during Treatment Phase-1 will cross-over to experimental 3.0 K+/2.5 Ca++ 
dialysate with Lokelma supplementation (on off-dialysis days) for Treatment Phase-2.   
4.3 
Follow-up period 
Assessments during the Follow-up period will be carried out according to the schedule provided 
in Table 1. 
After patients complete the 8-week Treatment Phase-2, all cardiac loop recording and non-
standard of care blood draws will stop.  
As part of the Follow-up, patients will be seen by the electrophysiologist (EP) cardiologist (or 
qualified implanter) for removal of the LINQ device unless they decide to leave it implanted.  
All equipment including the Care monitor recording device will be returned to the Sponsor. 
For each patient, removal of the LINQ device marks the study completion (the end of their study 
participation). 
5. 
STUDY ASSESSMENTS 
The Investigators will ensure that data are recorded on the eCRFs as specified in the study 
protocol and in accordance with the instructions provided. 
The Investigators are responsible for the accuracy, completeness, and timeliness of the data 
recorded and of the answers to data queries according to the Research Agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site. 
5.1 
Efficacy Assessments 
5.1.1 
Atrial Fibrillation 
As described in Section 2.1, the primary objective of this study is to determine whether 
increasing the K+ concentration in a standard hemodialysis bath from 2.0 K+/2.5 Ca++ to a 3.0 
K+/2.5 Ca++ composition with Lokelma will reduce the incidence of atrial fibrillation events.  
Atrial fibrillation will be defined as irregular heart rhythms and irregular R-R intervals in the 
absence of definable P waves for a minimum of 6 minutes.  

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Atrial fibrillation events will be detected, recorded, and stored by the Medtronic LINQ device; 
see Section 4.1.8. This data will be downloaded on a weekly basis during both 8-week treatment 
periods (Treatment Phase-1 and Treatment Phase-2); see Section 4.2.2 for details. 
Each atrial fibrillation event will be adjudicated and validated as a true atrial fibrillation event 
centrally by cardiologist who will be blinded to the treatment assignment.t.  
5.1.2 
Clinically Significant Cardiac Arrhythmias 
As detailed in Section 2.2, the frequency and duration of post-dialysis CSCAs (defined as 
bradycardia, ventricular tachycardia and/or asystole) observed during experimental treatment 
compared to standard treatment will be evaluated as part of the secondary endpoints of the study.  
CSCA events will be defined as follows: 
§ Bradycardia: Heart rate of £ 40 beats per minute (BPM) for a minimum duration of 6 
seconds. 
§ Ventricular Tachycardia: Regular tachy-arrhythmia of ³ 130 BPM for a minimum 
duration of 30 seconds  
§ Asystole: Absence of detectable ventricular conduction for a minimum of 3 seconds. 
The occurrence of these typically silent arrhythmias will be detected, recorded, and stored by 
the Medtronic LINQ device; see description of the device in Section 4.1.8. Patients “sensing” a 
cardiac arrhythmia during dialysis will “mark” the event with the LINQ marking device. This 
data will be downloaded on a weekly basis during both 8-week treatment periods (Treatment 
Phase-1 and Treatment Phase-2); see Section 4.2.2 for details. Upon concluding that a cardiac 
arrhythmia is occurring, the dialysis technician will draw a Green Top and Tiger Red Top tubes 
from the dialysis line as the dialysis is being terminated.  
All “patient marked” events will be adjudicated centrally by the reviewing cardiologist and 
reported to the Site PI if it considered that immediate attention is required. 
5.1.3 
Potassium Measurements 
A further secondary objective of the study (see Section 2.2) is to determine whether the addition 
of oral sodium zirconium cyclosilicate (Lokelmaâ) during the 2-month treatment phase with the 
3.0 K+/2.5 Ca++ dialysate bath will reduce the number of days outside the “K+ safety range” of 
4.0 to 5.5 mEq/L compared to the 2-month treatment phase with the 2.0 K+/2.5 Ca++ dialysate 
bath.  
K+ Piccolo POCT will be performed weekly during the two 8-week Treatment phases, as 
follows: pre-dialysis, and promptly before dialysis termination and 30 minutes prior to rinse 
back (along with Ca++ and PO4 measurements); see Section 4.2.1. 
5.1.4 
Correlations Between Laboratory Parameters and Clinical Events 
The study will also evaluate the correlation between PBUTs (PCS, indoxyl sulfate, and ADMA) 
and the frequency of atrial fibrillation events, as well as the correlation between electrolyte 
levels and clinical events (intradialytic hypotension, muscle cramping, and cardiac 
arrhythmias); see Section 2.4.  

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Measurements of PBUTs and electrolytes are described in Section 4.2.1. The recording and 
assessment of cardiac arrhythmias are detailed in Section 4.2.2 and Section 5.1.2, respectively.  
The occurrence of other clinical events (intradialytic hypotension, muscle cramping) will be 
recorded during dialysis throughout the two 8-week treatment periods.  
Intradialytic hypotension is defined as a systolic blood pressure (SBP) < 90 mmHg and any of 
the following events: 
• A requirement to reduce the ultrafiltration rate  
• A requirement for administration of a saline bolus 
• Development of altered sensorium or level of alertness 
• Onset of shortness of breath (SOB) or angina-like symptoms. 
Muscle cramping is defined as any episode of painful muscle spasm that prompts the patient to 
alert the Dialysis staff of his/her discomfort. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood samples for determination of select clinical chemistry parameters will be collected and 
analyzed as indicated in the Study Plan (see Table 1). 
As part of the safety objectives of the study, the number of hypokalemic events defined as 
Piccolo POCT or laboratory-measured K+ of < 3.5 mEq/L, and the number of events of pre- or 
post-dialysis Ca++ < 2.5 Ca++ mEq/L , PO4 levels <3.0 mEq/L and Mg++< 2.0 mg/dL will be 
evaluated and compared between the two treatments (experimental vs standard); see Section 
2.3.  
All Piccolo POCT measurements will be completed locally. The Piccolo POCT device and 
methodology are described in Section 8, and the blood draws, including sample tubes and 
volumes collected are detailed in Section 4.2.1. In addition, the following laboratory variables 
will be measured at the site as part of the Piccolo POCT renal panel: 
Table 2 
Piccolo Renal Function Panel 
Sodium (Na+) 
Potassium (K+) 
Phosphorus (PHOS) 
Blood urea nitrogen (BUN) 
Calcium (Ca++) 
Albumin (ALB) 
Glucose (GLU) 

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Creatinine (CRE) 
Estimated Glumerular Filtration Rate (eGFR) 
Chloride (Cl-) 
 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. For information on how AEs based on laboratory tests should be 
recorded and reported, see Section 6.4.6.  
5.2.2 
Physical examination 
As described in Section 4.1.5, at screening (prior to the placement  of the implantable loop 
recorder), patients will undergo a complete physical examination that will focus on general 
appearance, respiratory and cardiovascular systems, and lower extremities, and will include a 
limited neurological exam. No subsequent physical exams will be mandated.  
5.2.3 
Cardiac Monitoring 
In this study, continuous cardiac recordings will be performed as part of efficacy evaluations 
throughout the two 8-week treatment phases, using the Medtronic insertable loop recorder (ILR, 
LINQ device). Insertion of the cardiac loop recorder is described in Section 4.1.8. Cardiac data 
recordings are detailed in Section 4.2.2. 
5.2.3.1 
12-lead ECG 
As indicated in Section 4.1.7, Standard resting 12-lead ECG recording will be performed at 
Screening only and used for confirmation of eligibility. 
5.2.4 
Vital signs 
As indicated in Section 4.1.6, measurement of vitals is standard of care throughout each dialysis 
session, and will include blood pressure, pulse, and body temperature.  
For information on how AEs based on vital signs measurements should be recorded and 
reported, see Section 6.4.6. 
5.2.5 
Other safety assessments – Concomitant Medications 
All concomitant medications taken by the subject from the time of their consent signature will 
be recorded; see Section 7.7.  
5.2.6 
Pregnancy Test for Females of Childbearing Potential 
As indicated in Section 4.1.4, a pregnancy test should be performed during screening for 
females of childbearing potential to confirm eligibility. 
 

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5.3 
Safety Protocols 
5.3.1 
Safety Protocol for Patients with Piccolo POCT-Confirmed Hypokalemia or 
Hyperkalemia 
Hyperkalaemia will be defined as a K+ > 7.0 mEq/L and measured using Piccolo POCT 
technology in pre-dialysis obtained after the long dialysis “weekend”. Unless clinically 
unstable, patients with hyperkalaemia will be dialyzed and managed according to the judgment 
of the Site PI. Dose adjustments of Lokelma will be with each patient prior to discharge.  
Hypokalemia is defined as pre-dialysis K+ level of < 3.5 mEq/L. Patients experiencing a 
minimum of two (2) hypokalemic events while taking Lokelma will have their Lokelma 
adjusted or discontinued at the discretion of the site PI. 
Patients with clinically significant cardiac arrhythmias including bradycardia, ventricular 
tachycardia, and asystole that are recognized by the dialysis staff during an individual dialysis 
session will be managed according to site unit protocols and include necessary resuscitation and 
transfer to the nearest emergency department. 
5.3.2 
Safety Protocol for Patients with Intra-Dialytic Arrhythmias 
Patients developing clinically apparent dialysis-associated arrhythmia including atrial 
fibrillation with or without with rapid ventricular response (RVR), atrial tachycardia (defined 
as sustained pulse >130 bpm), bradycardia (defined a symptomatic pulse of < 40 bpm) will be 
sent to the nearest emergency department for treatment at the discretion of the PI. All such 
events will be marked by the LINQ marking device. 
If a complete metabolic panel is performed as standard of care, the results will be recorded in 
the patient’s source chart and electronic data capture system (EDC). 
5.3.3 
Safety Protocol for Patients with Intra-Dialytic Hypotensive Events 
All patients with a dialysis-associated hypotensive event (defined as a systolic blood pressure 
<90 mmHg) will be managed according to standard site unit protocols that may include:  
a) The termination of all ultrafiltration 
b) Administering a 500 ml saline bolus 
c) Documenting the presence of altered sensorium or level of alertness 
d) Documenting the presence of shortness of breath (SOB) or angina-like symptoms 
All patients “sensing” a cardiac arrhythmia during dialysis will “mark” the event with the LINQ 
marking device.  
If a complete metabolic panel is performed as standard of care, the results will be recorded in 
the patient’s source chart and EDC. 
Note: Should the patient quickly revive with the above listed maneuvers and the Site PI assesses 
that the patient can continue dialysis, the patient can complete their dialysis session. 

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5.3.4 
Safety Protocol for Patients with Intra-Dialytic Symptomatic Muscle 
Cramping 
A “symptomatic episode of muscle cramping” is defined as an event associated with any of the 
following:   
a) Requirement to lower the dialysis ultrafiltration rate 
b) Requirement for a saline bolus 
c) Patient request to terminate dialysis (whether the dialysis session is stopped or not) 
d) Decision to terminate dialysis. 
Patient management during each of the above clinical scenarios will be left to the discretion of 
the site PI or according to existing protocols within the participating dialysis unit. 
Upon onset of a “cramping event” the dialysis technician will follow typical dialysis unit 
protocols including reducing the ultrafiltration rate and giving a saline bolus. At this point the 
dialysis nurse or technician will draw a 5.0 ml Yellow Top SST tube from the dialysis line prior 
to the termination of the dialysis session, to be sent to the dialysis local lab for Mg++ and PO4 
levels (if possible).  
All patients developing an episode of “symptomatic muscle cramping will “mark” the event 
with the LINQ marking device.  
5.4 
Pharmacokinetics 
Not applicable. Pharmacokinetic samples will not be taken during the study. 
5.5 
Pharmacodynamics 
Not applicable. Pharmacodynamic samples will not be taken during the study. 
5.6 
Pharmacogenetics 
Not applicable. Pharmacogenetic samples will not be taken during the study.  
5.7 
Biomarker Analysis  
Not applicable. There will be no collection and storage of donated biological samples for 
exploratory biomarker analysis.  
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
Please refer to section 4.2.2 and 5.1.2  for detail of how serious arrhythmias are detected and 
treated per the safety protocol and refer to section 5.3.2 for Patients with Intra-Dialytic 
Arrhythmias. ILR will be interrogated weekly following the long “dialysis weekend” using the 
Patient Connector and the CareLink Express mobile app on a tablet. Cardiac data will be 

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managed via the CareLink network and reviewed by the Medtronic Monitoring Service, where 
clinically relevant cardiac data will be identified and prioritized based on clinically actionable 
events. If a patient’s arrhythmia meets any of the three CSCA categories, the principal study 
cardiologist and the site PI will be contacted to determine whether the patient requires further 
evaluation. Participating sites will receive copies of relevant cardiac events to enter into their 
patient’s medical records. 
6.1 
Definition of Adverse Events 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.2 
Definitions of Serious Adverse Event 
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Note: Adverse events of malignant tumors reported during a study should generally be assessed 
as SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should 
be used. In certain situations, however, medical judgement should be applied to clarify that the 
malignant tumour is a non-serious AE. For example, progression of a pre-existing tumour (i.e., 
included as medical history) during the study, that does not change treatment and/or prognosis 
of the malignant tumour, would be reported as an AE, but may not qualify for being assessed as 
serious. Also, some types of malignant tumors, which do not spread remotely after a routine 
treatment that does not require hospitalization, may be assessed as non-serious; examples 
include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the Investigator and reported to the Sponsor. 

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For further guidance on the definition of a SAE, see Appendix A (Additional Safety 
Information).   
6.3 
Definition of Suspected Unexpected Serious Adverse Event 
(SUSAR) 
A suspected adverse reaction related to an Investigational Product (IP) that is both unexpected 
and serious. 
6.4 
Recording of adverse events 
6.4.1 
Time period for collection of adverse events 
Adverse events will be collected from the time of first dose of Lokelmaâ, throughout the 
treatment and post-treatment follow-up period, up to the last study visit.  
SAEs will be reported from the time the patient signed the Informed Consent Form. 
6.4.2 
Follow-up of unresolved adverse events 
Any AEs that remain unresolved at the patient’s last study visit will be followed up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. It is 
acknowledged that the Company may request additional information after the completion of the 
study. 
6.4.3 
Variables  
The following variables will be collected for each AE: 
• AE (verbatim) 
• The date when the AE started and stopped 
• Intensity  
Adverse Event intensity will be assessed according to the following categories: 
o mild (awareness of sign or symptom, but easily tolerated) 
o moderate (discomfort sufficient to cause interference with normal activities) 
o severe (incapacitating, with inability to perform normal activities) 
• Whether the AE is serious or not 
• Investigator causality assessment /relationship to the study drug (yes or no) 
• Action(s) taken with regard to the study drug 
• AE caused the patient’s withdrawal from study (yes or no) 
• Outcome. 
In addition, the following variables will be collected for SAEs: 
• Date AE met criteria for serious AE 
• Date Investigator became aware of SAE 

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• Reason for assessing the AE as serious  
• For hospitalizations: 
o Date of hospitalization 
o Date of discharge 
• For AEs with a fatal outcome: 
o Date of death  
o Probable cause of death 
o Autopsy performed and finding(s) 
• Causality assessment in relation to study procedure(s)  
• Causality assessment in relation to other medication 
• Description of SAE. 
Note: It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria outlined in Section 6.2. An AE of severe 
intensity would not necessarily qualify as serious. For example, nausea that persists for several 
hours may be considered severe, but not a SAE unless it meets the criteria provided in Section 
6.2. On the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be a SAE if it satisfies the criteria provided in Section 6.2. 
6.4.4 
Causality collection 
The Investigator will assess causal relationship between the study drug and each AE, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the investigational product?’ 
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A (Additional Safety 
Information). 
6.4.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question from 
study personnel: ‘Have you had any health problems since your previous study visit?’ or 
revealed by observation will be collected and recorded in the eCRF. It is preferred that AE are 
recorded as diagnoses (when possible) rather than a list of signs and symptoms. However, if 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis and 
each sign or symptom should be recorded separately. 
6.4.6 
Adverse events based on examinations and tests 
The results from protocol-mandated laboratory tests and vital signs measurements will be 
summarized in the clinical study report. Deterioration from baseline in protocol-mandated 

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laboratory values or vital signs should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of study treatment. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
should use the clinical, rather than the laboratory term (e.g., anaemia versus low hemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or worsened (compared to baseline) clinically relevant abnormal physical examination 
findings should be reported as an AE. 
6.5 
Reporting of serious adverse events to the IRB and/or the 
Regulatory Authority 
The Lokelma Package Insert serves as the Reference Safety Information (RSI) for this study.  
All SAEs occurring from the time of consent and during the study have to be reported, whether 
or not considered causally related to the study drug.  
The Investigator or designated site personnel must inform the designated Sponsor representative 
immediately (no later than 24 hours) after becoming aware of an SAE occurring in their study 
patient.  
SAE reports should be submitted to the Sponsor representative using the following contact 
details: 
The designated Sponsor representative will work with the Investigator to ensure that all 
necessary information is collected within 1 calendar day of initial receipt for fatal and life 
threatening events and within 5 calendar days of initial receipt for all other SAEs. 
For fatal or life-threatening adverse events where important/relevant information is missing, 
active follow-up must be undertaken immediately. The Investigator or designated site personnel 
must inform the Sponsor representatives of any follow-up information on a previously reported 
SAE immediately (no later than 24 hours) after receipt of the follow-up information. 
Site PIs are responsible for informing the central Institutional Review Board (IRB) or their local 
IRB (as applicable) of SAEs as per their IRB requirements.  
The Sponsor is responsible for informing the United States Food and Drug Administration 
(FDA), using the MedWatch/AdEERs form, of any serious or unexpected AEs that occur during 
the study, in accordance with the reporting obligations of 21 CFR 312.32. It is the responsibility 
of the Sponsor to compile all necessary information and ensure that submission of the safety 
report is completed within the FDA-mandated reporting timelines.  
6.6 
Reporting of Serious Adverse Events to Company 
The Sponsor (NephroNet) is responsible for informing the Company (AstraZeneca) of all SAEs 
occurring during the study, whether or not considered causally related to the investigational 
product (IP).  SAEs assessed as related to the IP must be provided to the Company on an ongoing 

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basis as individual case reports. SAEs unrelated to the IP must be provided to the Company in 
the form of quarterly listings. 
SAE files (individual case reports and line listings) should be submitted along with a cover page 
to the following designated Company email address: 
AEmailboxclinicaltrialTCS@astrazeneca.com 
Suspected Unexpected Serious Adverse Reactions (SUSARs) must be reported to the Company 
at the same time these events are submitted to the FDA. 
SAEs that do not require expedited reporting to the FDA/IRB still need to be reported to the 
Company as individual case reports on an ongoing basis (related SAEs) or provided in the form 
of quarterly listings (unrelated SAEs).   
At the end of the study a final summary line listing of all SAEs submitted to the FDA and/or 
Company during the study, must be provided to the Company to enable reconciliation of safety 
information completed by the Company for its product. 
6.7 
Overdose 
Overdose of the study drug (sodium zirconium cyclosilicate) (Lokelmaâ) could lead to 
hypokalemia.  In case of suspected overdose (dosing above 15.0 g),  potassium levels should be 
checked and potassium supplemented, as needed at the discretion of the PI. 
The Investigator or designated site personnel must inform the Sponsor immediately (no later 
than 24 hours) of becoming aware of a study drug overdose. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.   
6.8 
Pregnancy 
All pregnancies and pregnancy outcomes should be reported to the Sponsor (NephroNet) and 
the Company (AstraZeneca) within the safety reporting guidelines. 
6.8.1 
Maternal exposure 
If a patient becomes pregnant during the “high dialysate” treatment period, the study drug 
should be discontinued immediately. 
Pregnancy itself is not regarded as an adverse event. However, congenital abnormalities/birth 
defects and spontaneous miscarriages should be reported and handled as SAEs.  Elective 
abortions without complications should not be handled as AEs.  The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was withdrawn from 
the study. 
The Investigator or designated site personnel must inform the Sponsor immediately (no later 
than 24 hours) of becoming aware of a pregnancy occurring in the study. All relevant 
pregnancy information should be provided to the Sponsor within 1 or 5 calendar days for SAEs 
(see Section 6.4) and within 30 days for all other pregnancies. The same timelines apply when 
pregnancy outcome information becomes available. 

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6.8.2 
Paternal exposure  
Not applicable. There will be no requirements or restrictions associated with paternal exposure. 
6.9 
Management of IP-related Toxicities / Dose Reductions 
The study drug (Lokelma) will be titrated from 5.0 grams per day (4 days/week) up to a 
maximum of 15.0 grams per day (4 days/week), to maintain  K+ within the desired target range 
(between 4.0 and 5.5 mEq/L).  potassium levels will be regularly monitored, and the study drug 
dose adjusted based on the potassium levels (i.e., increased [up to a maximum of 15.0 
grams/day] if potassium is >5.5 mEg/L, or decreased if potassium is <4.0 mEq/L).  
As described in Section 3.9, the study drug will be permanently discontinued in case the patient 
develops any of the following IP-related events:  
• Two (2) or more hypokalemic events (defined as pre-dialysis K+ level of < 3.5 mEq/L); < 
Refer to Section 3.9 for further details on events requiring permanent discontinuation of the 
study drug.  
Safety protocols for the management of intra-dialytic events are provided in Section 5.3. 
6.10 
Study Governance and Oversight 
Responsibilities for the study design, protocol development, scientific oversight, and 
coordination of the study rest with the NephroNet as the responsible Academic Research 
Organization (ARO), and the National Coordinating PI (James A. Tumlin, MD). 
No study committees will be established. Given the open label study design, and the underlying 
condition involving the management of routine and frequent complications of dialysis, site PIs 
will be responsible for all emergency medical decisions related to their study patients. Site PIs 
will meet with the National Coordinating PI on quarterly basis to review safety data and 
determine if changes to the protocol design or study conduct are required. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of Investigational Product(s) 
The investigational product (IP) in this study is sodium zirconium cyclosilicate (Lokelmaâ), a 
potassium binder product for oral administration. It is indicated for the treatment of 
hyperkalemia in adults (Lokelma United States Prescribing Information [USPI], 19th October 
2021).  
Lokelma, powder for oral suspension will be supplied in 5.0 gram packets to study participants. 
Investigational product 
Dosage form and strength 
sodium zirconium cyclosilicate 
(Lokelmaâ) 
For oral suspension: 5 g of 
white to grey powder in a foil-
lined packet. 

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Note: In this protocol, the terms investigational product, IP, and study drug are used 
interchangeably.  
7.2 
Dose and Treatment Regimens 
7.2.1 
Dosing Regimen 
Patients will take Lokelma supplementation on off-dialysis days (4 days/week) while receiving 
hemodialysis with 3.0 K+/2.5 Ca++ mEq dialysate bath (8-week treatment phase): 
• Patients on a Monday-Wednesday-Friday dialysis schedule will take the study drug on 
Tuesday, Thursday, Saturday, and Sunday 
• Patients on a Tuesday-Thursday-Saturday dialysis schedule will take the study drug on 
Monday, Wednesday, Friday, and Sunday. 
The individual starting dose will be 5.0 grams (4 days/week), and will be titrated weekly in 5.0 
gram increments up to a maximum of 15.0 grams (4 days/week) to maintain K+ within the 
desired target range (between 4.0 and 5.5 mEq/L): 
• Patients who fail to achieve a pre-dialysis K+ of < 5.5 mEq/L after one week of 5.0 grams 
Lokelma will be treated with 10.0 grams on off-dialysis days for an additional 7 days.  
• Patients failing to achieve a pre-dialysis K+ of < 5.5 mEq/L after one week of 10.0 grams 
Lokelma will have their study drug dose increased to 15.0 grams. 
• Patients failing to achieve the target K+ after a 7-day course of 15.0 grams Lokelma on off-
dialysis days will be considered a treatment failure and withdrawn from the study. 
Potassium levels will be regularly monitored throughout the 8-week treatment phase, and the 
study drug dose adjusted based on the potassium levels (i.e., increased [up to a maximum of 
15.0 grams/day] if potassium is >5.5 mEq/L, or decreased if potassium is <4.0 mEq/L). 
7.2.2 
Study Drug Dispensation and Instructions for Reconstitution and Dosing 
The allow for adequate dosing (including dose-titration, as described in Section 7.2.1), the study 
drug will be dispensed to patients on a weekly basis, as follows: 
Table 3 
IP Dispensing Schedule and Dosing Instructions 
IP Dose Level 
IP Packets 
dispensed 
Instructions for Patients 
(For dosing on off-dialysis days): 
5.0 grams, 4 days/week 
4 x 5.0 g packets 
On each dosing day (4 off-dialysis days per 
week): Dissolve in water and drink the content of 
one 5.0 gram packet [1] 
10.0 grams, 4 days/week 8 x 5.0 g packets 
On each dosing day (4 off-dialysis days per 
week): Dissolve in water and drink the content of 
two 5.0 gram packet [1] 
15.0 grams, 4 days/week 12 x 5.0 g packets  
On each dosing day (4 off-dialysis days per 
week): Dissolve in water and drink the content of 
three 5.0 gram packet [1] 

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[1] Patients should be instructed to (i) empty the entire contents of the packet(s) into a drinking glass containing 
approximately 3 tablespoons of water or more if desired; (ii) stir well and drink immediately; (iii) if powder remains 
in the drinking glass, add water, stir, and drink immediately; (iv) repeat until no powder remains to ensure the 
entire dose is taken. 
7.3 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling.   
7.4 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions, at a 
temperature between 15°C-30°C (59°F-86°F). The study drug label will specify the appropriate 
storage conditions. 
At the study site, study drug will be stored at the participating dialysis unit, separate from other 
similar agents (Patiromer). 
7.5 
Compliance 
During the 8-week “high dialysate” treatment period, patients will be asked to return to the site 
all used (including empty) packets of study drug (Lokelma) on a weekly basis. These will be 
assessed by the study coordinator to confirm treatment compliance. In case of a discrepancy 
between the planned vs actual number of packets used, the patient will be asked whether they 
had missed any of the prescribed study drug doses. Information about missed doses will be 
recorded in the patient’s source records. An additional “internal control” of study drug 
compliance will be the pre-dialysis K+ level after the long dialysis weekend. Patients reporting 
compliance with the study drug but K+ above the 5.5 mEq/L goal will be up-titrated to the next 
Lokelma dose. 
Study drug administration should also be recorded in the appropriate section of the eCRF. 
7.6 
Accountability 
The study drug (Lokelma) provided for this study will be used only as directed in this protocol. 
The study nurse coordinator will be responsible for recording all study drugs dispensed to and 
returned by the patient. Any unused packets of study drug will either be returned to the Company 
under the directive of the Company, or destroyed locally upon approval by the Company, and 
according to applicable local Standard Operating Procedures (SOPs).  
7.7 
Concomitant and Other Treatments  
All concomitant medications must be recorded in the appropriate sections of the eCRF. 
7.7.1 
Prohibited Treatment 
Use of the following medications is prohibited during the study: 
 Prohibited Medication/Class of drug 
Washout Period* 
Amiodarone or other anti-arrhythmic therapy 
2 weeks prior to Screening 

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Patiromer or other drugs for treatment of hyperkalemia 
1 week prior to Screening 
*Washout of the of the prohibited medications can occur after signing of informed consent as 
applicable.  
7.7.2 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
subject’s safety and well-being, may be given at the discretion of the Investigator, and recorded 
in the appropriate sections of the Case Report Form. 
The study drug (Lokelma) can transiently increase gastric pH, and as a result, it can change the 
absorption of co-administered drugs that exhibit pH-dependent solubility. Therefore, patients 
who are taking other oral medications will be advised to take these medications at least 2 hours 
before or 2 hours after the study drug. 
7.8 
Post Study Access to Study Treatment 
Not applicable. 
8. 
STATISTICAL ANALYSES  
8.1 
Statistical Considerations 
Analyses will be performed by the Sponsor or its representatives.     
A comprehensive Statistical Analysis Plan (SAP) may be prepared within 90 days of the date 
of the first participant enrolled, and any further changes during the course of the study will be 
included (reflecting the final Clinical Study Protocol, including any amendments) prior to 
clinical database lock.  
The SAP will include a more technical and detailed description of the statistical analyses 
described in the following sections.  
8.2 
Sample Size Estimate 
The primary statistical hypothesis of the study is that the rate of atrial fibrillation events during 
hemodialysis using the 3.0 K+ dialysate bath supplemented with sodium zirconium cyclosilicate 
(Lokelmaâ) is not equal to  the rate of events incurred during hemodialysis using the 2.0 K+ 
dialysate bath.  
The sample size estimation is based upon the primary statistical hypothesis, and its details were 
separately documented. 
With >90% power to reject the primary hypothesis, 40 subjects would need to be randomized 
into one of two treatment sequences in the 2x2 cross-over study using the simulation study  with 
a 2-sided alpha of 0.05, assuming an event rate of 4.6 with the 2.0 K+ dialysate bath, an 
overdispersion parameter of 0.07 and a reduction of rate ratio of 25%. It is expected that 10% 
of randomized subjects will not complete both study periods. Accounting for this estimated 10% 

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attrition rate, 44 subjects per treatment sequence or 88 subjects in total will be randomized in 
the study. 
8.3 
Definitions of Analysis Sets and Analysis Periods 
The analysis of data will be based on different analysis sets according to the purpose of analysis, 
i.e., efficacy or safety. 
8.3.1 
All-participants Analysis Set 
The all-participants analysis set will consist of all participants who were screened for the study.  
8.3.2 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized participants, with participants being 
analyzed as randomized, rather than as treated. All efficacy endpoints will be analyzed using 
the FAS. 
8.3.3 
Safety Analysis Set 
The Safety Analysis Set will include all randomized participants who during the first treatment 
period (study Phase I): (i) received at least one dose of the study drug (Lokelma) during 
treatment with the 3.0 K+ dialysate bath; or (ii) completed Visit 2 during treatment with the 2.0 
K+ dialysate bath. All safety endpoints will be analyzed using the SAS. 
The number of participants in each analysis set, and the number excluded and associated reasons 
will be summarized by treatment group and overall. In addition, the following periods will be 
defined for the purpose of reporting: 
Table 4 
Analysis Periods 
 
Treatment Phase-1 
Treatment Phase-2 
Treatment Sequence A 
3.0K+ dialysate bath + SZC 
2.0K+ dialysate bath 
Treatment Sequence B 
2.0K+ dialysate bath 
3.0K+ dialysate bath + SZC 
Abbreviations: SZC = sodium zirconium cyclosilicate (Lokelmaâ) 
 
8.4 
Outcome Measures for Analyses 
8.4.1 
Primary Efficacy Endpoint: Frequency of Atrial Fibrillation Events 
The primary efficacy endpoint is the frequency of atrial fibrillation events occurring during the 
8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods. 
Atrial fibrillation will be defined as irregular heart rhythms and irregular R-R intervals in the 
absence of definable P waves for a minimum of 6 minutes. Each atrial fibrillation event will be 
adjudicated and validated as a true atrial fibrillation event by a central cardiologist who is 
blinded to dialysate K+ content. 
The total number of atrial fibrillation events will be compared between the two dialysate groups. 

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The primary objective of the study will have been achieved if the frequency of atrial fibrillation 
events occurring during experimental treatment (hemodialysis using 3.0K+/2.5 Ca++ dialysate 
bath, with Lokelma supplementation on off-treatment days) is lower compared to standard 
treatment 
(hemodialysis 
using 
2.0K+/2.5 
Ca++ 
dialysate 
bath, 
without 
Lokelma 
supplementation). 
8.4.2 
Secondary Efficacy Endpoint #1: Frequency and duration of Clinically 
Significant Cardiac Arrhythmia Events 
Frequency and duration of CSCAs (bradycardia, ventricular tachycardia and/or asystole) events 
during the 8-week Phase-I dialysate cross-over period and the 8-week Phase-II cross-over 
period is a secondary efficacy endpoint. Definitions of CSCA events are provided in Section 
5.1.2. 
This secondary objective will have been achieved if the frequency of post-dialysis CSCAs event 
(bradycardia, ventricular tachycardia and/or asystole) is lower during experimental compared 
to standard treatment or if a total duration of post-dialysis CSCAs event (bradycardia, 
ventricular tachycardia and/or asystole) is shorter during experimental compared to standard 
treatment.  
8.4.3 
Secondary Efficacy Endpoint #2: Events Outside the Optimal K+ “Window”  
The number of events of  K+ outside of the 4.0 to 5.5 mEq/L safety range is a secondary efficacy 
endpoint in this study, The total number of events of pre- or post-dialysis K+ falling outside the 
“K+ safety range” will be averaged and compared between the two dialysate groups. 
The study aims to show that patients experience less risk of K+ falling outside the range of 4.0 
to 5.5 mEq/L while receiving experimental compared to standard treatment. 
8.4.4 
Exploratory Efficacy Endpoint #1:Relationship Between PBUTs and Atrial 
Fibrillation Rates   
The study will also evaluate the correlation between PBUTs (indoxyl sulfate, PCS, and ADMA) 
and the frequency of atrial fibrillation events. 
8.4.5 
Exploratory Efficacy Endpoint #2: Correlation Between Electrolytes and 
Clinical Events 
The following correlations will be explored: 
Ø Correlation between electrolyte levels and clinical events (intradialytic hypotension, muscle 
cramping, and cardiac arrhythmias). 
Ø Correlation between electrolytes falling below threshold levels (Ca++ < 7.0 mEq/L, PO4 
levels <3.0 mEq/L, Mg++< 2.0 mg/dl, and K+ of < 3.5 mEq/L) and clinical events (cardiac 
arrhythmias). 
8.4.6 
Safety Endpoint #1: Lokelma Induced Hypokalemia 
To evaluate whether the use of Lokelma during periods when patients are  receiving a 3.0 K+/2.5 
Ca++ bath is associated with hypokalemic events, the total number of hypokalemic events 
(defined as Piccolo POCT or laboratory-measured K+ of < 3.5 mEq/L) will be summarized. 

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8.4.7 
Safety Endpoint #2: Incidence of Dialysis-related Hypokalemia, 
Hypomagnesemia, Hypophosphatemia, or  Low Calcium 
This endpoint is defined as the number of events promptly prior to the termination of dialysis 
where a Piccolo POCT measurement of K+ is  < 2.0 mEq/L OR Ca++ is < 7.0 mEq/L, OR Mg++ 
is < 2.0 mg/dl OR a PO4 level is <3.0 mEq/L. 
All episodes where a specific electrolyte falls below the above listed threshold will be considered an 
“event” for that electrolyte. The total number of “events” will be recorded during the 8-week Treatment 
Phase-1 and the 8-week Treatment Phase-2 cross-over periods. Each electrolyte will be its own ”safety” 
objective independently. 
8.4.8 
Safety Endpoint #3: Adverse Experiences 
The frequencies of AEs, SAEs, and withdrawals due to AEs will be summarized, with focus on 
treatment-related events. 
8.5 
Methods for statistical analyses 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. 
8.5.1 
General Considerations 
Inference concerning the primary analysis will be performed at the 2-sided 5% significance 
level. All point estimates will be presented together with confidence intervals of 2-sided 95% 
coverage. 
The analysis assumes that there is no carry-over effect given that the wash-out period is deemed 
appropriate to rule out this effect by design.  
Intercurrent events are handled as outlined within each section for the primary and secondary 
endpoint analyses below. For the primary endpoint and secondary endpoints, missing data will 
occur in the case where participants are lost to follow-up, provide insufficient evaluable data, 
withdraw consent, or die during the study. The proportion of participant missing data will be 
presented as appropriate. 
For each participant, baseline is defined as the last available assessment prior to or on the date 
of the randomization visit, unless otherwise specified. A period baseline is defined as the last 
available assessment prior to or on the date of each of periods 
In general terms, the Full Analysis Set (FAS) will be used for the efficacy analyses and the 
Safety Analysis Set will be used for the safety analyses. 
In general, all baseline characteristics and efficacy and safety variables will be summarized 
using descriptive statistics as appropriate. Continuous variables will be summarized by 
descriptive statistics including number of participants (n), mean, standard deviation, minimum, 
median, and maximum. Categorical variables will be summarized using frequencies and 
percentages, where the denominator of the calculation is the underlying analysis set population 
unless otherwise stated. 

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Descriptive statistics of quantitative efficacy and safety parameters by scheduled visits will be 
provided on observed cases (i.e., including only participants who have non-missing assessments 
at a given visit). 
8.5.1.1 
COVID Considerations 
It is anticipated that additional sensitivity and supplementary analyses will be required to 
determine the impact of the COVID-19 pandemic on this trial and its endpoints. Planned 
sensitivity analyses will distinguish between pandemic and non-pandemic-related intercurrent 
events in terms of the approach taken for sensitivity analyses. Further details will be included 
in the SAP. 
8.5.2 
Analysis of the Primary Variable 
The primary efficacy endpoint is the frequency of atrial fibrillation events occurring during the 
8-week Treatment Phase-1 and the 8-week Treatment Phase-2 dialysate cross-over periods. 
The primary analysis will test the null hypothesis that there is no difference in the rate of atrial 
fibrillation events between the 3.0K+ dialysate bath with Lokelma and the 2.0K+ dialysate bath 
without Lokelma, against the alternative hypothesis that there is a difference in the rate of atrial 
fibrillation events between the 3.0K+ dialysate bath with Lokelma and the 2.0K+ dialysate bath 
without Lokelma. Statistical hypothesis testing will be completed at a 2-sided 0.05 significance 
level. 
The primary analysis will not account for missing values. However, sensitivity analyses will be 
conducted using the pattern mixture model with multiple imputation (PM-MI) method. Details 
of the PM-MI method will be provided in the SAP. 
A generalized linear model assuming the distribution of negative binomial will be used, with 
fixed effect terms for the treatment groups (3.0K+ dialysate bath with Lokelma and 2.0K+ 
dialysate bath without Lokelma), the study period, and log (the duration of period) as an offset 
variable1. An unstructured working variance-covariance will be employed. Additional model 
terms may be included, details of which will be described in the SAP. The estimated risk ratio 
between groups and its 95% robust confidence interval (CI) will be displayed. The null 
hypothesis will be rejected if the p-value (based upon the Wald statistics) is less than 0.05. 
8.5.3 
Analysis of the Secondary Variables 
Each secondary endpoint will be analyzed individually, and no multiplicity control will be 
applied. Analyses of secondary variables will not account for missing values. 
The secondary endpoint of clinically significant arrhythmia events will be analyzed similarly to 
the primary endpoint. 
The secondary endpoint of a total duration of clinically significant arrhythmia events will be 
analyzed by a linear mixed model. Details of the model specifications will be in the SAP 
The secondary endpoint of risk of outside K+ safe range will be analyzed with a similar approach 
of the primary endpoint but with a logit link function. Details of the model specification will be 
included in the SAP. 

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A nominal p-value and a 95% C.I. of the effect between two treatment groups will be reported 
for each of secondary endpoints. 
 
8.5.4 
Analysis of the Exploratory Variables 
All exploratory endpoints will be analysed using the FAS. A full description of the exploratory 
endpoints and analyses will be included in the SAP. 
8.5.5 
Subgroup analysis  
The primary and select secondary variables may be analyzed based on the following pre-defined 
subgroups:   
1) 
ESRD patients with diabetes mellitus: 
     Patients with diabetic nephropathy as their proximate cause of ESRD will be pre-     identified 
as a group of patients with increased risk for post-dialysis atrial fibrillation. 
2) 
ESRD patients with a prior history of atrial fibrillation: 
     Patients with a history of atrial fibrillation but in stable sinus rhythm will be pre-     identified 
as a group with increased risk for post-dialysis atrial fibrillation. 
3) 
ESRD Patients with grade II or higher levels of diastolic dysfunction 
     Patients with echocardiogram-defined grade II diastolic dysfunction are defined as having 
an E/e’ ratio of  > 12 within 12 months of study entry.  
4) 
ESRD patients with confirmed left ventricular hypertrophy (LVH) 
Patients with LVH are defined as having left ventricular wall thickness > 1.2 cm confirmed by 
echocardiogram within 12 months of study entry. 
8.5.6 
Safety Analyses 
Lokelma-induced hypokalemia will be evaluated based on the total number of hypokalemic 
events defined as Piccolo POCT or laboratory-measured K+ of < 3.5 mEq/L. 
The incidence of dialysis-related hypokalemia, hypomagnesemia, hypophosphatemia, and low 
calcium will be evaluated based on the number of events promptly prior to the termination of 
dialysis where a Piccolo POCT measurement of K+ is < 2.0 mEq/L OR Ca++ is < 7.0 mEq/L, 
OR Mg++ is < 2.0 mg/dl, OR a PO4 level is <3.0 mEq/L. All episodes where a specific electrolyte 
falls below the above listed threshold will be considered an “event” for that electrolyte. The 
total number of “events” will be recorded during the 8-week Treatment Phase-1 and the 8-week 
Treatment Phase-2 cross-over periods and compared between the treatments. 
Safety will also be assessed in terms of the frequency of AEs, SAEs, and withdrawals due to 
AEs, with focus on treatment-related events. Appropriate summaries of these data will be 
presented by treatment group and/or study period. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class (SOC) and preferred term (PT). A treatment-emergent AE 

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(TEAE) is defined as an AE with the start date on or after the first dose date and up to (and 
including) 14 days after the last dose date in each of study periods when patients received 3K 
Bath with Lokelma. However, when patients received 2K Bath without Lokelma, A treatment-
emergent AE (TEAE) is defined as an AE with the start date on or after the first visit date and 
up to (and including) 14 days after the last visit date in each of study periods. Only TEAEs will 
be included in table summaries. 
The number and percentage of participants experiencing AEs, SAEs, AEs that led to 
withdrawal, AEs that led to death, and the number of such events, will be summarised by SOC, 
PT, and treatment group and study period. The number and percentage of participants 
experiencing AEs will further be summarised by intensity and will be presented with the number 
of events at each level of intensity. 
Additionally, the number and percentage of participants with AEs leading to discontinuation of 
Lokelma will be presented by SOC and PT, and the number and percentage of participants with 
any AE will be presented by SOC, PT, and relationship to Lokelma as assessed by the 
investigator. Each of these summaries will also include the number of events. 
All AEs, SAEs, AEs that led to withdrawal or death and treatment-related AEs will be included 
in per-patient listings.  
Clinical safety laboratory assessments will be summarised and listed. Shift tables will be 
provided for select tests, where shift from screening baseline to the worst value within each of 
study periods will be summarised. Laboratory data outside the reference ranges will be indicated 
in all listings. 
All safety analyses will be performed on the Safety Set. In general, safety assessments will be 
reported descriptively by treatment group and/or study period. Full details on safety analyses 
will be provided in the SAP. 
8.5.7 
Interim analysis 
No interim analysis is planned. 
9. 
STUDY AND DATA MANAGEMENT  
9.1 
Training of study site personnel 
Before the first patient is entered into the study, a Sponsor representative will review and discuss 
the requirements of the Clinical Study Protocol and related documents with the investigational 
staff and train them in any study-specific procedures.  
The site PI will ensure that appropriate training relevant to the study is given to all study staff 
at their site, and that any new information relevant to the performance of this study is forwarded 
to the staff involved. 
The site PI will maintain a record of all individuals involved in the study (medical, nursing, and 
other staff). 

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9.2 
Monitoring of the study 
Site management and monitoring will be the responsibility of the Sponsor (NephroNet). During 
the study, a Sponsor representative will have regular contacts with the study sites, including 
visits to: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are being 
performed 
• Perform source data verification (a comparison of the data in the eCRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study), including 
verification of informed consent of participants. This will require direct access to all original 
records for each study patient (e.g., clinic charts) 
The Sponsor representative will be available between visits if the Investigator(s) or other staff 
at the study site needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the Research Agreement for location of source data.  
9.2.2 
Research Agreement(s) 
Site PIs should comply with all the terms, conditions, and obligations of the Research 
Agreement, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the Research Agreement, the terms of the Clinical Study Protocol shall 
prevail with respect to the conduct of the study and the treatment of patients. In all other 
respects, not relating to study conduct or treatment of patients, the terms of the Research 
Agreement shall prevail. 
Agreements between the Sponsor and the site PI should be in place before any study-related 
procedures can take place, or patient are enrolled. 
9.2.3 
Archiving of study documents 
The Sponsor follows the principles outlined in the Research Agreement (RA). 
The study site/site PI will retain the essential documents specified in the Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonisation (ICH) (e.g., source 
document such as medical records, contract, signed consent form). Essential documents should 
be retained at the study site as per regulatory obligations for a Phase IV clinical trial, and 
thereafter destroyed after approval from the Sponsor.   
9.2.4 
Deviation from the clinical study protocol 
The Investigator(s) must not deviate from or make any changes to the protocol without 
documented approval from the Sponsor and the reviewing IRB, except in case of a medical 

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emergency, where the deviation or change is necessary to avoid an immediate hazard to study 
patients. In such case, the site PI must provide details of the deviation or change (including 
reason), and the proposed revision(s) to the protocol, to the Sponsor and IRB as soon as possible, 
in order to obtain their approval.  
All deviations from the protocol should be documented in the eCRF regardless of their reasons.  
9.3 
Study Timetable and End of Study 
The end of the study is defined as Last Patient Last Visit (LPLV). 
The study is expected to start in April 2022 and to end by end of June 2023. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP, or if recruitment is slow. The Sponsor may also terminate the 
entire study prematurely if concerns for patient safety arise within this study. 
9.4 
Data Management  
Data management activities will be performed by according to the Data Management Plan.  
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA). Medications 
will be classified according to the current version of the World Health Organization (WHO) 
Drug Dictionary. Classification coding will be performed by a designated Consultant Medical 
Coder. 
The data collected through third party sources will be obtained and reconciled against study 
data. Data queries will be raised for inconsistent, impossible, or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan.  Quality control procedures 
will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. The Data Management Plan will also clarify the roles and responsibilities 
of the various functions and personnel involved in the data management process. 
When all data have been coded, validated, and locked, clean file will be declared, and the 
clinical database will be locked. 
Serious Adverse Event (SAE) Reconciliation 
SAE reconciliation reports will be produced and reconciled with the study clinical database.  
Management of external data 
During both 8-week treatment phases, ILR will be interrogated weekly following the long 
“dialysis weekend” using the Patient Connector and the CareLink Express mobile app on a 
tablet, as described in Section 4.2.2. Cardiac data will be managed via the CareLink network 
and reviewed by the Medtronic Monitoring Service, where clinically relevant cardiac data will 
be identified and prioritized based on clinically actionable events. Refer to Section 4.2.2 for 
details.   

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10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, and applicable 
regulatory requirements. 
10.2 
Patient Data Protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy 
legislation. 
Patients will be informed that all study data will be stored in secure password-protected 
computer databases, and patient confidentiality will be maintained as mandated by Federal Law. 
10.3 
Ethics and Regulatory Review 
10.3.1 
Ethics Review 
Appropriate written IRB approval must be obtained for the final study protocol and Informed 
Consent Form, as well as any other written information and/or materials to be provided to study 
patients (e.g., advertising used to recruit patients for the study). The site PI will be responsible 
for submitting these documents to the applicable IRB, and for providing the written IRB 
approval to the Sponsor before enrollment of any patient into the study.  
The Sponsor (NephroNet) should approve any modifications to the Informed Consent Form 
template that are needed to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the IRB annually. 
The Sponsor will provide IRBs and site PIs with safety updates/reports according to local 
requirements. Each site PI is responsible for providing the IRB with reports of any serious and 
unexpected adverse drug reactions from any other study conducted with the investigational 
product. The Company (AstraZeneca) will provide this information to the site PIs so that they 
can meet these reporting requirements. 
10.3.2 
Regulatory Review 
The National Coordinating PI (James A. Tumlin, MD) submitted the Investigational New Drug 
(IND) application to the FDA, and the FDA ruled that this study is IND exempt. 
10.4 
Informed consent 
Investigators will ensure that: 
• Each patient is given full and adequate oral and written information about the nature, 
purpose, possible risks, and benefits of the study 
• Each patient is explained that they are free to discontinue from the study at any time 
• Each patient is given the opportunity to ask questions and allowed time to consider the 
information provided 

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• Each patient provides signed and dated informed consent before conducting any procedure 
specifically for the study 
• Original, signed Informed Consent Form(s) is/are stored in the Investigator’s Study File 
• A copy of the signed Informed Consent Form is given to the patient 
• Any incentives for patients who participate in the study as well as any provisions for patients 
harmed as a consequence of study participation are described in the informed consent form 
that is approved by the IRB. 
10.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without approval from the Sponsor. 
If there are any substantial changes to the study protocol, these changes will be documented in 
a study protocol amendment. The amendment is to be approved by the relevant IRB. The 
Sponsor will distribute the protocol amendment to each site PI for submission to their IRB; see 
Section 10.3.  
If a protocol amendment requires a change to a site’s Informed Consent Form, the Sponsor and 
the site’s IRB are to approve the revised Informed Consent Form before it is used.  
Administrative change(s) will be communicated to each IRB as per local requirements. 
10.6 
Audits and inspections 
Authorized representatives of the Sponsor, a regulatory agency, or an IRB may perform site 
audits or inspections, including source data verification. The purpose of an audit or inspection 
is to systematically and independently examine all study-related activities and documents, to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, ICH GCP guidelines, and any applicable 
regulatory requirements. The Investigator will notify the Sponsor immediately if contacted by 
a regulatory agency about an inspection at the center. 
11. 
LIST OF REFERENCES 
Airy M, Schold JD, Jolly SE, et al. Cause-Specific Mortality in Patients with Chronic Kidney 
Disease and Atrial Fibrillation. Am J Nephrol. 2018;48(1):36-45. doi:10.1159/000491023 
Aoki K, Teshima Y, Kondo H, et al. Role of Indoxyl Sulfate as a Predisposing Factor for Atrial 
Fibrillation in Renal Dysfunction. J Am Heart Assoc. 2015 Oct 9;4(10):e002023. doi: 
10.1161/JAHA.115.002023. 
Avari Silva JN, Bromberg BI, Emge FK, et al. Implantable Loop Recorder Monitoring for 
Refining Management of Children With Inherited Arrhythmia Syndromes. J Am Heart Assoc. 
2016 May 26;5(6):e003632. doi: 10.1161/JAHA.116.003632. 
Diggle PJ, Heagerty P, Liang K-Y, and Zeger S. (2001) Analysis of Longitudinal Data. 2nd 
edition, Oxford University Press 

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Fishbane S, Ford M, Fukagawa M, et al. A Phase 3b, Randomized, Double-Blind, Placebo-
Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis 
Hyperkalemia. J Am Soc Nephrol. 2019 Sep;30(9):1723-1733. doi: 10.1681/ASN.2019050450.  
Krijthe BP, Heeringa J, Kors JA, et al. Serum potassium levels and the risk of atrial fibrillation: 
the 
Rotterdam 
Study. 
Int 
J 
Cardiol. 
2013 
Oct 
15;168(6):5411-5. 
doi: 
10.1016/j.ijcard.2013.08.048. 
Ohnishi T, Kimachi M, Fukuma S, et al. Postdialysis Hypokalemia and All-Cause Mortality in 
Patients Undergoing Maintenance Hemodialysis. Clin J Am Soc Nephrol. 2019 Jun 7;14(6):873-
881. doi: 10.2215/CJN.07950718. 
Pun PH, Lehrich RW, Honeycutt EF, et al. Modifiable risk factors associated with sudden 
cardiac arrest within hemodialysis clinics. Kidney Int. 2011 Jan;79(2):218-27. doi: 
10.1038/ki.2010.315. 
Roy-Chaudhury P, Tumlin JA, Koplan BA, et al; MiD investigators and committees. Primary 
outcomes of the Monitoring in Dialysis Study indicate that clinically significant arrhythmias are 
common in hemodialysis patients and related to dialytic cycle. Kidney Int. 2018 Apr;93(4):941-
951. doi: 10.1016/j.kint.2017.11.019.  
Sacher F, Jesel L, Borni-Duval C, et al. Cardiac Rhythm Disturbances in Hemodialysis Patients: 
Early Detection Using an Implantable Loop Recorder and Correlation With Biological and 
Dialysis 
Parameters. 
JACC 
Clin 
Electrophysiol. 
2018 
Mar;4(3):397-408. 
doi: 
10.1016/j.jacep.2017.08.002.  
Severi S, Pogliani D, Fantini G, et al. Alterations of atrial electrophysiology induced by 
electrolyte variations: combined computational and P-wave analysis. Europace. 2010 
Jun;12(6):842-9. doi: 10.1093/europace/euq042.  
Soliman EZ, Prineas RJ, Go AS, et al. Chronic kidney disease and prevalent atrial fibrillation: 
the chronic renal insufficiency cohort (CRIC). Am Heart J 2010;159:1102–1107. doi: 
10.1016/j.ahj.2010.03.027. 
Tsikas D, Schubert B, Gutzki FM, et al. Quantitative determination of circulating and urinary 
asymmetric dimethylarginine (ADMA) in humans by gas chromatography-tandem mass 
spectrometry as methyl ester tri(N-pentafluoropropionyl) derivative. J Chromatogr B Analyt 
Technol Biomed Life Sci. 2003 Dec 5;798(1):87-99. doi: 10.1016/j.jchromb.2003.09.001. 
Tang WH, Wang CP, Chung FM, et al. Uremic retention solute indoxyl sulfate level is 
associated 
with 
prolonged 
QTc 
interval 
in 
early 
CKD 
patients. PLoS 
One. 
2015;10(3):e0119545. Published 2015 Apr 20. doi:10.1371/journal.pone.0119545 
Writing Group Members; Mozaffarian D, Benjamin EJ, Go AS et al; American Heart 
Association Statistics Committee; Stroke Statistics Subcommittee.  Heart disease and stroke 
statistics-2016 update: A report from the American Heart Association. Circulation. 2016 Jan 
26;133(4):e38-360. doi: 10.1161/CIR.0000000000000350. 
 
 

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Appendix A 
Additional Safety Information 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the subject’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. Simply stopping the suspect drug does not mean that it 
is an important medical event; medical judgement must be used. 
Examples: 
• Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization 
• Development of drug dependency or drug abuse 
A Guide to Interpreting the Causality Question 
When assessing causality, consider the following factors when deciding if there is a ‘reasonable 
possibility’ that an AE may have been caused by the drug: 
• Exposure to suspect drug:  Has the patient actually received the suspect drug?   
• Time Course:  Did the AE occur in a reasonable temporal relationship to the administration 
of the suspect drug? 

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• Consistency with known drug profile: Was the AE consistent with previous knowledge of 
the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological 
class? Could the AE be anticipated from its pharmacological properties? 
• De-challenge experience: Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• No alternative cause:  The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors. 
• Re-challenge experience:  Did the AE reoccur if/when the suspected drug was reintroduced 
after it had been stopped? Sponsor would not normally recommend or support a re-
challenge. 
• Laboratory tests:  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
• Is this a recognized feature of overdose of the drug? 
• Is there a known mechanism? 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility. 

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Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document 
Not applicable. 
 

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Appendix C 
Pharmacogenetics Research 
Not applicable.