Conditions: Heart Failure
Keywords: Heart Failure Chronic Heart Failure Hyperkalaemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 182
Healthy volunteers: no

Brief summary:
This is an international, multicentre, parallel-group, randomised, double-blind, placebo controlled, phase II study to evaluate the benefits and risks of using sodium zirconium cyclosilicate (ZS) to initiate and intensify renin angiotensin aldosterone system inhibitor (RAASi) therapy in heart failure patients.

Detailed description:
Patients with chronic heart failure (NYHA II-IV) and serum potassium \> 5.0 mmol/L or at high risk of developing hyperkalaemia will be enrolled. Patients signing informed consent will be screened for up to 14 days. Patients meeting the inclusion criteria, but not the exclusion criteria, are then randomized in a 1:1 ratio to receive ZS or placebo for 3 months while titrating RAASi therapies. Approximately 280 patients will be randomized in the study. Study treatment in this study refers to ZS or placebo, while RAASi therapies are considered background therapy and will not be provided by the study sponsor. Patients will participate in the study for approximately 16 to 18 weeks in total, depending on the duration of the screening period. A Safety Review Committee will be established to review emerging safety data

Arms:
arm 1: Powder for oral suspension arm 2: Powder for oral suspension

Interventions: intervention 1: Sodium Zirconium Cyclosilicate intervention 2: Placebo
Intervention descriptions: intervention 1: Oral use for approximately 3 months intervention 2: Oral use for approximately 3 months

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
AZD7270 / Sodium 
Zirconium Cyclosilicate (ZS)
Study Code
D9484C00001
Version
5.0
Date
26May2020
A Phase II, Randomised, Double-Blind, Placebo Controlled, Parallel-Group, 
Multicentre, Three Month Duration Potassium Reduction Initiative to 
Optimize RAAS Inhibition Therapy with Sodium Zirconium CyclosilicatE in 
Heart Failure (PRIORITIZE HF)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
EudraCT number: 2018-000175-33; FDA IND number: 108951
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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................................1
TABLE OF CONTENTS................................................................................................... 17
1.
PROTOCOL SUMMARY ................................................................................. 21
1.1
Schedule of Activities (SoA).............................................................................. 21
1.2
Synopsis ............................................................................................................ 24
1.3
Schema .............................................................................................................. 28
2.
INTRODUCTION ............................................................................................. 29
2.1
Study rationale................................................................................................... 29
2.2
Background........................................................................................................ 29
2.3
Benefit/risk assessment ...................................................................................... 31
2.4
COVID-19 Pandemic Modifications .................................................................. 32
3.
OBJECTIVES AND ENDPOINTS.................................................................... 33
4.
STUDY DESIGN............................................................................................... 35
4.1
Overall design.................................................................................................... 35
4.2
Scientific rationale for study design ................................................................... 35
4.2.1
Rationale for patient population ......................................................................... 35
4.2.2
Rationale for blinding and randomisation........................................................... 36
4.2.3
Rationale for treatment groups ........................................................................... 37
4.2.4
Rationale for objectives and endpoints ............................................................... 37
4.3
Justification for dose.......................................................................................... 37
4.4
End of study definition....................................................................................... 38
5.
STUDY POPULATION .................................................................................... 38
5.1
Inclusion criteria ................................................................................................ 38
5.2
Exclusion criteria ............................................................................................... 40
5.3
Lifestyle restrictions........................................................................................... 42
5.3.1
Meals and dietary restrictions............................................................................. 42
5.3.2
Caffeine, alcohol, and tobacco............................................................................ 42
5.4
Screen failures ................................................................................................... 42
6.
STUDY TREATMENTS................................................................................... 42
6.1
Treatments administered .................................................................................... 43
6.1.1
Investigational products ..................................................................................... 43
6.2
Preparation/handling/storage/accountability....................................................... 43


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6.3
Measures to minimise bias: randomisation and blinding..................................... 44
6.4
Treatment compliance........................................................................................ 44
6.5
Concomitant therapy.......................................................................................... 44
6.5.1
RAASi treatment................................................................................................ 45
6.5.2
Other concomitant treatment .............................................................................. 48
6.5.3
Rescue medication ............................................................................................. 48
6.5.4
Drugs with pH-dependent absorption .................................................................49
6.6
Dose modification.............................................................................................. 49
6.7
Treatment after end of study treatment ............................................................... 50
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL ............................................................................................... 50
7.1
Discontinuation of study treatment..................................................................... 50
7.1.1
Temporary discontinuation................................................................................. 51
7.1.2
Procedures for discontinuation of study treatment .............................................. 51
7.2
Lost to follow-up ............................................................................................... 52
7.3
Withdrawal from the study................................................................................. 52
7.4
Study and Site Closure....................................................................................... 53
8.
STUDY ASSESSMENTS AND PROCEDURES............................................... 53
8.1
Efficacy assessments.......................................................................................... 54
8.1.1
RAASi treatment intensity ................................................................................. 54
8.1.2
Potassium........................................................................................................... 54
8.1.3
Patient reported outcomes (PROs)...................................................................... 54
8.1.4
NYHA class....................................................................................................... 56
8.1.5
Urine analysis .................................................................................................... 56
8.2
Safety assessments............................................................................................. 56
8.2.1
Clinical safety laboratory assessments................................................................ 56
8.2.2
Physical examinations........................................................................................ 58
8.2.3
Vital signs.......................................................................................................... 59
8.2.4
Electrocardiograms ............................................................................................ 59
8.3
Collection of adverse events............................................................................... 60
8.3.1
Method of detecting AEs and SAEs ................................................................... 60
8.3.2
Time period and frequency for collecting AE and SAE information ................... 60
8.3.3
Follow-up of AEs and SAEs .............................................................................. 60
8.3.4
Adverse event data collection............................................................................. 61
8.3.5
Causality collection............................................................................................ 61
8.3.6
Adverse events based on signs and symptoms.................................................... 62
8.3.7
Adverse events based on examinations and tests ................................................ 62
8.3.8
Hy’s law ............................................................................................................ 62
8.4
Safety reporting and medical management ......................................................... 62


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8.4.1
Reporting of serious adverse events ................................................................... 62
8.4.2
Pregnancy .......................................................................................................... 63
8.4.3
Overdose............................................................................................................ 64
8.4.4
Medication error ................................................................................................ 65
8.5
Pharmacokinetics (PK)....................................................................................... 65
8.6
Pharmacodynamics ............................................................................................ 65
8.7
Genetics............................................................................................................. 65
8.7.1
Optional exploratory genetic sample .................................................................. 65
8.7.2
Storage and destruction of genetic samples ........................................................ 65
8.8
Biomarkers ........................................................................................................ 66
8.8.1
Storage, re-use and destruction of biomarker samples ........................................ 66
8.9
Medical Resource Utilization and Health Economics ......................................... 66
8.10
Demography and medical history....................................................................... 66
9.
STATISTICAL CONSIDERATIONS................................................................ 66
9.1
Statistical hypotheses ......................................................................................... 66
9.2
Sample size determination.................................................................................. 67
9.3
Populations for analyses..................................................................................... 67
9.4
Statistical analyses ............................................................................................. 67
9.4.1
Efficacy analyses ............................................................................................... 67
9.4.2
Safety analyses................................................................................................... 68
9.4.3
Other analyses.................................................................................................... 69
9.4.4
Methods for multiplicity control......................................................................... 69
9.5
Interim analyses.................................................................................................69
9.5.1
Data Monitoring Committee (DMC) .................................................................. 69
10.
REFERENCES .................................................................................................. 70
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS......................................................................................... 72
LIST OF TABLES
Table 1 
Study Assessments................................................................................21
Table 2
Study objectives....................................................................................33
Table 3
Study Treatments ..................................................................................43
Table 4
Restricted medications ..........................................................................45
Table 5
RAASi treatments .................................................................................47


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Table 6 
Drugs with pH dependent absorption.....................................................49
Table 7 
Laboratory safety variables ...................................................................58
Table 8 
IP Dose adjustment table.......................................................................90
LIST OF FIGURES
Figure 1                Study design..........................................................................................29
LIST OF APPENDICES
Appendix A
Appendix A Regulatory, ethical and study oversight 
considerations .......................................................................................73
Appendix B
Adverse event definitions and additional safety information..................77
Appendix C
Handling of Human Biological Samples................................................81
Appendix D
Genetics................................................................................................83
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law .........................................................................86
Appendix F
IP (ZS or placebo) dose titration............................................................90
Appendix G
New York Heart Association (NYHA) Functional Classification...........92
Appendix H
Patient Reported Outcome (PRO) questionnaires ..................................93
Appendix I
Abbreviations........................................................................................98


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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
Table 1
Study Assessments
Visit
1*
(Screening)
2*
3
4
5
6
7
8
(EoT)
9
10
Dose change for either RAASi 
or IP 
Details in CSP section 
or Appendix
Week (Day 1 of)
-2 to 1
1
2
3
5
7
9
13
14
17
Day 
-14 to 1
1
8
15
29
43
57
85$
92 (or 7d 
after last 
IP)$
115 (or 30d 
after last 
IP)$
7d after every titration (±2) /
3d after MRA initiation (±1)
Window
-14 to 1
±2
±3
±3
±7
±7
±7
±2
±7
Informed consent 
X
Section 5.1
Inclusion /exclusion 
criteria
X
X
Sections 5.1 and 5.2
Routine clinical procedures
Demography
X
Section 8.10
Physical 
examination
X
Section 8.2.2
Targeted physical 
examination
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
Medical history and 
comorbid 
conditions
X
Section 5.1
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.3
NYHA class
X
X
X 
X 
Section 8.1.4
Height
X
Section 8.2.2
Weight
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
ECG 
X
X
X
Section 8.2.4


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Visit
1*
(Screening)
2*
3
4
5
6
7
8
(EoT)
9
10
Dose change for either RAASi 
or IP 
Details in CSP section 
or Appendix
Week (Day 1 of)
-2 to 1
1
2
3
5
7
9
13
14
17
Day 
-14 to 1
1
8
15
29
43
57
85$
92 (or 7d 
after last 
IP)$
115 (or 30d 
after last 
IP)$
7d after every titration (±2) /
3d after MRA initiation (±1)
Window
-14 to 1
±2
±3
±3
±7
±7
±7
±2
±7
Concomitant 
medication
At every visit and may be conducted by phone if not tied to a visit.
Section 6.5
Routine safety measurements
Adverse events
At every visit and may be conducted by phone if not tied to a visit.
Section 8.3
Pregnancy test 
(serum or urine)
X
X
Section 5.1
Safety laboratory 
assessments 
(central) 
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.1
Local lab potassium 
and creatinine#
X
X
X
X
X
X
X
X
X
X
X
Sections 8.2.1 and 8.1.2
Biomarker analyses
Biomarker blood 
sample collection
X
X
X
X
Section 8.8
Morning spot urine
X
X
Section 8.1.5
PRO measurements
KCCQ
X
X
X
Section 8.1.3.2
PGIC
X
Section 8.1.3.1
Pharmacogenetic sampling (optional)
Blood sample 
X
Section 8.7
Study treatment administration and procedures
Randomisation
X
Section 6.3
Study treatment  
dispensed
X
X
X
Section 6


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Visit
1*
(Screening)
2*
3
4
5
6
7
8
(EoT)
9
10
Dose change for either RAASi 
or IP 
Details in CSP section 
or Appendix
Week (Day 1 of)
-2 to 1
1
2
3
5
7
9
13
14
17
Day 
-14 to 1
1
8
15
29
43
57
85$
92 (or 7d 
after last 
IP)$
115 (or 30d 
after last 
IP)$
7d after every titration (±2) /
3d after MRA initiation (±1)
Window
-14 to 1
±2
±3
±3
±7
±7
±7
±2
±7
Study treatment 
returned
X
X
X
Section 6
ZS / placebo 
titration
X
X
X
X
X
  
X
Section 6.7
ACEi/ARB/ARNI/
MRA titration
X
X
X
X
X
X
X
X
Section 6.5.1
ACEi/ARB/ARNI/
MRA to baseline or 
lowest dose
X
Section 6.5.1
* Visits 1 and 2 may be combined into one visit. It is acceptable to have a 24-hour window between the local lab draw and the rest 
of the visit procedures. When V2 occurs within one calendar day after V1, it will still be considered a single combined visit. In this 
case, Investigators should ensure no other entry criteria (e.g., medications) have changed from V1 to V2.
# Data results from local lab samples should be obtained as soon as possible after sample collection, but no later than 24 hours after 
the sample collection. If blood samples for local lab are taken at the study visit and the results are not known prior to the subject 
leaving the visit, the investigator may call the subjects or bring them back the following day for instructions regarding concomitant 
medication titration and IP dosing. Alternatively, if more feasible for the subject and investigator, blood samples for the local lab 
may be collected one day before study procedure in cases when the local lab sample analysis time is expected to be longer than the 
duration of the subject’s clinic visit. $ While the intention was for all subjects enrolled under Amendment 3 to have all study visits 
in order, despite any premature IP discontinuation, the COVID-19 pandemic necessitated some patients skipping ahead to an early 
termination visit with Visit 8 procedures performed (See Appendix I). In these cases, the investigator unblinded the patients for 
medical management, and the 7-day and 30-day safety follow visits were performed relative to the date Visit 8 occurred. An 
additional potassium measurement was also recommended 48 hours post-last IP dose for patients on active IP or with large RAASi 
changes. Note this skipping ahead to Visit 8 and unblinding for some patients during the COVID-19 pandemic is similar to the 
procedures followed for patients enrolled during Amendments 1, 2, and 3.


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1.2
Synopsis
International co-ordinating investigator: Jean-Claude Tardif
Protocol Title:
A Phase II, Randomised, Double-Blind, Placebo Controlled, Parallel-Group, Multicentre, 
Three Month Duration Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy 
with Sodium Zirconium CyclosilicatE in Heart Failure (PRIORITIZE HF)
Short Title:
PRIORITIZE HF 
Rationale: 
Heart failure (HF) patients are frequently not administered renin-angiotensin aldosterone 
system inhibitor (RAASi) therapies at recommended doses due to hyperkalaemia, despite 
proven mortality and morbidity benefits. Sodium zirconium cyclosilicate (ZS) is a novel non-
absorbed potassium trap proven to lower serum potassium (S-K) and maintain 
normokalaemia. The purpose of PRIORITIZE HF is to assess if a treatment regimen 
containing ZS will allow RAASi therapies to be up-titrated to target doses in patients with 
heart failure and elevated serum potassium or at high risk of developing elevated serum 
potassium.
Study Objectives
Primary Objective:
Endpoint/Variable:
To determine if there is a difference between ZS and 
placebo in RAAS blockade treatment.
Proportion of subjects in the following categories at 3 
months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose


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Safety Objective:
Endpoint/Variable:
To evaluate the safety and tolerability of ZS in this 
patient population.

Serious Adverse Events (SAEs)

Discontinuation of IP due to 
Adverse Events (DAEs)

Adverse Events (AEs)

Changes in clinical laboratory 
parameters, including assessment 
of creatinine and renal function 
(eGFR).

Vital signs

ECGs
To explore whether ZS compared with placebo will 
affect the incidence of high and/or low S-K levels.
Number of subjects and number of events with central 
lab levels of S-K: 

>6.0 mmol/L

>5.5 mmol/L

<3.5 mmol/L

<3.0 mmol/L
Exploratory Objectives
Endpoint/Variable:
To explore the difference between ZS and placebo in 
RAAS blockade treatment in subjects with local lab-
K> 5.0 mmol/L at last assessment before 
randomization
Proportion of subjects in the following categories at 3 
months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose


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To explore the difference between ZS and placebo in 
RAAS blockade treatment in subjects with local lab-
K ≤5.0 mmol/L at last assessment before 
randomization
Proportion of subjects in the following categories at 3 
months:

No ACEi/ARB/ARNI or at less than target 
dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose
To explore the difference between ZS and placebo in 
facilitating the initiation and maintenance of MRA 
treatment
Proportion of subjects treated with MRA at 3 months 
Proportion of subjects at target dose of MRA therapy 
at 3 months
To explore the difference between ZS and placebo in 
RAASi therapy
Proportions of subjects on higher dose of RAASi 
compared to baseline
Mean equipotent doses of MRA at 3 months
Dose intensity score as calculated in Vasudevan et al 
(Vasudevan et al 2017), with the exception of only 
considering RAASi drugs
A scoring system to assess the intensity of RAASi 
therapy is defined in the Statistical Analysis Plan.
To explore change of blood pressure (BP) in the ZS 
group compared with the placebo group.
Change in systolic and diastolic BP from baseline.
To explore change of urinary albumin to creatinine 
ratio (UACR) in the ZS group compared with the 
placebo group.
Change in UACR from prior to the first increase in 
RAASi therapy (Visit 3), in the subset of subjects 
with albuminuria (UACR > 30 mg/g) at Visit 3.
To explore change in NYHA class in the ZS group 
compared with the placebo group.
Change in NYHA class from baseline.
To explore the effect of treatment with ZS versus 
placebo on the Patient Global Impression of Change 
(PGIC) and Kansas City Cardiomyopathy 
Questionnaire (KCCQ) Overall Summary Score.
Change in health status measured by PGIC.
Change from baseline measured at 3 months in the 
overall summary score of KCCQ, a specific HF 
patient reported outcome questionnaire.
To explore any change in biomarkers as surrogates 
for cardiac and renal function associated with ZS
Changes in biomarkers N-terminal pro b-type 
natriuretic peptide (NT-pro-BNP) and troponin.
To collect and store samples of plasma and serum for 
future exploratory biomarker and (optional) genetic 
research.
Results to be reported outside of the clinical study 
report (CSR).
Overall design:
This is an international, multicentre, parallel group, randomised, double-blind, placebo-
controlled Phase II study to evaluate the benefits and risks of using sodium zirconium 
cyclosilicate (ZS) to initiate and intensify RAASi therapy. Patients with chronic heart failure 


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(NYHA II-IV) and mild hyperkalaemia or at high risk of developing hyperkalaemia will be 
enrolled. Eligible subjects will be randomised in a 1:1 ratio to receive ZS or placebo for 3 
months while titrating RAASi therapies.
COVID-19 Pandemic Modifications Summary: The study was terminated prematurely 
because of the COVID-19 pandemic, and study procedures were modified to ensure patient 
safety and trial integrity. The full details of these changes, in addition to their impact, can be 
found in Appendix I.
Specifically, as of April 01, 2020, all sites were asked to discontinue patients from the active 
treatment phase of the study. Sites were told to bring forward all patients who had not yet 
completed Visit 8 (End-of-Treatment visit) to conduct Visit 8 as soon as possible. At the end 
of Visit 8, sites were requested to withdraw the IP, and unblind each patient to the IP via the 
IVRS/ IWRS system. For patients on placebo, the patients should have been managed as 
deemed appropriate by the investigator. For the patients on Lokelma, patients should have 
been RAASi down-titrated to pre-randomization (or lowest) doses, and potassium should have 
been checked at 48 hours and also 7 days post IP discontinuation. Visit 9, a safety follow-up 
visit 7 days after IP discontinuation, should have been conducted for all patients.  
Study Period:
Date of first subject enrolled: 26 June 2018
Estimated date of last subject completed: Q2 2020
Number of Subjects:
Approximately 280 subjects were planned to be randomized, but due to the premature 
termination, 182 patients were randomized..
Treatments and treatment duration:
As detailed in the Schedule of Activities (SoA) above, subjects signing informed consent will 
be screened for up to 14 days. Patients meeting the inclusion criteria, but not the exclusion 
criteria, are then randomized and start study therapy. It is allowed to perform all screening 
activities at a single visit, allowing subjects to be screened and randomized at a single visit.
Study treatment in this study refers to ZS or placebo, while RAASi therapies are considered 
background therapy and will not be provided by the study sponsor. Note that sodium 
zirconium cyclosilicate can be abbreviated as either ZS or SZC in documents and refer to the 
same product.
Patients with serum potassium concentration as measured using the site’s local lab (local lab-
K) >5.0 mmol/L at the last assessment before randomization will be randomized to receive ZS 
10 g or placebo three times a day (tid) for 2 days followed by ZS 5 g or placebo once a day 
(qd). Patients with local lab-K ≤ 5.0 mmol/L at the last assessment before randomization will 
be randomized to receive ZS 5 g qd or placebo qd. The total treatment duration will be 


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approximately 12 weeks. Also, ZS / placebo will be up / down titrated in the range ZS 5 g 
every other day (qod) to ZS 15 g qd (or matching doses of placebo) to maintain the subject in 
the normokalaemic range (S-K 3.5 to 5.0 mmol/L inclusive) during the randomized treatment 
period.
During the randomized treatment period the RAASi therapy will be up-titrated, if possible, 
depending on local lab-K and other laboratory and clinical parameters. RAASi therapy should 
be uptitrated in patients with local lab-K <5.0 mmol/L; in patients with local lab-K > 5.0 
uptitration may be attempted when potassium levels are moving towards normal, e.g. upon 
Investigational Product (IP) dose increase.
Up-titration of RAASi therapy means increasing the dose of ACEi/ARB/ARNI to a target 
dose or a maximum tolerated dose AND adding or uptitrating a mineralocorticoid receptor 
antagonist (MRA) and titrating the MRA to a target/maximum tolerated dose (Table 5). Refer 
to Section 6.5.1 for specific details.
Patients will participate in the study for approximately 16 to 18 weeks in total, depending on 
the duration of the screening period.
Data Monitoring Committee (DMC):
A data monitoring committee (which can also refer to a Safety Review Committee) will be 
established to review emerging safety data. See Appendix A for details. 
Statistical methods
The primary analysis to determine if there is a difference between ZS and placebo in RAAS 
blockade treatment will be performed using the Full analysis set. The null hypothesis is that 
there is no difference between treatments in the distribution of proportion of patients in the 
RAAS blockade treatment categories, and the alternative hypothesis is that there is a 
difference. The hypothesis will be tested at a significance level of 5% using a chi-square test 
for homogeneity.
The study will employ a 1:1 randomization scheme. A sample size of 280 subjects will allow 
for estimation of the effect in the primary objective. Due to lack of prior knowledge of the 
distribution in the placebo group, the following considerations were made with regards to 
sample size. Assuming a difference in proportion of MRA use at 3 months of 0.2 between 
treatment groups, a sample size of 140 subjects per group provides at least 90% power for a 
significance level of 5% using a chi-square test. 
Due to the premature termination, 182 patients were randomized.
1.3
Schema
The general study design is summarised in Figure 1.




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Europe (Ambrosy et al 2014). The annual global economic burden in 2012 was estimated to 
be $108 billion (Cook et al 2014) and is projected to increase dramatically as the population 
ages.
The current treatment paradigm for HF involves the simultaneous targeting of multiple 
pathways including the renin-angiotensin-aldosterone system (RAAS), the autonomic system, 
and symptomatic treatment with diuretics.
Even with the best possible treatment, the five-year survival rate for HF is worse than for most 
cancers (Braunwald 2015). For patients with chronic HF, worsening symptoms require prompt 
medical attention, add to the burden of hospital and non-hospital settings and also have a 
considerable economic impact (Ponikowski et al 2016, Okumura et al 2016).
Inhibition of the RAAS using RAAS inhibitors (RAASi) has been proven to provide survival 
benefits for patients with HF. RAASi drug classes include angiotensin converting enzyme 
inhibitors (ACEi), angiotensin receptor blockers (ARB), combined angiotensin receptor / 
neprolysin inhibitors (ARNI), and mineralocorticoid receptor antagonists (MRA).
International HF guidelines from American College of Cardiology Foundation (ACCF) and 
American Heart Association (AHA) and the European Society of Cardiology (ESC) 
recommend administration of one ACEi, ARB or ARNI, and one MRA to patients with 
HFrEF and ejection fraction <40% (Ponikowski et al 2016, Yancy et al 2017). Unfortunately, 
a significant proportion of patients do not receive ACEi/ARB/ARNI and/or MRA treatments 
as recommended, or do not receive the treatments at the recommended doses, frequently due 
to fear of hyperkalaemia (Epstein et al 2016).
The prevalence of hyperkalaemia has been reported to be 3-4% in hospitalized patients, and 
the risk is considerably increased in persons with advanced chronic kidney disease, heart 
failure, diabetes and/or treatment with RAASi (Einhorn et al 2009, Fleet et al 2012, Kovesdy 
2015). Hyperkalaemia often presents without symptoms or with nonspecific symptoms 
including malaise, confusion, muscle weakness or signs of cardiac arrhythmias (Henneman et 
al 2016). Even mild elevations of S-K is associated with higher mortality, but a causal 
relationship remains to be established (Einhorn et al 2009, Nakhoul et al 2015).
ZS is a non-absorbed, inorganic crystalline compound that selectively captures potassium ions 
in exchange for sodium and hydrogen ions in the gastrointestinal tract after oral 
administration.  Thereby excess potassium are removed from the body through faecal 
excretion and serum potassium is decreased.
A global clinical programme including more than 1800 patients with hyperkalaemia 
demonstrated the efficacy of ZS compared with placebo for correction of hyperkalaemia, with 
88% of patients reaching normal S-K after 48 hours of treatment with ZS 10 g three times a 
day (tid).  Maintenance of normokalaemia was also demonstrated, with lower mean S-K and 
increased number of normokalaemic days with ZS 5 g or 10 g once daily (qd) compared with 
placebo, and a lasting maintenance effect for up to 12 months.  More details on the 
pharmacological properties, efficacy and safety of ZS are given in the Investigators’ Brochure.


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As ZS has been proven to be a safe and efficacious treatment for hyperkalaemia, a medication 
regimen containing ZS may allow more intensive RAASi therapy among patients otherwise 
not able to achieve treatment with RAASi at recommended doses due to hyperkalaemia. The 
underlying hypothesis is that more intense heart failure therapy, especially increased MRA 
use, will be safely facilitated by a treatment regimen containing ZS.
The current study is designed to evaluate the dose intensification of RAASi therapies on ZS or 
placebo. Intensified heart failure therapy is anticipated to reduce left ventricular wall stress, 
which will be assessed in this study using NT-pro-BNP and other endpoints. 
2.3
Benefit/risk assessment
This study will recruit subjects who are mildly hyperkalemic or who are at high risk of 
developing hyperkalaemia, randomise such subjects to ZS or placebo, and subsequently 
attempt to up-titrate doses of RAASi therapies administered to target doses recommended in 
international heart failure guidelines. RAASi therapies have the potential to increase serum 
potassium and, hence hyperkalaemia is the major medical risk for subjects participating in the 
trial, especially as HF patients may be at an increased risk of hyperkalaemia induced 
arrhythmias. In addition, up-titration of RAASi therapies may result in hypotension and/or 
decreased renal function, as assessed by estimated glomerular filtration rate (eGFR). The 
following study design features were included to minimize the risk to subjects:

Local labs will be used by sites to allow dose adjustments to occur rapidly at each 
visit by providing investigators with up-to date serum K and creatinine 
measurements.

Subjects with local lab-K > 5.5 mmol/L before randomization are excluded to 
minimize the risk of subjects developing severe hyperkalaemia. Additionally, the 
provision to not up-titrate RAASi in subjects with a local lab S-K >5.0 mmol/L 
before levels start to decrease towards normal should also protect subjects against 
the risk of developing severe hyperkalaemia.  

Stopping rules are provided for subjects with local lab-K > 6.5 mmol/L or local lab-
K <3.0 mmol/L as these subjects require immediate attention to the treatment of the 
potassium disorder.

To minimize the potential risk of rebound hyperkalaemia when IP is discontinued, 
after IP discontinuation (Visit 8 or early discontinuation) the investigator should 
return to the original RAASi dose the patient was on prior to randomization and 
manage the subject as per standard of care. In instances in which the investigator 
had down-titrated or stopped RAASi medications, then the subject should remain on 
the lowest dose at the end of randomized therapy. 

Hypokalaemia has been reported in subjects treated with ZS. ZS titration down to 5 
g every other day (qod), stopping rules for subjects with severe hypokalaemia, the 
use of local lab monitoring is included in this protocol to minimize the risk of 
hypokalaemia to recruited subjects. 


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
Oedema related events (grouped terms include preferred terms of oedema, oedema 
peripheral, generalized oedema, fluid overload, fluid retention, hypervolaemia, 
localised oedema, and peripheral swelling) have been reported by patients treated 
with ZS, in particular at higher doses. Patients with HF have a high likelihood of 
experiencing oedema. A physical examination will be performed, and the subject 
will be weighed at each visit to ensure any oedema development will be caught 
early and appropriately managed.
Prior studies with ZS have included patients with HF and on RAASi therapy. RAASi dose up-
titration was allowed in study ZS-005 and did occur in some patients but was not required by 
the protocol. Earlier studies, including ZS-003, ZS-004 and ZS-004E did also include patients 
with HF, but RAASi up-titration was not allowed. The previous experience with ZS in 
patients with HF and treated with RAASi have not to date generated any safety signal 
precluding the use of ZS in patients with HF and on RAASi therapy.
Detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of ZS may be found in the Investigator’s Brochure.
Participating subjects, irrespective of treatment allocation, may benefit from more intense
monitoring and attention to their underlying condition. Patients randomised to receive ZS may 
benefit by being able to be treated with guideline-recommended target doses of RAASi, but 
due to the limited duration of this trial they are not expected to experience any significant 
clinical benefit by participating in this study. In the larger perspective the main potential 
benefit of conducting PRIORITIZE HF lies in the possibility to develop an improved 
treatment regimen for patients with moderate to severe heart failure with hyperkalaemia or at 
high risk of hyperkalaemia, and in the long term to improve outcomes for such patients.
Due to the limited potential risks to recruited subjects, the risk mitigation efforts included in 
this protocol to minimize risk to participants, and the potential long-term benefits of 
developing a treatment regimen for HF patients with or at high risk of hyperkalaemia, it is 
concluded that the study as proposed exposes recruited subjects to an acceptable risk 
considering the considerable potential long-term benefit of conducting the trial.
2.4
COVID-19 Pandemic Modifications
The study was terminated prematurely because of the COVID-19 pandemic, and study 
procedures were modified to ensure patient safety and trial integrity. The full details of these 
changes, in addition to their impact, can be found in Appendix I.
Specifically, as of April 01, 2020, all sites were asked to discontinue patients from the active 
treatment phase of the study. Sites were told to bring forward all patients who had not yet 
completed Visit 8 (End-of-Treatment visit) to conduct Visit 8 as soon as possible. At the end 
of Visit 8, sites were requested to withdraw the IP, and unblind each patient to the PI via the 
IVRS/ IWRS system. For patients on placebo, the patients should have been managed as 
deemed appropriate by the investigator. For the patients on Lokelma, patients should have 
been RAASi down-titrated to pre-randomization (or lowest) doses, and potassium should have 


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been checked at 48 hours and also 7 days post IP discontinuation. Visit 9, a safety follow-up 
visit 7 days after IP discontinuation, should have been conducted for all patients.  
3.
OBJECTIVES AND ENDPOINTS
Table 2
Study objectives
Primary Objective:
Endpoint/Variable:
To determine if there is a difference between ZS and 
placebo in RAAS blockade treatment.
Proportion of subjects in the following categories at 3 
months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose
Safety Objectives:
Endpoint/Variable:
To evaluate the safety and tolerability of ZS in this 
patient population.

Serious Adverse Events (SAEs)

Discontinuation of IP due to Adverse 
Events (DAEs)

Adverse Events (AEs)

Changes in clinical laboratory 
parameters, including assessment of 
creatinine and renal function (eGFR).

Vital signs

ECG


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To explore whether ZS compared with placebo will 
affect the incidence of high and/or low S-K levels.
Number of subjects and number of events with
central lab levels of S-K:

>6.0 mmol/L

>5.5 mmol/L

<3.5 mmol/L

<3.0 mmol/L
Exploratory Objectives
Endpoint/Variable:
To explore the difference between ZS and placebo in 
RAAS blockade treatment in subjects with local lab-
K > 5.0 mmol/L at last assessment before 
randomization.
Proportion of subjects in the following categories at 3 
months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose
To explore the difference between ZS and placebo in 
RAAS blockade treatment in subjects with local lab 
K ≤5.0 mmol/L at last assessment before 
randomization.
Proportion of subjects in the following categories at 3 
months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose
To explore the difference between ZS and placebo in 
facilitating the initiation and maintenance of MRA 
treatment
Proportion of subjects treated with MRA at 3 months
Proportion of subjects at target dose of MRA therapy 
at 3 months
To explore the difference between ZS and placebo in 
RAASi therapy
Proportions of subjects on higher dose of RAASi 
compared to baseline
Mean equipotent doses of MRA at 3 months
Dose intensity score as calculated in Vasudevan et al 
(Vasudevan et al 2017), with the exception of only 
considering RAASi drugs
A scoring system to assess the intensity of RAASi 
therapy is defined in the Statistical Analysis Plan.


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To explore change of blood pressure in the ZS group 
compared with the placebo group.
Change in systolic and diastolic BP from baseline.
To explore change of urinary albumin to creatinine 
ratio (UACR) in the ZS group compared with the 
placebo group.
Change in UACR from prior to the first increase in 
RAASi therapy (Visit 3), in the subset of subjects 
with albuminuria (UACR > 30 mg/g) at Visit 3.
To explore change in NYHA class in the ZS group 
compared with the placebo group.
Change in NYHA class from baseline.
To explore the effect of treatment with ZS versus 
placebo on the Patient Global Impression of Change 
(PGIC) and Kansas City Cardiomyopathy 
Questionnaire (KCCQ) Overall Summary Score.
Change in health status measured by PGIC.
Change from baseline measured at 3 months in the 
overall summary score of KCCQ, a specific HF 
patient reported outcome questionnaire.
To explore any change in biomarkers as surrogates 
for cardiac and renal function associated with ZS
Changes in biomarkers NT-pro-BNP and troponin.
To collect and store samples of plasma and serum for 
future exploratory biomarker and (optional) genetic 
research.
Results to be reported outside of the clinical study 
report (CSR).
4.
STUDY DESIGN
4.1
Overall design
This is an international, multicentre, parallel group, randomised, double-blind, placebo-
controlled Phase II study to evaluate the benefits and risks of using sodium zirconium 
cyclosilicate (ZS) to intensify RAASi therapy in patients with heart failure, in particular 
through the initiation of MRA treatment, but also through up-titration of ACEi, ARB or ARNI 
therapy, without inducing clinically significant hyperkalemia. Eligible subjects will have 
chronic heart failure (NYHA II-IV) and be mildly hyperkalaemic (S-K: 5.1-5.5) and/or be at 
high risk of developing hyperkalaemia. Subjects will be randomised in a 1:1 ratio to receive 
ZS or placebo for 3 months while titrating RAASi therapies.
For an overview of the study design, see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments Administered.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.
For details on the COVID-19 pandemic impact, see Appendix I.
4.2
Scientific rationale for study design
4.2.1
Rationale for patient population
Eligible subjects with HF but not receiving recommended target doses of RAASi therapies 
(MRA therapy and/or ACEi/ARB/ARNI therapy) with hyperkalaemia or at high risk to 
develop hyperkalaemia will be included in the study, as this is the population in which ZS is 
anticipated to be able to provide a benefit to patients.


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Eligible HF subjects must have ejection fraction ≤ 40%, be assessed as NYHA functional 
class II-IV, and receive ACEi/ARB/ARNI therapy as per guidelines. Subjects are expected to 
be receiving a beta-blocker per standard of care guidelines, however patients in whom beta-
blockers are contraindicated are eligible for inclusion. 
Since MRAs are more often associated with hyperkalaemia that limits adequate dosing, it is 
important to demonstrate that ZS allows MRA introduction and up-titration. Therefore, 
patients treated with MRA at target doses at baseline are excluded. Instead, patients should be 
on either no MRA or a low dose MRA that was not increased specifically due to prior, 
documented hyperkalemia. Low dose is defined as less than or equal to spironolactone 12.5 
mg QD (or 25 mg QOD) or equivalent for the patient to qualify. 
The patient population will be enriched for subjects at risk of developing hyperkalaemia 
during up-titration of RAASi therapies by limiting inclusion to subjects with eGFR between 
20 and 59 ml/min/1.73 m2, and by requiring that subjects with eGFR ≥ 45 ml/min/1.73 m2
should be either mildly hyperkaelemic or have a history of hyperkalaemia upon RAASi 
therapy even if normokaelemic at inclusion. This patient population would benefit the most 
from the use of ZS. 
Patients with local lab-K >5.5 mmol/L are excluded since the up-titration of RAASi in such 
subjects may pose a risk in subjects receiving placebo.
Patients receiving agents binding potassium in the gastrointestinal tract, such as sodium 
polystyrene sulfonate (SPS), calcium polystyrene sulfonate (CPS) or patiromer, are excluded 
to avoid pharmacodynamic interactions with ZS.
4.2.2
Rationale for blinding and randomisation
The study employs blinding to minimize the risk for bias introduced by subjects, investigators 
and sponsor or sponsor representatives. Minimizing bias introduced by investigators and 
subjects is imperative as the primary endpoints of the trial can be influenced significantly by 
treatment choices made by the investigators in the trial and agreed with participating subjects.
Note that unblinding to the investigator, to facilitate patient management, was recommended 
to sites as part of the response to the COVID-19 pandemic (see Appendix I for details) once 
patients discontinued IP. Additionally, patients in the original protocol up through 
Amendment 3 were also unblinded after IP discontinuation, then managed by an unblinded 
investigator, for medication management. However, neither of these situations are expected to 
increase bias relating to the primary endpoint, as the unblinding occurred after collection of 
the primary endpoint data, and was not shared with the Sponsor. Randomisation is employed 
to minimize the risk for bias and produce comparable groups, and a 1:1 randomisation scheme 
was selected to maximize power and thereby minimize the number of subjects needed to be 
recruited.


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4.2.3
Rationale for treatment groups
Patients randomised to receive ZS with local lab-K >5.0 mmol/L at the last assessment before 
randomization will be treated with ZS 10 g tid for 2 days followed by ZS 5 g qd, while 
normokalemic subjects will start ZS 5 g qd immediately after randomisation. The initial ZS 10 
g tid treatment will ensure S-K is brought down to the normokalemic range rapidly, thereby 
increasing the chance RAASi up-titration can start at Visit 3 one week after randomisation. 
RAASi up-titration should not be initiated in subjects with local lab-K >5.0 mmol/L until 
there is evidence that S-K levels are decreasing toward normal, e.g. upon IP titration.
Patients randomised to placebo will continue their therapy as before randomisation, but may 
benefit from additional monitoring of their local lab-K and then subsequent up- or down-
titration of their RAASi therapy.
Titration of ZS based on local lab-K values at each visit will be employed to ensure all 
subjects receive ZS at an individually optimized dose. Patients randomized to receive placebo 
will undergo mock titration to maintain the study blinding.
Placebo is used as comparator in PRIORITIZE HF as the primary efficacy endpoints could be 
affected by treating physicians knowing the treatment allocation of individual subjects, and as 
there is no other drug currently approved or widely used to allow up-titration of RAASi in 
patients at high risk of hyperkalaemia. Hence placebo is a necessary and appropriate 
comparator.
4.2.4
Rationale for objectives and endpoints
The purpose of PRIORITIZE HF is to assess if a treatment regimen containing ZS will allow 
RAASi therapies to be up-titrated to target doses in patients with heart failure and elevated 
serum potassium or at high risk of developing elevated serum potassium.
RAASi therapies are well known to improve cardiovascular and patient outcomes in HF, but 
are frequently underutilized in patients with HF due to concern for hyperkalaemia (Epstein et 
al 2016). This is particularly true for MRA use. The main objective of nothis study is to 
determine if there is a difference between ZS and placebo in RAASi treatment. 
4.3
Justification for dose
ZS 10 g tid for 2 days hasbeen proven to be a tolerable and efficacious therapy to normalize S-
K in hyperkalaemic patients (see data on the Correction Phase for studies ZS-003, ZS-004 and 
ZS-005 in the Investigator’s Brochure).
ZS 5 g, 10 g, and 15 g qd has been proven to be tolerable and efficacious dose during longer 
term therapy in prior ZS studies (see data on the Maintenance Phase for studies ZS-004 and 
ZS-005 in the Investigator’s Brochure)
The ZS / placebo dose will be titrated during this study based on a dose titration schedule 
further developed from the ZS dose titration schedule previously successfully used in ZS-005, 
see Section 6.6 for details.


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4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last subject completing the 
study.
A subject is considered to have completed the study when he/she has completed visit 10.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomised to a study intervention.  Under no circumstances can 
there be exceptions to this rule. Subjects who do not meet the entry requirements are screen 
failures, refer to Section 5.4.
In this protocol “enrolled” subjects are defined as those who signed informed consent and 
received an enrolment number. “Randomised” subjects are defined as those who undergo 
randomisation and received a randomisation number.
For procedures for the withdrawal of incorrectly randomized subjects see Section 7.3.
5.1
Inclusion criteria
Subjects are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply, with the exception of inclusion criterion 3:
Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
2.
Provision of a signed and dated, written informed consent form prior to any mandatory 
study-specific procedures, sampling, and analyses.
3.
Provision of signed and dated written genetic informed consent prior to the collection 
of the samples for genetic analysis. Individuals refusing to provide informed consent 
for genetic testing may still be included in the study, but will not have to provide 
samples for genetic analysis.
The ICF process is described in Appendix A 3.


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Age
4.
Subject must be ≥18 years of age inclusive, at the time of signing the informed consent 
form.
Type of subject and disease characteristics
5.
Individuals with established documented diagnosis of symptomatic HFrEF (NYHA 
functional class II-IV), which has been present for at least 3 months.
6.
Individuals with left ventricular ejection fraction ≤ 40% (any measurement made 
within the past 12 months using echocardiography, multiple gate acquisition scan, 
computer tomography scanning, magnetic resonance imaging or ventricular 
angiography is acceptable, provided no subsequent measurement above 40%).
7.
Individuals receiving background standard of care for HFrEF and treated according to 
locally recognized guidelines with both drugs and devices, as appropriate. Therapy 
with ACEi/ARB/ARNI, MRA and beta-blocker should have been stable for ≥4 weeks 
prior to randomization. Subjects must be treated with an ACEi or an ARB or ARNI to 
be eligible. Subjects who are not being treated with beta-blockers because of a 
contraindication are eligible. Subjects should be taking no MRA or a low dose of MRA 
(spironolactone, eplerenone, or canrenone) defined as less than or equal to 12.5 mg QD 
or 25 mg QOD. If patients are taking a low dose MRA, the rationale for the low dose 
must be the patient could not tolerate a higher dose due to documented hyperkalemia 
observed at higher doses.
8.
Individuals with mild hyperkalaemia or at risk of developing hyperkalaemia during the 
study, as defined by meeting all of the criteria in any one of the 3 categories listed 
below:
a.
eGFR 20-44 ml/min/1.73m2 by CKD-EPI and local lab-K 4.0-5.5 mmol/L 
inclusive, or
b. eGFR 45-59 ml/min/1.73m2 by CKD-EPI and local lab-K 5.1-5.5 mmol/L 
inclusive, or
c.
eGFR 45-59 ml/min/1.73m2 by CKD-EPI and local lab-K 4.0-5.0 mmol/L inclusive 
and a documented history of S-K > 5.0 mmol/L due to RAASi.
Reproduction
9.
Women of childbearing potential must have a negative pregnancy test during screening 
(before the first dose of IP) performed locally. Sexually active women of childbearing 
potential must be using a highly effective medically acceptable contraception method 
such as:

combined hormonal contraception associated with inhibition of ovulation,

progesterone only hormonal contraception, associated with inhibition of ovulation,

intrauterine device (IUD), 


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
intrauterine hormone-releasing system (IUS), 

bilateral tubal occlusion, 

vasectomized partner, or

sexual abstinence (true abstinence in line with the subjects preferred and usual 
lifestyle). Subjects practicing abstinence will agree to have a documented second 
acceptable method of birth control such as a combination of the following: (1) oral 
contraceptive, depo progesterone or intrauterine device; and (2) a barrier method 
(condom or diaphragm), should they become sexually active during the course of 
study participation).
Women who are surgically sterile or those who are postmenopausal for at least 2 years are not 
considered to be of childbearing potential.
Contraceptive methods must be practiced upon being randomized to the study and through 12 
weeks after the last dose of study treatment. If a subject discontinues prematurely, the 
contraceptive method must be practiced for 12 weeks following the final administration of the 
study drug.
5.2
Exclusion criteria 
Medical conditions
1.
HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, 
hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease.
2.
Current acute decompensated HF, hospitalization due to decompensated HF within 
4 weeks prior to enrolment, or Myocardial infarction (MI), unstable angina, stroke 
or transient ischemic attack (TIA) within 12 weeks prior to enrolment.
3.
Coronary revascularization (percutaneous coronary intervention [PCI] or coronary 
artery bypass grafting [CABG]) or valvular repair/replacement within 12 weeks 
prior to enrolment or planned to undergo any of these operations after 
randomization.
4.
Implantation of a Cardiac Resynchronization Therapy (CRT) device or Implantable 
Cardioverter Defibrillator (ICD) within 12 weeks prior to enrolment or intent to 
perform atrial fibrillation ablation or to implant a CRT device.
5.
Previous cardiac transplantation or implantation of a ventricular assistance device 
(VAD) or similar device, or transplantation or implantation expected after 
randomization.
6.
Symptomatic bradycardia or second (Mobitz type 2) or third-degree heart block 
without a pacemaker.


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7.
Symptomatic hypotension or systolic blood pressure (BP) <95 mmHg on 2 
consecutive measurements.
8.
Receiving dialysis or anticipated by the investigator to require dialysis therapy 
within 3 months.
9.
Prior history of hypersensitivity to a RAASi drug, including but not limited to 
development of angioedema, icterus, hepatitis, or neutropenia or thrombocytopenia 
requiring treatment modification.
10.
Addison’s disease or other causes of hypoaldosteronism.
11.
Known hypersensitivity to ZS.
12.
Any condition outside the cardiovascular (CV) and renal disease area, such as but 
not limited to malignancy, with a life expectancy of less than 2 years based on 
investigator´s clinical judgement.
13.
Active malignancy requiring treatment.
Prior/concomitant therapy
14.
MRA therapies that are mainly investigational and/or are not widely available as an 
oral dosing formulation (eg, canrenoate and finerenone) are excluded.
15.
Treated with potassium binding resins such as sodium polystyrene sulfonate (SPS; 
e.g. Kayexalate®) or calcium polystyrene sulfonate (CPS; e.g. Resonium®) or the 
cation exchange polymer, patiromer sorbitex calcium (Veltassa®) within 7 days 
prior to the first dose of study drug.
16.
Treated with potassium supplements within 7 days prior to randomization.
Prior/concurrent clinical study experience
17.
Participation in another clinical study with ZS at any time or treatment with any 
investigational product (IP) during the last 3 months.
Other exclusions
18.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff, AstraZeneca representatives, and/or staff at the study site).
19.
Judgment by the investigator that the subject should not participate in the study if 
the subject is unlikely to comply with study procedures, restrictions and 
requirements.
20.
Previous randomisation in the present study.


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21.
Subjects with a family history of long QT syndrome, presence of cardiac 
arrhythmias or conduction defects that require immediate treatment, or a QTc of 
≥550 msec.
5.3
Lifestyle restrictions
No additional lifestyle restrictions are required by this study. Study sites are encouraged to 
instruct participants to adhere to any lifestyle restrictions they apply for similar patients not 
participating in a trial.
5.3.1
Meals and dietary restrictions
No additional dietary restrictions are required by this study. Study sites are encouraged to 
instruct participants to adhere to any dietary restrictions they apply for similar patients not 
participating in a trial.
5.3.2
Caffeine, alcohol, and tobacco
No general restrictions but see the Section 8.2.3 on restrictions prior to blood pressure 
measurement. 
5.4
Screen failures
Screen failures are defined as subjects who signed the informed consent form to participate in 
the clinical study and assigned enrolment number but are not subsequently randomly assigned 
randomization codes.  A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any adverse event (AE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Patients that are rescreened should not be given a new enrolment number.
These subjects should have the reason for screen failure recorded in the electronic Case 
Report Form (eCRF).
6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the study protocol. Study treatment in this study refers to ZS or 
placebo. 


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6.1
Treatments administered
6.1.1
Investigational products 
Table 3
Study Treatments
Treatment 1
Treatment 2
Study treatment name:
Sodium Zirconium 
Cyclosilicate (ZS)
Placebo
Dosage formulation:
Powder for oral suspension in 
a 5 g sachet
Powder for oral suspension in a 
sachet
Route of administration
Oral use
Oral use
Dosing instructions:
A single dose consists of 
one to three sachets that 
should be suspended in 45 
mL of water by the subject.
A single dose consisting of one 
to three sachets that should 
be suspended in 45 mL of 
water by the subject.
Packaging and labelling
Study treatment will be 
provided in sachets packed 
in a box. Each sachet and 
box will be labelled in 
accordance with Good 
Manufacturing Practice 
(GMP) Annex 13 and per 
country regulatory 
requirement.
Study treatment will be 
provided in sachets packed 
in a box. Each sachet and
box will be labelled in 
accordance with Good 
Manufacturing Practice 
(GMP) Annex 13 and per 
country regulatory 
requirement.
Provider
AstraZeneca 
AstraZeneca
6.2
Preparation/handling/storage/accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment will 
depend on local regulations in a given study country.


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The randomized treatment phase will have a double-blind design. Patients will take by mouth 
assigned dose from the sachet(s) containing either ZS or placebo. The content of the sachet(s) 
is to be swirled down in 45ml water before ingestion. Sachets are enclosed in a carton with a 
tamper evident seal intended to be broken exclusively by subjects just before taking the study 
drug.
6.3
Measures to minimise bias: randomisation and blinding
Eligible subjects will be assigned a unique randomisation code and randomised to study 
treatment using an interactive voice response system or interactive web response system 
(IVRS/IWRS). Before the study is initiated, the telephone number and call-in directions for 
the IVRS/IWRS and/or the log-in information and directions for the IVRS/IWRS will be 
provided to each site. Randomization will be stratified by country.
If a subject withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. Withdrawn subjects will not be replaced. 
The IVRS/IWRS will provide to the Investigator(s) or pharmacists the kit identification 
number to be allocated to the subject at the dispensing visit. Routines for this will be described 
in the IVRS/IWRS user manual that will be provided to each centre.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the subject requires knowledge of the treatment randomisation. 
The Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Randomisation codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
subject have been made and documented.
6.4
Treatment compliance
Any change from the dosing schedule, dose interruptions, dose reductions, dose 
discontinuations should be recorded in eCRF.
The Investigational Product Storage Manager is responsible for managing the Investigational 
medicinal products (IMP) from receipt by the study site until the destruction or return of all 
unused IMP.  The Investigator(s) is responsible for ensuring that the subject has returned all 
unused IMP.
6.5
Concomitant therapy
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrolment or receives 
during the study must be recorded along with:


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
Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency

Fixed-dose combination therapies (FDCs) will be recorded using the brand name 
for the FDC, except for FDCs where one of the components is a RAASi therapy 
listed in Table 5. FDCs containing a RAASi therapy component will instead be 
reported as a separate treatment for each FDC component on the concomitant 
medications Case Report Form (CRF) page to allow proper assessment of RAASi 
treatment intensity. An exception to this requirement is the administration of an 
ARNI; for that class of medication (see Table 5) it should be reported using the 
brand name as one entry.
Table 4
Restricted medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it is allowed ).
Drugs administered primarily to lower S-K
(e.g. potassium binders). Diuretics 
administered to manage HF symptoms are 
allowed.
All treatments intended to lower S-K must be 
withheld during the treatment period, except as 
detailed in Section 6.5.3.
Potassium substitution or other drugs 
administered primarily to raise S-K (e.g. 
KCl)
All treatments intended to raise S-K must be 
withheld during the treatment period, except as 
detailed in Section 6.5.3.
Drugs with pH dependent absorption (see 
Section 6.5.4 for details)
Drugs with pH-dependent absorption should be 
administered at least 2 hours before or 2 hours 
after ZS to mitigate the risk of drug interactions.
6.5.1
RAASi treatment
RAASi treatments include two types: 1) ACEis, ARBs, or ARNIs, and 2) MRAs.
The titration of both types of RAASi treatments to the highest tolerable dose is the main 
objective of the trial, and as such should be given appropriate attention by investigators and 
study staff. Reasons for not increasing RAASi treatment while the patient is taking IP will be 
collected in the CRF.
General principles for titration of RAASi treatment:

Up-titration of RAASi therapy should be done in the following order:
1. Adding an MRA (if patient is not already on a low dose), THEN 
2. Titrating the MRA to the target or maximum tolerated dose, THEN


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3. Increasing ACEi/ARB/ARNI to a target dose or a maximum tolerated dose if 
not already at target dose (Table 5). 

When MRA is initially added (if the patient is not already on low-dose MRA):
o
The patient must be seen 3 (+/-1) days later.
o
The typical starting dose for spironolactone is 25 mg QD. However, 
investigators may consider lower doses (eg, 25 mg QOD, 12.5 mg QD, or 12.5 
mg QOD) if medically warranted. Similar adjustments may be considered for 
other MRAs (Table 5).

At every study visit during the treatment period an attempt should be made to 
initiate or up-titrate the RAASi therapy administered. Patients who are at a target 
dose with one MRA and one ACEi/ARB/ARNI, or, in the opinion of the 
investigator, are already titrated to the maximum safe and tolerated RAASi 
treatment, should not be further up-titrated.  

Each up- or down-titration of RAASi therapy will require an additional study visit 
to be performed 7 (+/-2) days later, with the exception of MRA initiation that 
requires reassessment in 3 (+/-1) days later (see Schedule of Activities (SoA) for 
details). The investigator should always consider an earlier study visit if he or she 
has any concerns of subject safety (eg, in cases of hyperkalemia). If MRA initiation 
and IP and/or ACEi/ARB/ARNI titration occur at the same visit, requiring a dose 
change visit within 3 (+/-1) days and another within 7 (+/-2) days, only the earliest 
dose change visit should be performed.

Evidence of poor RAASi tolerability may include, but is not limited to, local lab-K 
> 5.0 mmol/L, hypotension, clinically significant decline of eGFR (based on 
investigator judgement), and eGFR < 20 ml/min/1.73m2. If a subject exhibits any of 
the above, the following should be considered:
o
Up-titration of RAASi therapies should not be performed until tolerability 
improves, e.g. S-K is decreasing towards normality, e-GFR is stabilizing and 
equal or above 20 ml/min/1.73m2 
o
Down-titration of RAASi therapies may be considered based on investigator 
judgement
o
If local lab K >5.0 and <6.0 mmol/L, consideration should be given to first up-
titrating IP (see Section 6.6 and Appendix F), then rechecking K within 7 days 
to determine if K is decreasing toward normokalemia, prior to down-titrating 
RAASi. 

After IP discontinuation, if subjects had RAASi medication increases or new 
medications added, the subjects should be switched back to the doses of RAASi 
therapy they were on prior to randomization. If subjects had RAASi medication 
down-titrated or stopped from their baseline during the study, they should be given 
the lowest RAASi medication doses. For any study visits following at least one 
week after drug discontinuation (eg, Visits 9 and 10 if the subjects discontinues at 


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Visit 8 per protocol), investigators should optimize RAASi medication based on 
their clinical judgement.
The following are recommendations for the investigator to consider, but not following these 
recommendations will not constitute a protocol deviation:

As per HF treatment guidelines subjects should only receive one drug from the 
ACEi, ARB and ARNI classes.

It is allowed to switch between ACEis/ARBs/ARNIs, e.g. if a subject experiences 
dose limiting cough.

Switching between ACEis/ARBs/ARNIs is done by stopping the ACEi/ARB/ARNI 
and starting the new ACEi/ARB/ARNI on the subsequent day (when stopping 
ACEi) or the day thereafter (when stopping ARBs or ARNI).
Proposed starting doses, dose escalation steps, and target doses for RAASi treatments are 
displayed in Table 5.
Table 5
RAASi treatments
Drug Class:
Drug
Initial dose
Dose escalation
Target dose
ACEi
Benazepril
5-10mg qd
10, 20, 40
40mg qd
Captopril
6.25mg tid
6.25, 12.5, 25, 50
50mg tid
Cilazapril
0.5mg qd
0.5, 1, 2.5, 5
2.5-5mg qd
Delapril
7.5mg bid
7.5, 15, 30
30mg bid
Enalapril
2.5mg bid
2.5, 5, 10, 20
10-20mg bid
Fosinopril
5-10mg qd
5, 10, 20, 40
40mg qd
Moexipril
7.5mg qd
7.5, 15, 30
30mg qd
Lisinopril
2.5-5mg qd
2.5, 5, 10, 20, 40
20-35/40mg qd
Perindopril
2mg qd
2, 4, 8, 16
8-16mg qd
Quinapril
5mg bid
5, 10, 20
20mg bid
Ramipril
1.25-2.5mg qd
1.25, 2.5, 5, 10
10mg qd
Trandolapril
1mg qd
1, 2, 4
4mg qd


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Drug Class:
Drug
Initial dose
Dose escalation
Target dose
ARB
Azilsartan
40-80mg qd
40, 80
80mg qd
Candesartan
4-8mg qd
4, 8, 16, 32
32mg qd
Eprosartan
400-600mg qd
400, 600
600mg qd
Irbesartan
75mg qd
75, 150, 300
300mg qd
Losartan
25-50mg qd
25, 50, 100, 150
50-150mg qd
Olmesartan
20mg qd
20, 40
40mg qd
Telmisartan
40mg qd
40, 80
80mg qd
Valsartan
20-40mg bid
20, 40, 80, 160
160mg bid
ARNI
Sacubitril/Valsart
an
24/26mg bid
24/26, 49/51, 97/103
97/103mg bid
MRA
Spironolactone
25mg qd (consider 
lower if needed; 
25 mg qod, 12.5 
mg qd, or 12.5 mg 
qod)
50 mg qd (or, 
intermediate dose if 
starting <25 mg qd)
50 mg qd 
Eplerenone
25mg qd
25, 50
50mg qd
Canrenone
25-50mg qd
25, 50, 100
50-100mg qd
Table adapted from: Ponikowski et al 2016, Yancy et al 2017, and spironolactone US package insert. Wherever a 
range is provided in the Target dose column the lower end of the range is considered the Target dose for purposes 
of the statistical analysis.
6.5.2
Other concomitant treatment
Any medication considered necessary for the subject’s safety and wellbeing, may be given at 
the discretion of the Investigator, but must be recorded in the appropriate sections of the Case 
Report Form.
6.5.3
Rescue medication
Rescue medication for subjects presenting with local lab-K ≥6.0 mmol/L or local lab-K <3.0 
mmol/L will not be provided. Instead, subjects developing local lab-K ≥6.0 mmol/L or local 
lab-K <3.0 mmol/L at any time during the study should be treated according to the 
investigator’s medical judgement using standard of care and monitored more intensely until 
local lab-K has been confirmed to be between 3.5 and 5.5 mmol/L inclusive. RAASi 


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treatments may be down-titrated/discontinued and potassium binders, insulin and glucose, 
other potassium lowering drugs, or potassium supplements may be administered at the 
investigator’s discretion and as medically appropriate. Additional study visits may occur at 
any time at the investigator’s discretion to ensure safety and protocol adherence. 
6.5.4
Drugs with pH-dependent absorption
When co-administered with ZS, some oral medications with gastric pH-dependent 
bioavailability may exhibit a clinically meaningful increase or decrease in their 
bioavailability. Therefore, these drugs should be administered at least 2 hours before or 2 
hours after study treatment to mitigate the risk of drug interactions.
Drugs that should be taken 2 hours before or after study treatment to avoid a possible raised 
gastric pH drug interaction are listed in Table 6.
Table 6
Drugs with pH dependent absorption
Class of drug
Drugs
Anti-HIV drugs
Amprenavir, atazanavir, delavirdine, fosamprenavir, 
indinavir, ledipasvir, nelfinavir, raltegravir, 
rilpivirine, ritonavir, saquinavir
Antibiotics
Cefditoren, clarithromycin
Antiepileptics
Gabapentin, phenytoin
Antimycotics
Itraconazole, ketoconazole, posaconazole,
Voriconazole
Bisphosphonates
Risedronic acid
Cardiac glycosides
Digoxin
Immunosuppressants
Methotrexate, mycophenolate mofetil,
mycophenolic acid, tacrolimus
Intestinal anti-inflammatory agents
Mesalamine
Iron preparations
Iron salts
Tyrosine kinase inhibitors
Acalabrutinib, dasatinib, erlotinib, gefitinib, nilotinib, 
pazopanib 
6.6
Dose modification
IP should be up- or down-titrated depending on the currently administered dose of IP and the 
local lab-K at every study visit. Each up- or down-titration of IP will require an additional 
study visit to be performed 7 (+/-2) days later (see Schedule of Activities (SoA) for details).
See Appendix F for further information regarding the titration of IP.
If an IP titration and MRA initiation occur at the same visit, requiring a dose change visit 
within 3 (+/-1) days and another within 7 (+/-2) days, only the earliest dose change visit 
should be performed.


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6.7
Treatment after end of study treatment
After the end of randomised therapy (Visit 8 or early treatment discontinuation) the 
investigator should return to the original RAASi dose the patient was on prior to 
randomization and will manage the subject as per standard of care. In instances in which the 
investigator had down-titrated or stopped RAASi medications, then the subject should not be 
returned to their original dose and should be given the lowest RAASi doses at the end of 
randomized therapy. 
For any study visits following at least one week after drug discontinuation (eg, Visits 9 and 10 
if the subject discontinues at Visit 8 per protocol), investigators may optimize RAASi 
medication based on their clinical judgement. Further down-titrating or stopping RAASi 
therapies, or starting commercially available potassium lowering therapies, are acceptable 
options to manage subjects with hyperkalaemia or at high risk of developing clinically 
significant hyperkalaemia at the end of the trial after the final safety visit (Visit 10).
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
Please refer to Appendix I for specific procedures impacted by the COVID-19 pandemic. In 
summary, many patients were asked to discontinue the active treatment phase of the study due 
to COVID-19 and to conduct Visit 8 as soon as possible. At the end of Visit 8, PIs withdraw 
the IP, and unblinded patients via IVRS to enable medical management. 
7.1
Discontinuation of study treatment 
Every reasonable effort should be made to continue study treatment, and if study treatment 
must be discontinued, to keep the subject in the study. Note that discontinuation from study 
treatment is different from complete withdrawal from the study. After IP discontinuation 
(Visit 8 or early treatment discontinuation) the investigator should return to the original 
RAASi dose the patient was on prior to randomization and will manage the subject as per 
standard of care. In instances in which the investigator had down-titrated or stopped RAASi 
medications, then the subject should not be returned to their original dose and should be 
provided the lowest RAASi doses at the end of randomized therapy. For any study visits 
following at least one week after drug discontinuation (eg, Visits 9 and 10 if the subjects 
discontinue at Visit 8 per protocol), investigators may optimize RAASi medication based on 
their clinical judgement. 
Subjects may be discontinued from the investigational product (IP) in the following situations.

Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse Event precluding further therapy

Severe non-compliance with the Clinical Study Protocol


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
Deteriorating renal function resulting in the initiation of permanent scheduled 
dialysis.

Local lab-K <3.0 mmol/l or local lab-K >6.5 mmol/l, as detailed in Appendix F. See 
also guidance in Section 6.5.3 on rescue medications.

If an absolute QTc >550msec, or an increase in QTc interval > 60msec from 
baseline to more than 500msec is reached the subject should immediately receive 
appropriate medical attention and be discontinued from the study treatment. The 
QTcF (corrected QT interval by Fredericia algorithm) is recommended. 
All patients meeting the QTc>500ms criterion should have S-K assessed by local
lab, collected within 1 hour of the collection of the ECG. 

Pregnancy (see Section 8.4.2).
7.1.1
Temporary discontinuation
Subjects temporarily discontinuing IP may continue in the study and may re-initiate IP 
treatment. During the temporary discontinuation, additional unscheduled visits should be 
performed as outlined for “Dose change” visits in the Schedule of Activities (SoA). The 
investigator must take particular care to ensure subject safety during temporary 
discontinuation of IP, as the subject may be at risk to develop hyperkalaemia, and additional 
visits or assessments are allowed at the investigator’s discretion. 
The investigator should handle the RAASi titration during a temporary discontinuation in the 
same way as during a permanent discontinuation. Specifically, after temporary IP 
discontinuation, the investigator should return to the original RAASi dose the patient was on 
prior to randomization and will manage the subject as per standard of care. In instances in 
which the investigator had down-titrated or stopped RAASi medications, then the subject 
should not be returned to their original dose and should be given the lowest dose of RAASi. If 
the patient restarts IP, then the investigator can re-optimize RAASi therapy as per protocol 
guidelines.
7.1.2
Procedures for discontinuation of study treatment
The investigator should instruct the subject to contact the site before or at the time if study 
treatment is stopped.  A subject that decides to discontinue study treatment will always be 
asked about the reason(s) and the presence of any AEs. The date of the last intake of study 
treatment should be documented in the CRF.  All study treatment should be returned by the 
subject at their next on-site study visit.
Following IP discontinuation, the study site and subject should continue to complete all visits 
as defined in the Schedule of Activities (SoA). The subject should continue attending 
subsequent study follow-up visits and data collection should continue. If the subject does not 
agree to continue in-person study visits, a modified follow-up must be arranged to ensure the 
collection of endpoints and safety information. This could be a telephone contact with the 
subject, a contact with a relative or treating physician, or information from medical records. 
The approach taken should be recorded in the medical records. A subject that agrees to the 


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modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study
7.2
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule.

Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject or next of kin by e.g. repeat telephone 
calls, certified letter to the subject´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the subject’s medical 
record.

Efforts to reach the subject should continue until the end of the study. Should the 
subject be unreachable at the end of the study the subject should be considered to be 
lost to follow up with unknown vital status at the end of the study.

Data on unreachable subjects may be collected from third parties, e.g. the subject’s 
treating physician, if the subject has provided consent for this on the informed 
consent form.
7.3
Withdrawal from the study
A subject may withdraw from the study (eg, withdraw consent), at any time (investigational 
product and assessments) at his/her own request, without prejudice to further treatment.
A subject who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).
Data collection from third parties, e.g. the subject’s treating physician, may continue if the 
subject has provided consent for this on the informed consent form, except for if the subject 
withdraws this consent.
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records.


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A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE). The Investigator will follow up subjects as medically indicated. All 
study treatment should be returned by the subject.
7.4
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. The investigator may 
initiate study-site closure at any time, provide there is reasonable cause and sufficient notice is 
given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) or local health 
authorities, the sponsor’s procedures, or Good Clinical Practice (GCP) guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the Schedule of Activities (SoA).
Study specific procedures should only be performed after signed informed consent has been 
obtained. 
Consented subjects will be assigned a unique enrolment number via IVRS/IWRS. The 
enrolment number will be used throughout the study and will not be used for any other 
participant.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the subject’s routine clinical management (eg, blood count)
and obtained before signing of the ICF may be utilised for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the Schedule of Activities (SoA).
Eligible subjects will be assigned a unique randomisation code and randomised to study 
treatment using an IVRS/IWRS. 


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The investigator will ensure that data are recorded on the electronic Case Report Forms 
(CRFs).
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed CRFs.  A copy of the completed CRFs will be archived at 
the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (SoA), is essential and required for study conduct.
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required (assumed to be 5 x ‘Dose Change’ 
visits), should be approximately 250 ml. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
Refer to Appendix I for all changes due to the COVID-19 pandemic.
8.1
Efficacy assessments
The primary efficacy outcome measurement is based on the RAASi treatment intensity 
achieved.
8.1.1
RAASi treatment intensity
RAASi treatment intensity will be estimated based on the data provided by investigators in the 
CRF. The CRF will capture all concomitant drugs administered, and the RAASi treatment 
intensity will be derived from the collected data. The target doses provided for each RAASi 
drug in Table 5 will be used to assess if the target dose has been achieved. Details will be 
provided in the Statistical analysis plan (SAP).
8.1.2
Potassium
Serum samples will be analysed locally using local lab to generate local lab-K for the 
purposes of study inclusion and monitoring. Samples drawn at the same time-points will be 
prepared and shipped to the Central Laboratory for analysis of S-K. 
All serum samples should be examined and any hemolysed samples must be redrawn. 
See the laboratory manual for details on drawing, preparation and analysis of blood samples.
8.1.3
Patient reported outcomes (PROs)
PROs are an umbrella term referring to all outcomes and symptoms that are directly reported 
by the patient. PROs have become important endpoints for regulatory and reimbursement 
authorities when evaluating the effectiveness of treatments in clinical trials. The following 


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PROs will be administered in the study: PGIC and KCCQ (see Appendix H). Patients will be 
asked to complete the PROs at the visits as specified in the SoA.
8.1.3.1
Patient global impression of change (PGIC)
The PGIC question will be used to capture subjects overall change in HF symptoms since the 
start of the treatment.
8.1.3.2
Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KCCQ is a self-administered disease specific instrument and has shown to be a valid, 
reliable and responsive measure for patients with HF (Green et al 2000, Spertus et al 2005). 
The KCCQ consists of 23 items measuring HF-related symptoms, physical limitations, social 
limitations, self-efficacy, and health-related quality of life. The Clinical Summary Score 
incorporates the symptom and physical limitations domains into a single score. Scores are 
transformed to a range of 0-100. Higher scores represent a better outcome.
8.1.3.3
Administration of PROs
Patients will complete the PRO assessments at the study site using a paper questionnaire. Each 
site must allocate the responsibility for the administration of the PROs to a specific individual 
and, if possible, assign a backup person to cover if that individual is absent.
All PRO assessments should be completed as follows:

Patient must not receive help from relatives, friends, or site personnel to answer or 
clarify the PRO questionnaires in order to avoid bias. If a subject uses visual aids 
(eg, spectacles or contact lenses) for reading and does not have them at hand, the 
subject will be exempted from completing the PROs questionnaires on that visit.

Before other study procedures are conducted at a given visit is recommended.

Before being seen by the investigator.

PRO questionnaires must be completed by the subject in private.

The appointed site personnel should explain to subject the value and relevance of 
PRO assessments and inform them that these questions are being asked to find out, 
directly from subjects, how they feel. The appointed site personnel should also 
stress that the information is confidential.

The appointed site personnel must show subjects how to complete the questionnaire 
in accordance with the instructions provided.

The appointed site personnel should remind subjects that there are no right or wrong 
answers, and the subject should be given sufficient time to complete the 
questionnaire at his/her own speed.
If the subject is unable to read the questionnaire (eg, is blind or illiterate), the subject will be 
exempted from completing the PRO questionnaires and may still participate in the study. 
Patients exempted in this regard should be flagged appropriately by the site personnel.


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8.1.4
NYHA class
The definition of NYHA class is included in Appendix G. The investigator will evaluate this 
according to the Schedule of Activities (SoA) and assessment will be recorded in the CRF.
8.1.5
Urine analysis
First morning void spot urine will be collected at the time-points indicated in the Schedule of 
Activities (SoA). Urinary albumin and creatinine will be measured at the central laboratory 
and reported, and UACR will be calculated based on the measured urinary albumin and 
creatinine and reported.
Urine collection kits will be handed out at the visit before the visit when urine is to be 
collected to allow the subject to collect urine in the morning before the visit and on the 
morning the day before the visit. Hence two urine samples will be collected for each time-
point. Collected urine should be stored in a fridge until the subject leaves home for the visit.
In the event that a subject forgets to collect one or both first morning voids the samples can 
instead be collected on the first one or two mornings following the visit, and delivered to the 
study site.
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the Schedule of Activities 
(SoA).
8.2.1
Clinical safety laboratory assessments
See Table 7 for the list of clinical safety laboratory tests to be performed and to the Schedule 
of Activities (SoA) for the timing and frequency.  All protocol-required laboratory 
assessments, as defined in the table, must be conducted in accordance with the laboratory 
manual and the Schedule of Activities (SoA).
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results should be signed, dated and retained at centre 
as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
The routine clinical chemistry, haematology and urinalysis will be performed at a central 
laboratory, with the exception of K and creatinine measurements performed both locally using 
local lab and at the central lab at each visit, and pregnancy tests performed only locally. 
Samples for serum potassium and creatinine analysis using local labs should be collected 
according to sample collection and processing requirements for these parameters.  Potassium 
and creatinine measured locally will be used for subject management and for study inclusion 
(potassium and creatinine), and will be reported in the CRF, but samples collected at the same 
time and analysed at the central laboratory will be used for the main statistical analyses.


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Sites are encouraged to use local labs that can provide potassium and creatinine results as 
rapidly as possible. If the site can obtain the results in a reasonable time (as determined by the 
Investigator and the subject), the local labs can be drawn at the beginning of each visit, and 
then the patient medications titrated and/or IP dispensed before the patient leaves the clinic. 
The maximum amount of time between local lab sample collection and obtainment of data 
results should be one day. If blood samples for local lab are taken at the study visit and the 
results are not known prior to the subject leaving the visit, the investigator may call the 
subjects or bring them back the following day for instructions regarding concomitant 
medication titration and IP dosing. Alternatively, if more feasible for the subject and 
Investigator, blood samples for the local lab may be collected one day before study procedure 
in cases when the local lab sample analysis time is expected to be longer than the duration of 
the subject’s clinic visit. 
At Visit 2 potassium and creatinine performed locally using local lab will be analysed before 
assessment against the inclusion criteria and randomization. It is recommended to perform the 
Visit 2 local lab assessment of creatinine and potassium before other Visit 2 assessments, with 
the exception of the KCCQ questionnaire, as the local lab assessment is likely to trigger the 
most screening failures.
Additional safety samples may be collected ('unscheduled') if clinically indicated at the 
discretion of the Investigator. The date, time of collection and results (values, units and 
reference ranges) will be recorded on the appropriate CRF. If additional safety analyses of 
potassium or creatinine (with or without subsequent calculation of eGFR), then local lab 
should be used to perform the analysis of the additional safety samples.
Estimated GFR (eGFR) will be calculated using the CKD-EPI (chronic kidney disease 
epidemiology collaboration equation) formula for each time-point when creatinine is analysed.


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Table 7
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S-Creatinine
B-Leukocyte count
S-Bilirubin, total
B-Leukocyte differential count (absolute count)
S-Alkaline phosphatase (ALP)
B-Platelet count
S-Aspartate transaminase (AST)
S-Alanine transaminase (ALT)
S-Albumin
S-C-reactive protein (CRP)
S-Potassium
S-Calcium, total
S-Sodium
S-Phosphorous
S-Magnesium
S-Bicarbonate
S-Blood urea nitrogen (BUN)
S-Creatine kinase (CK)
NB. In case a subject shows an AST or ALT ≥ 3 × upper limit of normal (ULN) together with total bilirubin ≥ 2 
× ULN please refer to Appendix E ‘Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law’, for further instructions.
8.2.2
Physical examinations
A complete physical examination will be performed at baseline as indicated in the Schedule of 
Activities (SoA) and will include an assessment of general appearance, respiratory system, 
cardiovascular system (including signs of fluid overload), abdomen, skin, head, and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid gland, musculo-skeletal system 
(including spine and extremities) and neurological system.
A targeted physical examination will be performed at the time-points indicated in the 
Schedule of Activities (SoA) and will include an assessment of general appearance, 
respiratory system, cardiovascular system (including signs of fluid overload), and abdomen.
Investigators should pay special attention to clinical signs related to previous serious illnesses 
(including HF, renal impairment, signs of fluid overload, and diabetes). New or worsening 
abnormalities may qualify as adverse events, see Section 8.3.7 for details. 
Height will be assessed using locally available tools without the subject wearing shoes, and 
recorded in the CRF.


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Weight will be assessed using the same scale, properly maintained and calibrated at each visit, 
and with the subject wearing a similar amount of clothes (e.g. underwear only or light indoor 
clothing only) at each visit.
8.2.3
Vital signs
Vital signs will be taken before blood collection for laboratory tests, and will consist of pulse 
and systolic and diastolic blood pressure measurements.
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the subject in a quiet setting without distractions (e.g., television, cell phones).
Systolic and diastolic blood pressure will be measured by an adequately trained health care 
professional. Measurements with a calibrated sphygmomanometer are preferred. If not 
available, another device calibrated carefully in proportion to a mercury sphygmomanometer 
is preferred. The use of aneroid manometers should be avoided. An appropriate cuff size must 
be used to ensure accurate measurement.
The disappearance of sound (Korotkov phase V) should be used for the diastolic reading. 
Three (3) readings separated by 2 minutes should be averaged, and the average result will be 
recorded in the eCRF. If the first two readings of systolic blood pressure (SBP) differ by more 
than 5 mmHg, additional readings should be obtained.
Blood pressure should be measured in either supine or sitting position. No shift from one 
position to another should be made during the study. Supine or sitting posture should be 
adopted for at least 5 minutes before measurement. The subject should be relaxed and with the 
arm outstretched and supported.
Blood pressure should be measured under standardized conditions, as nearly as possible at the 
same time each visit, on the same arm (preferably the dominant arm), by the same personnel, 
and with the same apparatus.
8.2.4
Electrocardiograms
12-lead ECG will be obtained at the time-points indicated in the SoA (see Section 1.1) using a 
digital ECG machine that automatically calculates the heart rate and measures PR, QRS, and 
QT (using QTcF) intervals. For patients with pacemakers and ECGs demonstrating paced 
rhythms, there should be a manual reading of PR, QRS and QT to increase accuracy of the 
assessment in this population, while the automatically read values should be reported for non-
paced ECGs.


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8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see Section 8.3.3
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse Events will be collected from time of signature of informed consent form throughout 
the treatment period and including the follow-up period until the last contact in the study.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B.  The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However,
if the investigator learns of any SAE, including a death, at any time after a subject’s last visit 
and he/she considers the event to be reasonably related to the Study treatment or study 
participation, the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject 
at subsequent visits/contacts. All AEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the subject is lost to follow-up. 
Any AEs that are unresolved at the subject’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF.  
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.


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8.3.4
Adverse event data collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication
8.3.5
Causality collection
The Investigator will assess the causal relationship between Investigational Product and each 
Adverse Event, 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 B to the Clinical 
Study Protocol.


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8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit?, or 
revealed by observation will be collected and recorded in the CRF. When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms.  
However, if a diagnosis is known, and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR. Deterioration as compared to baseline in protocol-mandated 
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 treatment with the investigational
product.
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 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin 
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 aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
8.3.8
Hy’s law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN may need 
to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Potential Hy’s Law.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site 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.


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For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the Electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff on how to proceed.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study subject has received any study drug
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  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 subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.


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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
8.4.3
Overdose
ZS has been given to subjects at doses of up to 30 g per day for 1 to 3 days and up to 15 g per 
day for 11 months.
PRIORITIZE-HF requires a 48-hour “correction phase” with ZS 10g TID (only in patients 
with local lab serum-K >5.0 mmol/L), followed by a “maintenance phase” for all patients with 
doses ranging from 5g QOD to 15g QD. For this study, overdose is defined as any of the 
following:

During the initial 2-day correction phase (applicable only for patients with pre-
randomization local lab serum-K >5.0 mmol/L), any ZS dose greater than 30g within 
one day, or continuation of the correction dose (10g TID) for more than 72 hours

During the maintenance period for all patients, a dose higher than 15g per day will be 
considered an overdose
AstraZeneca does not recommend any specific treatment for an overdose. Monitoring and 
symptomatic therapy, potentially including potassium substitution therapy to treat any 
hypokalaemia, may be considered by the investigator.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF 
module
If an overdose on an AstraZeneca study drug occurs during the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.

For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.3.2. For other overdoses, reporting must occur within 30 days.


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8.4.4
Medication error
If a medication error occurs during the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B.
8.5
Pharmacokinetics (PK)
PK parameters are not evaluated in this study.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
8.7.1
Optional exploratory genetic sample
Approximately 6 ml of blood sample for deoxyribonucleic acid (DNA) isolation will be 
collected from subjects who have consented to participate in the genetic analysis component 
of the study. Participation is optional. Subjects who do not wish to participate in the genetic 
research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.
See Appendix D for Information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in the Laboratory 
Manual.
8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples may be stored for a maximum of 15 
years or as per local regulations from the date of the Last Subject’s Last Visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. The 
results of any further analyses will be reported separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA


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8.8
Biomarkers
Biomarkers NT-pro-BNP and high sensitivity troponin I will be tested in plasma/serum to 
evaluate how they are affected by the addition of ZS.
In addition, samples will be collected and analysis may be performed on biomarkers thought 
to play a role in HF, chronic kidney disease, or potassium homeostasis to evaluate their 
association with observed clinical responses to ZS or the effect of ZS on the biomarkers.
Other samples may be used for research to develop methods, assays, prognostics and/or 
companion diagnostics related to ZS, HF, chronic kidney disease, hyperkalaemia, and/or other 
diseases.
8.8.1
Storage, re-use and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed. The results of this biomarker research will be 
reported either in the CSR itself or as an addendum, or separately in a scientific report or 
publication. The results of this biomarker research may be pooled with biomarker data from 
other studies with the study drug to generate hypotheses to be tested in future research.
8.9
Medical Resource Utilization and Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
8.10
Demography and medical history
Demographic parameters to be collected from subjects include sex, date of birth, race, and 
ethnic group.
Medical history parameters to be collected include relevant medical and surgical history. In 
addition, prior dialysis therapy will be collected.
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The primary objective is to determine if there is a difference between ZS and placebo in 
RAAS blockade treatment.
The null hypothesis is that there is no difference between treatments in the distribution of 
proportion of patients in the RAAS blockade treatment categories, and the alternative
hypothesis is that there is a difference. The hypothesis will be tested at a significance level of 
5% using a chi-square test for homogeneity.


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9.2
Sample size determination 
The study will employ a 1:1 randomization scheme. A sample size of 280 subjects will allow 
for the estimation of the effect in the primary objective. Due to lack of prior knowledge of the 
distribution of the primary endpoint categories in the placebo group, the following 
considerations were made with regards to sample size. Assuming a difference in proportion of 
MRA use at 3 months of 0.2 between treatment groups, a sample size of 140 subjects per 
group provides at least 90% power for a significance level of 5% using a chi-square test. 
Due to the COVID-19 pandemic the study was prematurely terminated with a total sample 
size of 182 patients.
9.3
Populations for analyses
For purposes of analysis, the following analysis sets are defined:
Analysis set
Description
Enrolled 
All subjects who sign the ICF.
Full analysis set
All randomised subjects.
Safety analysis set
All subjects randomly assigned to Study treatment and who take at 
least 1 dose of IMP.
9.4
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock 
and Clinical Study Protocol deviations identified.
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan describes the subject populations to be included in the analyses, and procedures 
for accounting for missing, unused, and spurious data. This section is a summary of the 
planned statistical analyses of the primary endpoint. Any deviations from this plan will be
reported in the clinical study report.
For analyses involving potassium values, the central laboratory S-K will be used primarily. 
Demographics and subject characteristics, relevant medical history, prior medications and 
subject disposition will be summarized by treatment group using frequency and percentages 
(for categorical variables) and descriptive statistics of mean, standard deviation, minimum, 
median, and maximum (for continuous variables) using the Full analysis set.
9.4.1
Efficacy analyses
All efficacy analyses will be based on the Full analysis set including all randomised subjects. 
Subjects will be analyzed according to their randomized study medication.


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9.4.1.1
Primary efficacy variable
The primary outcome measure is the proportions of subjects in the following categories at 3 
months: 

No ACEi/ARB/ARNI or at less than target dose and no MRA 

ACEi/ARB/ARNI at target dose and no MRA 

MRA at less than target dose 

MRA at target dose. 
The RAAS blockade dose used in the primary variable will be the dose the patient is on the 
day before visit 8 (i.e. before any potential RAAS blockade titration/change based on 
unblinded information is made on visit 8).
Missing RAASi dose data at 3 months will be partially imputed for the derivation of the 
primary variable. A detailed description of the imputation algorithm can be found in the 
Statistical Analysis Plan.
The hypothesis of a treatment difference (ZS vs placebo) in the distribution of RAAS 
blockade treatment will be tested at a significance level of 5% using a chi-square test for 
homogeneity. P-value will be presented.
Sensitivity analysis of primary analysis
Since imputed values are included in the primary analysis, sensitivity analyses of the primary 
analysis aimed at evaluating the impact of missing / imputed data will also be performed. All 
sensitivity analyses will be described in detail in the Statistical Analysis Plan.The consistency 
of potential effect of SZC across pre-defined sub-groups will also be evaluated as specified in 
the SAP.
9.4.2
Safety analyses
The safety analysis set will be used for all safety analyses. Erroneously treated subjects (eg. 
those randomized to ZS but actually given placebo throughout the study or vice versa) will be 
accounted for in the actual treatment group. A subject who in error has received both ZS and 
placebo will be accounted for in the randomized treatment group.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary and summarized for the treatment period. Number of subjects with 
events and percentages will be tabulated by preferred term and system organ class. Adverse 
events will also be summarized by intensity/severity and separately, by causality/relatedness 
(as determined by the investigator). Serious AEs, AEs leading to discontinuation of IP will be 
summarized in a generally similar manner. Adverse events, SAEs, AEs leading to death, and 
AEs leading to IP discontinuation will be summarized for each treatment group as applicable. 


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Adverse events occurring prior to randomization and during the follow-up period will be 
presented in listings.
Laboratory data will be summarized by presenting shift tables using normal ranges (baseline 
to the most extreme value during treatment) and by presenting summary statistics of observed 
and change from baseline values (means, medians, quartiles, ranges). The incidence of 
clinically notable lab abnormalities will be summarized. 
Proportion of subjects with S-K < 3.5 mmol/L and <3.0 mmol/L and S-K >5.5 mmol/L and 
>6.0 mmol/L will be presented.
Vital sign data will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital sign abnormalities will be 
summarized.
ECG intervals will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable ECG abnormalities will be 
summarized.
9.4.3
Other analyses 
Exploratory objectives will be presented using summary statistics. Ninety-five percent 
confidence intervals may be presented as measures of precision.
Further details on exploratory outcome measures (e.g. definition of i) RAASi dose increase for 
subjects who switch RAASi during treatment period, ii) equipotent MRA doses and iii) dose 
intensity score) are described in the SAP.
9.4.4
Methods for multiplicity control
Not applicable
9.5
Interim analyses 
There are no interim analyses planned in this study.
9.5.1
Data Monitoring Committee (DMC)
An independent data monitoring committee (also called a Safety Review Committee) that is 
independent of the sponsor will be utilized for this study.
Appendix A 5 provides more details on the rationale for and the remit of the committee.


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10.
REFERENCES
Ambrosy et al 2014
Ambrosy AP, Gheorghiade M, Chioncel O, Mentz R J, Butler J. Global perspectives in hospitalised 
heart failure: regional and ethnic variation in patient characteristics, management and outcomes. J Am 
Coll Cardiol 2014; 63:1123-33.
Braunwald 2015
Braunwald E.  The war against heart failure: the Lancet lecture.  Lancet 2015; 385:812-24.
Cook et al 2014
Cook C, Cole G, Asaria P, Jabbour R, Francis DP. The annual global economic burden of heart failure. 
Int J Cardiol 2014; 171:368-378.
Einhorn et al 2009
Citation. Lisa M. Einhorn, Min Zhan, Van Doren Hsu, Lori D. Walker, Maureen F. Moen, Stephen L. 
Seliger, Matthew R. Weir, Jeffrey C. Fink. The Frequency of Hyperkalemia and Its Significance in 
Chronic Kidney Disease. Arch Intern Med. 2009;169(12):1156–1162.
Epstein et al 2016
Epstein M, Alvarez PJ, Reaven NL, Funk SE, McGaughey KJ, Brenner MS, Benton W, Golestaneh L. 
Evaluation of clinical outcomes and costs based on prescribed dose level of renin-angiotensin-
aldosterone system inhibitors. Am J Manag Care. 2016 Aug;22(11 Suppl):s311-s324.
Fleet et al 2012
Fleet JL, Shariff SZ, Gandhi S, Weir MA, Jain AK, Garg AX. Validity of the International 
Classification of Diseases 10th revision code for hyperkalaemia in elderly patients at presentation to 
an emergency department and at hospital admission. BMJ Open. 2012;2: e002011.
Green et al 2000
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and Evaluation of the Kansas City 
Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure. J Am Coll Cardiol. 
2000 Apr; 35(5):1245-55.
Henneman et al 2016
Henneman A, Guirguis E, Grace Y, Patel D, Shah B. Emerging therapies for the management of 
chronic hyperkalemia in the ambulatory care setting. Am J Health Syst Pharm. 2016 Jan 15;73(2):33-
44.
Kovesdy 2015
Kovesdy CP. Management of Hyperkalemia: An Update for the Internist. Am J Med. 2015 
Dec;128(12):1281-7.


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Nakhoul et al 2015
Nakhoul GN, Huang H, Arrigain S, Jolly SE, Schold JD, Nally JV Jr, Navaneethan SD. Serum 
Potassium, End-Stage Renal Disease and Mortality in Chronic Kidney Disease. Am J Nephrol. 
2015;41(6):456-63.
Okumura et al 2016
Okumura N, Jhund PS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Swedberg K, Zile 
MR, Solomon SD, Packer M, McMurray JJ; PARADIGM-HF Investigators and Committees*. 
Importance of Clinical Worsening of Heart Failure Treated in the Outpatient Setting: Evidence From 
the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and 
Morbidity in Heart Failure Trial (PARADIGM-HF). Circulation. 2016 Jun 7;133(23):2254-62.
Ponikowski et al 2016
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, 
Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, 
Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; 
Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart 
failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the 
European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure 
Association (HFA) of the ESC.  Eur J Heart Fail. 2016 Aug;18(8):891-975.
Spertus et al 2005
Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones P, McCullough PA, Pina I, 
Tooley J, Weintraub WS, Rumsfeld JS; Cardiovascular Outcomes Research Consortium. Monitoring 
clinical changes in patients with heart failure: a comparison of methods. Am Heart J. 2005 
Oct;150(4):707-15.
Vasudevan et al 2017
Vasudevan A, Jazi HH, Won JI, Ball T, Patankar GR, Sarmast SA, Shin HJ, McCullough PA. Proc 
(Bayl Univ Med Cent). 2017 Apr; 30(2):139-142.
Yancy et al 2017
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, 
Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, 
Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA 
Guideline for the Management of Heart Failure: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart 
Failure Society of America. J Card Fail. 2017 Aug;23(8):628-651.


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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS


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Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable International Conference on Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an institutional review board (IRB)/independent 
ethics committee (IEC) by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated.
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed consent process


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The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
centre.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.
If a subject declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the subject and he/she will not be 
excluded from other aspects of the study.
If a subject partner becomes pregnant during the study, the partner is asked to sign the "Adult 
Study Informed Consent Form for Pregnant Partners of Study Subjects" and provide 
information about the pregnancy accordingly.
Subjects who are rescreened are required to sign a new ICF.
A 4
Data protection
Each subject will be assigned a unique identifier by the sponsor.  Any subject records or data 
sets transferred to the sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred.
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the subject.
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
An Executive Committee consisting of members independent of AstraZeneca has been 
established for the ZS development program in heart failure. See the Executive Committee 


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member contracts and/or charter for details. The Executive Committee designed significant 
aspects of this study protocol.
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with the Patient Safety function at AstraZeneca. 
Issues identified will be addressed; for example by amending the Clinical Study Protocol and 
letters to Investigators.
A data monitoring committee will be established to review emerging safety data at pre-defined 
intervals. The committee will include member(s) independent of the sponsor. See the 
independent data monitoring committee Charter for details on the scope and membership. The 
independent data monitoring committee may request unblinded data if needed to assess any 
emerging safety concerns. The independent data monitoring committee can recommend the 
study to be amended if necessary for the protection of the subjects participating in the trial.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical trial and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
A 7
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data).  The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 


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the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
A 9
Publication policy
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments.
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support the publication 
of multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with the International 
Committee of Medical Journal Editors authorship requirements.


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Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can, therefore, be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event 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-subject hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity.

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require 
medical treatment to prevent one of the outcomes listed above.
B 3
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).
B 4
Hospitalisation
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.
B 5
Important medical event or medical treatment


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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, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment 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.

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 hospitalisation

Development of drug dependency or drug abuse
B 6
Intensity rating scale:
1.
mild (awareness of sign or symptom, but easily tolerated)
2.
moderate (discomfort sufficient to cause interference with normal activities)
3.
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 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 when it satisfies the criteria 
shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the subject actually received the 
suspect drug? Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 


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pharmacological class? Or 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 aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca 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 an 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.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.
A medication error is not a lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error.

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:


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
Drug name confusion

Dispensing error e.g. medication prepared incorrectly, even if it was not actually 
given to the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as 
a solid tablet 

Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 

Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one 
of the above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication 
in open label studies, even if an AZ product
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an optional part of the study, then the subject may 
continue in the study.
The Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document


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LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number
and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient

temperature in IATA 650 compliant packaging
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.


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Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting subjects.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the subject´s DNA, i.e. the 
entire genome. 
The results of genetic analyses may be reported either in the clinical study report (CSR) or as 
an addendum, or separately in a scientific report or publication. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be stored for a maximum of 15 years from the date of the last subject’s last 
visit, after which they will be destroyed.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research.  Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit.  The subject will 
not be excluded from any aspect of the main study.
Inclusion criteria


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
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and provide informed 
consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research:  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 2 
randomisation.  Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding subjects who may withdraw due to an adverse event (AE), 
such subjects would be important to include in any genetic analysis.  If for any reason the 
sample is not drawn at Visit 2, it may be taken at any visit until the last study visit.  Only one 
sample should be collected per subject for genetics during the study.  Samples will be 
collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 15 
years, from the date of last subject last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).
The link between the subject enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements


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The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix B.
Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data.  In addition, Regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 
only use this information for health related research purposes.  Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers.  
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan may be prepared where appropriate.


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Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the IP.
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).  
Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than 
the IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., on 
the same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN


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
TBL ≥ 2 × ULN
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the 
AstraZeneca representative).  
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits (including both central and 
local laboratory results)
E 4
Follow-up
E 4.1
Potential Hy’s Law criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law criteria met
If the subject does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the Hy’s law lab kit should be used.  


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
Complete the three Liver CRF Modules as information becomes available 

If at any time (in consultation with the Study Physician the PHL case meets serious
criteria, report it as an SAE using standard reporting procedures.
E 5
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 


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outcome of the review amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined.


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IP (ZS or placebo) dose titration
Patients with local lab-K >5.0 mmol/L at the last assessment before randomization will be 
treated with IP 10 g tid for 2 days followed by IP 5 g qd, while normokalemic subjects will 
start IP 5 g qd immediately after randomisation. 
Table 8 
IP Dose adjustment table
Current dose
Local lab-K (mmol/L)
Dose Adjustment
5 g Every Other Day (qod)
<3.0
3.0 – 3.9
4.0 – 5.0
5.1 – 6.5
> 6.5
Discontinue dosing
No change1
No change
5 g qd
Discontinue dosing
5 g Once Daily (qd)
< 3.0
3.0 – 3.4
3.5 – 3.9
4.0 – 5.0
5.1 – 6.5
> 6.5
Discontinue dosing
5 g qod1
No change on first occasion1, 2
No change
10 g qd
Discontinue dosing
10 g qd
< 3.0
3.0 – 3.4
3.5 – 3.9
4.0 – 5.0
5.1 – 6.5
> 6.5
Discontinue dosing
5 g qd1
No change on first occasion1, 2
No change
15 g qd
Discontinue dosing


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Current dose
Local lab-K (mmol/L)
Dose Adjustment
15 g qd
< 3.0
3.0 – 3.4
3.5 – 3.9
4.0 – 5.0
5.1 – 6.5
> 6.5
Discontinue dosing
10 g qd1
No change on first occasion1, 2
No change
No change
Discontinue dosing
1 Increasing RAASi therapy should be considered at every visit as detailed in Section 6.5.1. However, for 
subjects exhibiting local lab-K < 4.0 mmol/L it is particularly important to attempt to increase the RAASi therapy 
administered.
2 The ZS dose should not be changed at the first visit when local lab-K is found to be between 3.5 and 3.9 
mmol/L. When local lab-K is between 3.5 and 3.9 mmol/L on the second consecutive visit the dose of ZS should
be reduced to the dose listed for local lab-K 3.0 - 3.4 mmol/L.


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New York Heart Association (NYHA) Functional 
Classification
NYHA Functional Classification
Class
Patient symptoms
I
No limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath).
II
Slight limitation of physical activity.  
Comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness 
of breath).
III
Marked limitation of physical activity.  
Comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without 
discomfort.  Symptoms of heart failure at rest.  If 
any physical activity is undertaken, discomfort 
increases.


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Patient Reported Outcome (PRO) questionnaires
H 1
Patient Global Impression of Change (PGIC) for Heart Failure 
Symptoms
Patient Global Impression of Change for Heart Failure Symptoms
Overall, how would you rate the change in your heart failure symptoms since starting this
study?
Much better
Moderately better
A little better
About the same
A little worse
Moderately worse
Much worse


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H 2
Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KC Cardiomyopathy Questionnaire
The following questions refer to your heart failure and how it may affect your life. Please read and 
complete the following questions.  There are no right or wrong answers.  Please mark the answer that 
best applies to you.
1.
Heart failure affects different people in different ways.  Some feel shortness of breath while others 
feel fatigue.  Please indicate how much you are limited by heart failure (shortness of breath or 
fatigue) in your ability to do the following activities over the past 2 weeks.
Place an X in one box on each line
Activity
Extremely 
Limited
Quite a bit 
Limited
Moderately 
Limited
Slightly 
Limited
Not at all 
Limited
Limited for 
other reasons or 
did not do the 
activity
Dressing yourself
□
□
□
□
□
□
Showering/Bathing
□
□
□
□
□
□
Walking 1 block on 
level ground
□
□
□
□
□
□
Doing yardwork, 
housework or 
carrying groceries
□
□
□
□
□
□
Climbing a flight of 
stairs without
□
□
□
□
□
□
Hurrying or jogging 
(as if to catch a bus)
□
□
□
□
□
□
2. Compared with 2 weeks ago, have your symptoms of heart failure (shortness of breath, 
fatigue, or ankle swelling) changed?
My symptoms of heart failure have become…
Much 
worse
Slightly 
worse
Not changed
Slightly 
better
Much 
better
I’ve had no symptoms 
over the last 2 weeks
□
□
□
□
□
□


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3. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs 
when you woke up in the morning?
Every morning
3 or more times a 
week, but not 
every day
1-2 times a week
Less than once a 
week
Never over the 
past 2 weeks
□
□
□
□
□
4. Over the past 2 weeks, how much has swelling in your feet, ankles or legs bothered you?
It has been ...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no
bothersome
bothersome
bothersome
bothersome
Bothersome
swelling
□
□
□
□
□
□
5. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do 
what you want?
All of the 
time
Several 
times per day
At least 
once a day
3 or more times 
per week but not 
every day
1-2 times 
per week
Less than once 
a week
Never over 
the past 2 
weeks
□
□
□
□
□
□
□
6. Over the past 2 weeks, how much has your fatigue bothered you?
It has been ...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had
bothersome
bothersome
bothersome
bothersome
bothersome
no fatigue
□
□
□
□
□
□
7. Over the past 2 weeks, on average, how many times has shortness of breath limited your 
ability to do what you wanted?
All of the 
time
Several
times per day
At least 
once a day
3 or more times 
per week but not 
every day
1-2 times 
per week
Less than 
once a week
Never over 
the past 2 
weeks
□
□
□
□
□
□
□


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8.
Over the past 2 weeks, how much has your shortness of breath bothered you?
It has been ...
Extremely
Quite a bit
Moderately
Slightly
Not at all
I’ve had no
bothersome
bothersome
bothersome
bothersome
bothersome
shortness of breath
□
□
□
□
□
□
9. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting 
up in a chair or with at least 3 pillows to prop you up because of shortness of breath?
Every night
3 or more times a 
week, but not every day
1-2 times a week
Less than once a 
week
Never over the past 
2 weeks
□
□
□
□
□
10. Heart failure symptoms can worsen for a number of reasons.  How sure are you 
that you know what to do, or whom to call, if your heart failure gets worse?
Not at all sure
Not very sure
Somewhat sure
Mostly sure
Completely sure
□
□
□
□
□
11. How well do you understand what things you are able to do to keep your heart failure 
symptoms from getting worse? (for example, weighing yourself, eating a low salt diet etc.)
Do not understand at 
all
Do not understand 
very well
Somewhat 
understand
Mostly understand
Completely 
understand
□
□
□
□
□
12. Over the past 2 weeks, how much has your heart failure limited you enjoyment of life?
It has extremely 
limited my 
enjoyment of life
It has limited my 
enjoyment of life 
quite a bit
It has 
moderately limited 
my enjoyment of 
life
It has slightly limited 
my enjoyment of life
It has not limited 
my enjoyment of 
life at all
□
□
□
□
□


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13. If you had to spend the rest of your life with your heart failure the way it is right now, how 
would you feel about this?
Not at all satisfied
Mostly dissatisfied
Somewhat 
satisfied
Mostly 
satisfied
Completely satisfied
□
□
□
□
□
14. Over the past 2 weeks, how often have you felt discouraged or down in the dumps because
of your heart failure?
I felt that way 
all of the time
I felt that way 
most of the time
I occasionally 
felt that way
I rarely felt that 
way
I never felt that 
way
□
□
□
□
□
15. How much does your heart failure affect your lifestyle? Please indicate how your heart 
failure may have limited your participation in the following activities over the past 2 
weeks?
Place an X in one box on each line
Activity
Severely 
Limited
Limited 
quite a bit 
Moderately 
Limited
Slightly 
Limited
Did not 
limit at all
Does not apply 
or did not do 
for other 
reasons
Hobbies, 
recreational 
activities
□
□
□
□
□
□
Working or 
doing household 
chores
□
□
□
□
□
□
Visiting family or 
friends out of  
your home
□
□
□
□
□
□
Intimate 
relationship with 
loved ones
□
□
□
□
□
□


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COVID-19 Pandemic – Study Management Plan
On 11 March 2020, the World Health Organization characterized the coronavirus disease, 
COVID-19, as a pandemic, and on 17 March 2020 the Sponsor decided to stop enrolment of 
new patients into the PRIORITIZE HF trial.
The Executive Committee, National Lead Investigators, and Sponsor thoroughly assessed the 
risk/benefit of the study, along with the rapidly evolving pandemic situation, in the 2 weeks 
following the enrolment stop. This study was unique in that vulnerable patients were not
simply given investigational product (IP), but also had RAASi medications actively titrated 
during the trial, which necessitated frequent potassium monitoring and clinic visits that were 
deemed imprudent to continue during a world pandemic.
On 01 April 2020, the PRIORITIZE HF Executive Committee and Sponsor communicated the 
following urgent actions to all study sites globally:
•
Bring forward ALL patients to conduct Visit 8 (End-of-Treatment visit) as soon as 
possible.
o
Complete Visit 8, following the protocol procedures described under this visit. 
Site or home visits can be considered, as permitted in your country, but must 
include a laboratory test for potassium. It is preferable to use your local 
laboratory per protocol, and also collect the V8 central laboratory samples. If 
that is not possible, please consider obtaining potassium results via another 
local commercial laboratory, iSTAT, or another point of care device, as 
available.
o
If the patient is found at Visit 8 (or when visit 8 is being arranged) to require 
medical attention outside the trial protocol, then a hospital/clinic visit should be 
organized according to the local arrangements currently in place. 
o
At the end of V8, withdraw the IP, and unblind each patient via IVRS/ IWRS.
•
For patients on placebo, manage the patient as deemed appropriate by 
the investigator. If RAASi medication was up-titrated during the trial, 
patient management might entail reduction of RAASi and continued 
potassium monitoring. For patients that did not have up-titration of 
RAASi, follow-up may be less intense.
•
For patients on sodium zirconium cyclosilicate (Lokelma), down-titrate 
RAASi to pre-randomization (or lowest) doses, check potassium at 
48 hours and also 7 days post IP discontinuation. 
•
Visit 9, a safety follow-up visit 7 days after IP discontinuation, should be conducted 
for all patients.


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o
Phone or other remote visits may be considered most appropriate unless there 
is a strong clinical rationale to see the patient in person. 
o
If possible, potassium should be measured per guidance in prior section 
(essential for patients who had been on sodium zirconium cyclosilicate 
(Lokelma) and/or who had RAASi changes at visit 8).
•
Visit 10, a protocol specified follow-up visit one month after IP discontinuation, can 
also be performed remotely, or, in person if considered safe to do so for the patient and 
site, does not place undue burden on your healthcare system or go against any local 
regulations for non-urgent care during the pandemic.
If the above instructions cannot be followed, for instance if potassium cannot be measured in 
any way because access to labs is severely limited, contact Sponsor immediately to discuss the 
situation and the possibility to continue open-label Lokelma treatment pending the availability 
of a laboratory service.
Thus, a summary of the urgent changes required due to COVID-19 primarily included:

A stop to enrolment on 17 March 2020

Ending treatment early for all patients in the treatment phase as of 01 April 2020 
o
Skipping all pre-planned visits between patients’ current visit and V8
o
Unblinding these patients to facilitate medical management and potentially 
reduce clinic and lab visits
o
Adding a 48-hour K+ measurement for those on active treatment, and 
suggesting more flexible K+ monitoring for placebo patients based on their 
condition and/or whether RAASi medications were modified during the study


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Benefit-Risk Assessment
AstraZeneca’s primary goal was to minimize the risk of COVID-19 infection in the vulnerable 
high-risk study population that required multiple study visits, to protect safety and well-being 
of our study participants, sites personnel\, and colleagues, and to reduce the work load 
pressure on the health care system.
This study is unique in that vulnerable patients are not simply given investigational product 
(IP), but also have RAASi medications actively titrated during the trial, which necessitates 
frequent potassium monitoring and clinic visits. Considering the cardiovascular risk in 
combination with the age of the patients, and to maintain the risk-benefit balance, 
AstraZeneca concluded it was in the best interest to:

Stop the enrolment and randomization of new patients

Withdraw IP in ongoing patients. Investigators to be unblinded via IVRS/ IWRS to 
facilitate the management of the patients and reduce the need to visit a laboratory for 
potassium checks

Allow follow-up visits 9 and 10 to be done as remote visits


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Abbreviations 
Abbreviation or 
special term
Explanation
ACCF
American College of Cardiology Foundation
ACEi
Angiotensin Converting Enzyme Inhibitors
AE
Adverse Event
AHA
American Heart Association
ALP
Alkaline Phosphatase
ALT
Alanine Transaminase
Anti-HIV
Anti-Human Immunodeficiency Virus
ARB
Angiotensin Receptor Blockers
ARNI
Angiotensin Receptor Blocker / Neprolysin Inhibitors
AST
Aspartate Transaminase
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CABG
Coronary Artery Bypass Grafting
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Novel disease caused by the coronavirus called SARS-CoV-2; declared a 
pandemic by World Health Organization on 11Mar2020
CPS
Calcium Polystyrene Sulfonate
CRF
Case Report Form (electronic/paper)
CRP
C-reactive Protein
CRT
Cardiac Resynchronization Therapy
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV
Cardiovascular
DAE
Discontinuation of Investigational Product due to Adverse Event
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid 


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Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to institutional review board (IRB) and 
independent ethics committee (IEC)
ECGs
Electrocardiograms
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
ESC
European Society of Cardiology
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FDCs
Fixed Dose Combination Therapies
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HF
Heart Failure
HFrEF
Heart Failure with Reduced Ejection Fraction
HIPAA
Health Insurance Portability and Accountability Act
HL
Hy’s Law
IATA
International Airline Transportation Association
ICD
Implantable Cardioverter Defibrillator
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Products
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine Device
IUS
Intrauterine Hormone-releasing System
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KCCQ
Kansas City Cardiomyopathy Questionnaire 
MRA
Mineralocorticoid Receptor Antagonist 


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Abbreviation or 
special term
Explanation
MedDRA
Medical Dictionary for Regulatory Activities 
MI
Myocardial Infarction
NT-pro-BNP
N-terminal pro b-type Natriuretic Peptide
NYHA 
New York Heart Association
PBO
Placebo
PCI
Percutaneous Coronary Intervention
PGIC
Patient Global Impression of Change
PHL
Potential Hy’s law
PK
Pharmacokinetics
PREGREP
Pregnancy Report
PREGOUT
Pregnancy Outcome
PRO
Patient Reported Outcome
qd
Once a Day 
qod
Every Other Day
QTcF
Corrected QT interval by Fredericia
RAASi
Renin Angiotensin Aldosterone System Inhibitor
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
S-K
Serum Potassium
SoA
Schedule of Activities
SPS
Sodium Polystyrene Sulfonate
TBL
Total Bilirubin 
TIA
Transient Ischemic Attack
tid
Three Times a Day
UACR
Urinary Albumin to Creatinine Ratio
ULN
Upper Limit of Normal
VAD
Ventricular Assistance Device
ZS
Sodium Zirconium Cyclosilicate (can also be abbreviated SZC in other 
documents)


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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9484c00001-csp-v5
Document Title:
D9484C00001 Clinical Study Protocol version 5
Document ID:
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
27-May-2020 10:15 UTC
Content Approval
27-May-2020 11:30 UTC
Content Approval
27-May-2020 13:08 UTC
Content Approval
27-May-2020 14:20 UTC
Content Approval
PPD
PPD
PPD
CCI
CCI
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D9484C00001
Edition Number
2.0
Date
21/08/2020
A Phase II, Randomised, Double-Blind, Placebo Controlled, 
Parallel-Group, Multicentre, Three Month Duration Potassium 
Reduction Initiative to Optimize RAAS Inhibition Therapy with 
Sodium Zirconium CyclosilicatE in Heart Failure (PRIORITIZE 
HF)


A Phase II, Randomised, Double-Blind, Placebo Controlled, 
Parallel-Group, Multicentre, Three Month Duration Potassium 
Reduction Initiative to Optimize RAAS Inhibition Therapy with 
Sodium Zirconium CyclosilicatE in Heart Failure (PRIORITIZE 
HF)
Study Statistician
Date21/08/2020
PPD


A Phase II, Randomised, Double-Blind, Placebo Controlled, 
Parallel-Group, Multicentre, Three Month Duration Potassium 
Reduction Initiative to Optimize RAAS Inhibition Therapy with 
Sodium Zirconium CyclosilicatE in Heart Failure (PRIORITIZE 
HF)
Global Product Statistician
Date21/08/2020
PPD


TABLE OF CONTENTS
1
STUDY DETAILS ........................................................................................... 13
1.1
Study objectives................................................................................................ 13
1.2
Study design ..................................................................................................... 15
1.3
Number of subjects........................................................................................... 16
2
ANALYSIS SETS ............................................................................................ 16
2.1
Definition of analysis sets ................................................................................. 16
2.2
Violations and deviations.................................................................................. 17
3
PRIMARY AND SECONDARY VARIABLES ............................................... 17
3.1
Primary variable ............................................................................................... 17
3.1.1
Variables for sensitivity analyses ...................................................................... 18
3.2
Secondary variables .......................................................................................... 18
3.3
Exploratory variables........................................................................................ 18
3.4
Safety variables ................................................................................................ 22
3.4.1
Adverse events.................................................................................................. 22
3.4.2
Laboratory safety variables ............................................................................... 22
3.4.3
Physical examinations....................................................................................... 22
3.4.4
Vital signs......................................................................................................... 22
3.4.5
ECGs................................................................................................................ 22
3.4.6
S-K................................................................................................................... 23
3.4.7
Other ................................................................................................................ 23
4
ANALYSIS METHODS................................................................................... 23
4.1
General principles............................................................................................. 23
4.2
Analysis methods.............................................................................................. 24
4.3
Analysis of the primary variable ....................................................................... 24
4.3.1
Sensitivity analyses........................................................................................... 26
4.4
Analysis of secondary variables ........................................................................ 26
4.5
Analysis of exploratory variables...................................................................... 26
4.6
Analysis of safety variables............................................................................... 29
4.6.1
Adverse events.................................................................................................. 29
4.6.2
Laboratory safety variables ............................................................................... 30
4.6.3
Vital signs......................................................................................................... 30
4.6.4
ECGs................................................................................................................ 30
4.6.5
S-K................................................................................................................... 31
4.6.6
Other ................................................................................................................ 31
4.7
Analysis of demographics and baseline characteristics...................................... 31
4.8
Analysis of concomitant and baseline medication ............................................. 31
5
INTERIM ANALYSES.................................................................................... 32
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 32


7
REFERENCES................................................................................................. 32
8
APPENDIX ...................................................................................................... 33
LIST OF TABLES
Table 1
Study objectives....................................................................................... 13
Table 2
Restricted concomitant medications......................................................... 34
LIST OF FIGURES
Figure 1
Study design............................................................................................ 16
LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
ACEi
angiotensin converting enzyme inhibitors
AE
adverse event
ARB
angiotensin receptor blockers
ARNI
angiotensin receptor blocker and neprolysin inhibitors
ATC
anatomical therapeutic chemical
BP
blood pressure
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CSP
clinical study protocol
CSR
clinical study report
DAE
discontinuation of investigational product due to adverse event
DMC
Data Monitoring Committee
ECG
electrocardiograms
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
HF
heart failure
i-STAT-K
potassium measured using an i-STAT device
IP
investigational product
KCCQ
Kansas City cardiomyopathy questionnaire 
MRA
mineralocorticoid receptor antagonist 


Abbreviation or special 
term
Explanation
MedDRA
Medical Dictionary for Regulatory Activities 
NT-pro-BNP
N-terminal pro b-type natriuretic peptide
NYHA 
New York Heart Association
PGIC
Patient Global Impression of Change
qd
once a day 
qod
every other day
RAAS
renin angiotensin aldosterone system
RAASi
renin angiotensin aldosterone system inhibitor
SAE
serious adverse event 
SD
standard deviation
S-K
serum potassium
ZS
sodium zirconium cyclosilicate Note that sodium zirconium cyclosilicate can be 
abbreviated as either ZS or SZC in documents and refer to the same product.
tid
three times a day
UACR
urinary albumin to creatinine ratio


CCI


CCI


CCI


CCI


CCI


CCI
CCI


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1
STUDY DETAILS
1.1
Study objectives
Table 1
Study objectives
Primary Objective:
Endpoint/Variable:
To determine if there is a difference between 
SZC and placebo in RAAS blockade 
treatment.
Proportion of subjects in the following 
categories at 3 months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose
Safety Objective:
Endpoint/Variable:
To evaluate the safety and tolerability of 
SZC in this patient population.

Serious Adverse Events (SAEs)

Discontinuation of IP due to Adverse 
Events (DAEs)

Adverse Events (AEs)

Changes in clinical laboratory 
parameters, including assessment of 
creatinine and renal function (eGFR).

Vital signs

ECG
To explore whether SZC compared with 
placebo will affect the incidence of high 
and/or low S-K levels.
Number of subjects and number of events 
with central lab levels of S-K:

>6.0 mmol/L

>5.5 mmol/L

<3.5 mmol/L

<3.0 mmol/L


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Exploratory Objectives
Endpoint/Variable:
To explore the difference between SZC and 
placebo in RAAS blockade treatment in subjects 
with local lab-Ka > 5.0 mmol/L at last 
assessment before randomization.
Proportion of subjects in the following 
categories at 3 months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose
To explore the difference between SZC and 
placebo in RAAS blockade treatment in subjects 
with local lab K ≤5.0 mmol/L at last assessment 
before randomization.
Proportion of subjects in the following 
categories at 3 months:

No ACEi/ARB/ARNI or at less than 
target dose and no MRA

ACEi/ARB/ARNI at target dose and no 
MRA

MRA at less than target dose

MRA at target dose
To explore the difference between SZC and 
placebo in facilitating the initiation and 
maintenance of MRA treatment

Proportion of subjects treated with MRA 
at 3 months

Proportion of subjects at target dose of 
MRA therapy at 3 months
To explore the difference between SZC and 
placebo in Renin angiotensin aldosterone 
system inhibitor (RAASi) therapy
Proportions of subjects on higher dose of 
RAASi compared to baseline

Mean equipotent doses of MRA at 3 
months

Dose intensity score as calculated in 
Vasudevan et al (Vasudevan et al 
2017), with the exception of only 
considering RAASi drugs

A scoring system to assess the 
intensity of RAASi therapy (see 
Section 3.3 for details)


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To explore change of blood pressure (BP) in 
the SZC group compared with the placebo 
group.
Change in systolic and diastolic BP from 
baseline.
To explore change of urinary albumin to 
creatinine ratio (UACR) in the SZC group 
compared with the placebo group.
Change in UACR from prior to the first 
increase in RAASi therapy (Visit 3), in the 
subset of subjects with albuminuria (UACR 
> 30 mg/g) at Visit 3.
To explore change in NYHA class in the 
SZC group compared with the placebo 
group.
Change in NYHA class from baseline.
To explore the effect of treatment with SZC
versus placebo on the Patient Global 
Impression of Change (PGIC) and Kansas 
City Cardiomyopathy Questionnaire 
(KCCQ) Overall Summary Score.

Change in health status measured by 
PGIC.

Change from baseline measured at 3 
months in the overall summary score of 
KCCQ, a specific HF patient reported 
outcome questionnaire.
To explore any change in biomarkers as 
surrogates for cardiac and renal function 
associated with SZC.
Changes in biomarkers NT-pro-BNP, and 
troponin.
To collect and store samples of plasma and 
serum for future exploratory biomarker and 
(optional) genetic research.
Results to be reported outside of the clinical 
study report (CSR).
a i-STAT for patients enrolled under CSP version 3 or earlier.
1.2
Study design
This is an international, multicentre, parallel group, randomised, double-blind, placebo-
controlled Phase II study to evaluate the benefits and risks of using sodium zirconium 
cyclosilicate (SZC) to intensify RAASi therapy. Patients with chronic heart failure (NYHA II-
IV) and mild hyperkalaemia, or at high risk of developing hyperkalaemia, will be enrolled. 
Eligible subjects will be randomised in a 1:1 ratio to receive SZC or placebo for 3 months 
while titrating RAASi therapies.
The general study design is summarised in Figure 1. Note that, as per CSP version 3 and 
earlier, i-STAT, and not local lab, was used to evaluate baseline K.


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Figure 1
Study design
* Subjects with local lab-K > 5.0 mmol/L will receive SZC 10g tid or placebo for 48h before starting continued 
treatment with SZC 5g qd or placebo; Subjects with local lab ≤ 5.0 mmol/L will immediately start continued 
treatment with SZC 5g or Placebo (PBO) qd. Continued treatment will be titrated within the range 5g qod to 15g 
qd.
# After the end of randomised therapy (Visit 8 or early treatment discontinuation), the investigator should return 
to the original RAASi dose the patient was on prior to randomization and will manage the subject as per standard 
of care. In instances in which the investigator had down-titrated or stopped RAASi medications, then the subject 
should remain on the lowest dose at the end of randomized therapy.
1.3
Number of subjects
The study will employ a 1:1 randomization scheme. A sample size of 280 subjects will allow 
for estimation of the effect in the primary objective. Due to lack of prior knowledge of the 
distribution of the primary endpoint categories in the placebo group, the following 
considerations were made with regards to sample size. Assuming a difference in proportion of 
MRA use at 3 months of 0.2 between treatment groups, a sample size of 140 subjects per 
group provides at least 90% power for a significance level of 5% using a chi-square test.
Due to the COVID-19 pandemic the study was prematurely terminated with a total sample 
size of 182 patients.
2
ANALYSIS SETS
2.1
Definition of analysis sets
For purposes of analysis, the following analysis sets are defined:


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Analysis set
Description
Enrolled 
All subjects who sign the informed consent form.
Full analysis set
All randomised subjects.
Safety analysis set
All subjects randomly assigned to study treatment and who take at 
least 1 dose of investigational medicinal product.
The Full analysis set will be used in the analysis of the primary objective.
2.2
Violations and deviations
The important protocol deviations will not imply exclusion from any analysis and will be 
summarized by randomized treatment group. A list of possible important protocol deviations 
can be found in section 4.1 in the Non-Compliance Handling Plan.
In addition, COVID-19 related important and non-important protocol deviations will be 
summarized and listed.
3
VARIABLES
Whenever an assessment or measurement at 3 months is referred to, it is the 
assessment/measurement at visit 8 that will be used, provided this visit took place at least 77 
days after the patient was randomized into the study. Note that, during the study interruption, 
and in case of early study discontinuation due to COVID-19, patients were called to attend 
visit 8 prematurely. In summary tables, visit 8 measurements occurring 3 months post 
randomization, as per original study schedule, are summarized separately.
If visit 8 occurred earlier than 77 days post-randomization, the 3 months measurement is 
regarded as missing (and, for the primary analysis, is imputed).
In the case of the subject who at the same time takes more than one medicine within 
ACEi/ARB/ARNI class or within MRA class, the medicine with the largest equipotent dose 
(see the definition of equipotent dose in section 3.3) will be selected per RAASi class 
(ACEi/ARB/ARNI and MRA separately) for all derivations and analyses in which RAASi 
dose is directly used. 
3.1
Primary variable
The primary outcome measure is the classification of subjects in the following four categories 
at 3 months: 

No ACEi/ARB/ARNI or at less than target dose and no MRA 

ACEi/ARB/ARNI at target dose and no MRA 


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
MRA at less than target dose 

MRA at target dose.
The RAASi dose used in the primary variable will be the dose the subject is on before any 
potential RAASi titration/change on the day of visit 8, i.e. the RAASi treatment(s) will have to 
have a start date before the date of visit 8 and either be ongoing at visit 8 or have the visit 8 
date as stop date. 
For the purpose of the primary analysis, missing RAASi dose data at 3 months will be 
imputed by Multiple Imputation technique implemented in SAS® in PROC MI. A detailed 
description of the imputation algorithm can be found in Section 4.2.1.
Wherever a range is provided in the target dose column in Table 5 in the Clinical Study 
Protocol (CSP), the lower end of the range will be considered the target dose in the derivation 
of the primary variable. If a dose reported in the electronic case report form (eCRF) is equal to 
or higher than the defined target dose, the reported dose will be assumed to be the target dose 
in the categorization.
3.1.1
Variables for sensitivity analyses
The primary variable and outcome measure will also be derived based on non-imputed data, 
i.e. using only available data at 3 months.
In addition, if the primary variable is missing at 3 months, the worse (lower) of the doses at 
the last two scheduled visits, randomization visit and onwards, with available data (for 
ACEi/ARB/ARNI and MRA respectively) will be used to derive the primary variable. If the 
subject doesn’t have two available non-missing values, then the dose(s) will be assumed to be 
zero.
A sensitivity analysis aiming at evaluating the impact of COVID-19 on the data will also be 
performed.
3.2
Secondary variables
Not Applicable.
3.3
Exploratory variables
Subject treated with MRA at 3 months
The binary variable “subject treated with MRA at 3 months (yes/no)” will be defined as yes if 
the subject is on an MRA dose greater than 0 at 3 months, and defined as no if subject is on no 
MRA dose at 3 months, or left as missing if 3-months data is missing.


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Subject at target dose of MRA at 3 months
The binary variable “subject at target dose of MRA at 3 months (yes/no)” will be defined as 
yes if the subject is on an MRA dose equal to or greater than the target dose as specified in 
CSP Table 5 at 3 months, and defined as no if subject is on an MRA dose less than the target 
dose or on no MRA at 3 months, or left as missing if 3-month data is missing.
Equipotent dose of MRA ≥50% at 3 months
The binary variable “Equipotent dose of MRA > 50% at 3 months (yes/no)” will be defined as 
yes if the subject is treated with equipotent MRA dose greater than 50% at 3 months and 
defined as no if the subject is on an equipotent MRA dose equal to or less than 50% at 3 
months, or left as missing if 3-month data is missing.
Higher dose of RAASi compared to baseline
The values of the binary variable “higher dose of RAASi compared to baseline (yes/no)” will 
be derived for multiple time points as specified in Section 4.4 . ACEi/ARB/ARNI and MRA
medications will be considered separately. The equipotent dose defined below (in ‘Equipotent 
doses of MRA’) will be compared.
If the dose of either ACEi/ARB/ARNI or MRA drug has been increased at a visit as compared 
to baseline, then the binary variables “higher dose of RAASi compared to baseline” will be set 
to ‘yes’, otherwise will be set to ‘no’.
Equipotent doses of RAASi
In general, equipotent dose of a RAASi treatment at a particular time point is defined as the 
ratio of achieved dose at that occasion and the corresponding target dose provided in Table 5 
in the CSP. When the frequency of drug intake is different than qd, then total daily dose is 
used for calculations. In particular, Sacubitril + Valsartan is administrated as 24/26 mg bid, 
49/51 mg bid, or 97/103 mg bid, where the latter is the target dose. Corresponding equipotent 
doses are 25%, 50% and 100%. 
The values of equipotent doses (denoted below as X) of ACEi/ARB/ARNI or MRA will be 
converted into categories, to be further used for the primary endpoint construction, as follows:

X ≤ 0% – consider as “no dose” category

0 < X < 100% – consider as “some, but less than target dose” category

X ≥ 100% – consider as “target dose” category.
Dose intensity score


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A “RAASi dose intensity score” based on the drug/dose intensity scores presented in 
Vasudevan et al (Vasudevan et al 2017) will be derived based on RAASi treatment data from 
visit 2, 5, 7 and 8 respectively (i.e. baseline and approximately at 1, 2 and 3 months) using the 
following rule, where target dose is the target dose in CSP Table 5 (lower limit if a range is 
given):

Score value 0: if patient receives no dose

Score value 1: if 0 < dose < (target dose)/2

Score value 2: if (target dose)/2 to ≤dose < target dose

Score value 3: if dose ≥ target dose.
A score will be derived for a subject with respect to ACEi/ARB/ARNI and MRA separately.
RAASi therapy intensity
Categorize the dose of ACEi/ARB/ARNI and MRA, respectively, as is done for the primary 
endpoint, namely into

no dose

some, but less than target dose

target dose.
There are nine possible combinations of such ACEi/ARB/ARNI and MRA dose categories for 
a subject. In an attempt to rank the intensity of RAASi therapy, an order of probable clinical 
benefit for the combined dose categories was defined by the members of the Executive 
Committee as follows:
Subject dose category
Ascending order of category of RAASi 
therapy intensity
ACEi/ARB/ARNI
MRA
0
No dose
No dose
1
Some
No dose
2
No dose
Some
3
Target
No dose
4
Some
Some
5
No dose
Target
6
Target
Some
7
Some
Target
8
Target
Target


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Change from baseline in BP
Change from baseline in systolic and diastolic BP will be derived as part of the standard vital 
signs evaluation (see Section 3.4.4).
Change in UACR 
As per the CSP, urinary albumin and creatinine will be provided by the central laboratory for
Visit 3 and Visit 8 only. Urinary albumin to creatinine ratio (UACR) will be calculated as the 
ratio of urine albumin and urine creatinine. The change in UACR is defined as the difference 
between the Visit 8 and Visit 3 values, respectively.
NYHA
The NYHA classification values are provided in Appendix G in the CSP and will be used 
directly in the analysis.
PGIC and KCCQ questionnaires
PGIC and KCCQ questionnaires are provided in Appendix H in the CSP. 
PGIC values will be used directly in the analysis.
The KCCQ is a self-administered disease specific instrument and has shown to be a valid,
reliable and responsive measure for patients with HF (Green et al 2000, Spertus et al 2005).
The KCCQ consists of 23 items measuring HF-related symptoms, physical limitations, social
limitations, self-efficacy, and health-related quality of life. 
The Overall Summary Score incorporates the symptom and physical limitations, quality of 
life and social limitations domains into a single score. Higher scores represent a better 
outcome. For more details regarding the Overall Summary Score derivation, see KCCQ-
Scoring-Instructions document.
The Total Symptom Score incorporates the frequency and limitations of the symptoms into a 
single score. Higher score represents a better outcome. For more details regarding the Total 
Symptom Score derivation, see KCCQ-Scoring Instructions document
The Clinical Summary Score incorporates the Total Symptom Score and the Physical 
Limitation Score into a single score. Higher scores represent a better outcome. For more 
details regarding the Clinical Summary Score derivation, see KCCQ-Scoring-Instructions 
document.


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3.4
Safety variables
3.4.1
Adverse events
Adverse Events will be collected from time of signature of informed consent form throughout 
the treatment period and including the follow-up period until the last contact in the study.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary version 21.0 or higher. 
3.4.2
Laboratory safety variables
The baseline value is defined as the last observation prior to first IP dose.
Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-EPI equation
(Levey at al 2009) for each time-point where creatinine is measured, using central laboratory 
creatinine.
Urinary albumin and creatinine will be provided by the central laboratory and will be used to 
calculate urinary albumin to creatinine ratio (UACR). 
3.4.3
Physical examinations
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. Hence, the results from 
the post-baseline physical examinations will be part of the AE reporting and not presented 
separately.
3.4.4
Vital signs
Vital signs assessments will consist of weight, pulse and systolic and diastolic BP 
measurements. Changes from baseline will be derived. The baseline value is defined as the 
last observation prior to the first IP dose.
3.4.5
ECGs
12-lead electrocardiograms (ECG), with PR, QRS and QT intervals automatically calculated,
will be obtained at screening, visit 8/end-of-treatment visit and visit 10.
QTc will be derived. Frederica’s correction will be used, with QTcF obtained from existing 
measurements as QTcF = QT/(60/HR)1/3.
The ECG baseline value will in general be the value obtained at the screening visit, since ECG 
is not measured at the randomization visit according to the study plan. If multiple baseline 
assessments exist, the baseline value will be  the last observation prior to IP dose.


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3.4.6
S-K
For the tabulation of high and low S-K levels, central laboratory S-K will be used. 
3.4.7
Other
Exposure to study drug will be defined as total length of period on study drug, calculated for 
each subject as date of last dose – date of first dose +1.
Actual exposure to the study drug will be defined as the number of days a subject was on IP, 
excluding any dose interruptions.
The percentage of study drug compliance for the randomized treatment period will be derived 
for each subject based on sachet counts, converted into grams of study drug, as the number of 
sachets taken (dispensed – returned) multiplied by 5 (as each sachet contains 5 mg of drug), 
relative to the expected grams of study drug taken. The expected amount of dose taken will be 
based upon the planned administration of study drug (dose and frequency) recorded by the 
investigator. 
4
ANALYSIS METHODS
4.1
General principles
The primary and explorative analyses will be based on the Full analysis set including all 
randomised subjects. Subjects will be analysed according to their randomized study 
medication.
In safety analyses the Safety analysis set will be used. Erroneously treated subjects (e.g. those 
randomized to SZC but actually given placebo throughout the study or vice versa) will be 
accounted for in the actual treatment group. A subject who in error has received both SZC and 
placebo will be accounted for in the randomized treatment group.
No imputation will be done for missing or partial missing dates, except for start and end date 
for concomitant medication, which will be imputed as follows: 

Missing start day - impute the 1st of the month unless month is same as month of first 
dose of study drug then impute first dose date. 

Missing start day and month – impute 1st January unless year is the same as first dose 
date, then impute first dose date. Ensure that the start date is prior to the end date of 
the concomitant medication. 

Start day completely missing - impute first dose date unless the end date suggests it 
could have started prior to this in which case impute the 1st January of the same year 
as the end date of the concomitant medication.


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When imputing a start date ensure that the new imputed date is sensible, i.e. is prior to the end 
date of the medication.

Missing end day - impute the last day of the month unless month is same as month of 
first dose of study drug then impute last dose date.

Missing end day and month – impute 31st December unless year is the same as first 
dose date then impute last dose date.

End date completely missing - if the ongoing flag is missing, then assume that the 
medication is still being taken, i.e. do not impute a date. If the medication has stopped 
and start date is prior to first dose date, then impute the 1st dose date. If it started on or 
after first dose date, then impute to be the last dose date.
All personnel involved with the analysis of the study will remain blinded until database lock 
and Clinical Study Protocol deviations identified.
Analyses will be performed by AstraZeneca or its representatives.
Data will be presented following the AZ Corporate CSR/HLD Reporting Standards.
4.2
Analysis methods
4.2.1
Analysis of the primary variable
The primary objective is to determine if there is a difference between SZC and placebo in 
RAASi treatment. The null hypothesis is that there is no difference between treatments in the 
distribution of proportion of subjects in the RAASi treatment categories, and the alternative 
hypothesis is that there is a difference. The hypothesis will be tested at a significance level of 
5%.
As already indicated in Section 3.1, missing RAASi dose data at 3 months requires special 
attention before conducting the primary analysis. Toward this aim, Multiple Imputation 
technique will be used. It is assumed that the missing data mechanism operating in this setting 
is Missing At Random and data for subjects with missing values will be imputed based on 
observed data from subjects within their own treatment arm.
The general workflow of the primary analysis will be outlined. The first step in the proposed 
procedure is to impute missing data for the primary variable with PROC MI implemented in 
SAS®, resulting in M complete datasets. Then, the hypothesis of a treatment difference (SZC
vs placebo) in the distribution of RAASi treatment across the four categories of the primary 
outcome measure will be tested using a chi-square test for homogeneity, applied for each of M 
complete datasets. Lastly, M chi-square test statistics will be combined into a single value, 
allowing the computation of a final p-value of the procedure. 


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The primary outcome measure is derived based on doses of the two classes of RAASi 
treatments, i.e. ACEi/ARB/ARNI and MRA. These are converted to one of four categories as 
specified in the definition of the primary variable, and the categories will be imputed for 
subjects with missing data at 3 months. Since it is allowed for subjects to switch between 
different RAASi medicines throughout the study, the RAASi categories (see definition, 
Section 3.3) will be used as categorical response variables in the imputation method.
Monotone methods in PROC MI will be utilized. A monotone method creates multiple 
imputations by imputing missing values sequentially over the variables taken one at a time, 
according to a specified order of variables to impute. In particular, a monotone discriminant
function method will be used to impute the RAASi categories. The model will include RAASi 
category at 3 months as the outcome variable and the following covariates: RAASi category, 
local lab-K, eGRF and systolic blood pressure measured at the last visit before the 3 months
visit when all the covariates’ data are available. The rationale to use such covariates in the 
imputation models is that the decision regarding the titration of RAASi treatments is taken 
based on, among others, local lab-K, eGFR, blood pressure levels and may depend indirectly 
on the previous RAASi dose.
Imputation will not be performed for subjects with no available post baseline values of 
equipotent doses of ACEi/ARB/ARNI or MRA.
In the multiple imputation process, ≥100 iterations will be performed. In order to allow to 
reproduce the results of multiple imputation procedure, seed to begin random number 
generator will be specified as 8823.
In next step, the primary outcome measure will be tested using a chi-square test for 
homogeneity for each complete dataset. 
Finally, M results of the chi-square test will be combined according to the following formulas:
 =

			

 − + 1
 −1 
1 + 
where 
			 =

 ∑




;
 = 1 +



 ∑

 −

 ∑








and k is the number of degrees of freedom in the single chi-square test.
The pooled p-value can be obtained from F distribution with 
 and  numerator and 
denominator, respectively, degrees of freedom as follows:
p-value=Pr( ,"# > )


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where  = 
 &
'( −1)(1 +

(#
			).
The pooled p-value will be compared to 5 % significance level.
For more details regarding the pooling procedure, see Ratitch et al 2013 or Li et al 1991.
The resulting pooled p-value will be presented alongside the averaged proportion of subjects 
in the four categories over M multiple imputation datasets. The denominator for the 
proportions will be the number of Full analysis set subjects with a non-missing value for the 
RAASi category (after imputation) in the respective treatment group. 
4.2.2
Sensitivity analyses
Sensitivity analyses of the primary analysis will be performed
(i)
by using only available non-imputed RAASi dose data at 3 months
(ii) by using the worse of the last two dose observations carried forward (see Section 
3.1.1 for full derivation of this variable).
(iii) by removing the observations potentially affected by COVID-19, defined as 
observations obtained on visits with visit dates later than 2020-03-11, and 
repeating the primary analysis on the resulting data set.
For sensitivity analysis (i) and (ii), the resulting chi-square p-value will be presented alongside 
the number and proportion of subjects in the four categories of the primary outcome measure.
The presentation for the (iii) will be the same as that for the primary endpoint.
4.3
Analysis of secondary variables
Not Applicable.
4.4
Analysis of exploratory variables
Exploratory objectives will be presented using summary statistics, and where specified below 
an estimated treatment difference with 95% CI will also be presented. No formal statistical 
inference is planned for exploratory endpoints, therefore no correction for multiplicity will be 
applied. For this reason, confidence intervals provided for any of the exploratory variables 
should be interpreted with great caution.
Except for sub-group analyses of the primary endpoint,  exploratory variables will be based on 
available data at the visits in question.
Subgroups for explorative subgroup analyses applied to the primary outcome measure will be 
defined as follows:


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1. Subjects with K >5.0 mmol/L at last assessment before randomization vs subjects with 
K ≤5.0 mmol/L at last assessment before randomization.
2. Subjects randomized pre CSP amendment 4, defined as randomization date less of 
equal to 12th June 2019 vs subjects randomized post CSP amendment 4.
Baseline K subgroups are determined by the latest non-central lab potassium assessment 
before randomization. This could be either an i-STAT or a local lab assessment, mainly 
depending on the version of the CSP (version 4 or earlier) under which patients were enrolled 
in the study. 
Subject treated with MRA at 3 months
Frequency and percentage of subjects treated with MRA at 3 months will be calculated per 
treatment group. In addition, the difference in proportions between the two treatment groups 
and a 95% CI of the difference, based on standard normal distribution approximation, will be 
calculated.
Subject at target dose of MRA at 3 months
Frequency and percentage of subjects at target dose of MRA at 3 months will be calculated 
per treatment group. In addition, the difference in proportions between the two treatment 
groups and a 95% CI of the difference, based on standard normal distribution approximation,
will be calculated.
Subject at the equipotent dose of MRA ≥50% at 3 months
Frequency and percentage of subjects treated with MRA > 50% (equipotent dose) will be 
calculated per treatment group. In addition, the difference in proportions between the two 
treatment groups and  a 95% CI of the difference, based on standard normal approximation, 
will be calculated.
Higher dose of RAASi compared to baseline
Frequency and proportions will be presented by treatment group for every scheduled post-
baseline time point through Visit 3 and Visit 8. In addition, the difference in the proportions 
between the treatment groups and its 95% confidence intervals, based on standard normal 
distribution approximation, will be provided.
Equipotent doses of MRA at 3 months
Analysis of the endpoint will consist of presenting the frequency and percentage of subjects 
with particular equipotent doses encountered in the study (expressed in %) falling into the 


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categories/intervals that include “0%”, “25%”, “50%”, “75%”, “100%”, “>100%”, “Other”, 
displayed per treatment group.
In addition, mean MRA equipotent dose per treatment group will be presented, along with the 
difference in the means of SZC and placebo arms, and 95% confidence interval for the 
difference based on standard normal distribution approximation.
Dose intensity score
The “RAASi dose intensity score” based on Vasudevan et al (Vasudevan et al 2017) will be 
presented per treatment group as ordered categorical data with frequency and percentage of 
subjects in the three score categories per time point (visit 2, 5, 7 and 8).
RAASi therapy intensity at 3 months
Frequency and proportion of subjects in the RAASi therapy intensity categories at 3 months
will be presented by treatment group.
Change from baseline in BP
Change from baseline in systolic and diastolic BP will be presented per treatment group using 
descriptive statistics as part of the standard safety presentations (see Section 4.5.3).
Change in UACR at 3 months
The analysis of change in UACR from Visit 3 to Visit 8 will be performed in the subset of 
subjects with albuminuria (UACR > 30 mg/g) at Visit 3 and displayed using standard 
summary statistics (n, mean, SD, median, quartiles, minimum and maximum) per treatment 
group. In addition, the difference in the means of SZC and placebo arms, and 95% confidence 
interval for the difference, based on standard normal distribution approximation, will be 
reported. The analysis will be replicated using UACR values converted to standard units.
NYHA at 3 months
NYHA classification will be summarized with shift table presenting changes from baseline to 
the 3 months measurement. Furthermore, the proportion of subjects with no worsening of 
NYHA classification at Visit 8 compared to baseline will be analyzed by a logistic regression 
model with treatment group and baseline NYHA as covariates. The odds ratio between 
treatment groups and its 95% confidence interval will be reported.
PGIC and KCCQ questionnaires at 3 months
For PGIC, frequency and percentage of subjects selecting each answer at 3 months will be 
shown per treatment group.


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Summary statistics (n, mean, SD, median, quartiles, minimum and maximum) per treatment
group will be provided for the change in KCCQ Overall Summary Score, Total Symptom 
Score and Clinical Summary Score at 3 months as compared to baseline, as well as the 
difference in the means of SZC and placebo arms, and 95% confidence interval for the 
difference based on standard normal distribution approximation.
Biomarkers
NT-pro-BNP and troponin data will be provided by the central laboratory and as such, will be 
summarized per treatment group with a standard laboratory table presenting n, mean, SD, 
median, quartiles, minimum and maximum at baseline and change from baseline at Visit 3, 8 
and 10, if available.
Increase in RAASi 
The eCRF captures the primary reason for not increasing RAASi dose at each visit. This data 
will be tabulated descriptively per treatment group.
The number of subjects with RAASi increase at each visit will also be tabulated.
Other
Number and percentage of subjects with S-K measurements in the interval [3.5, 5.0] mmol/L 
will be presented per treatment group and visit (only scheduled visits).
S-K will also be summarized per treatment group with descriptive statistics of observed and 
change from baseline values (n, mean, SD, median, quartiles, minimum and maximum) over 
time (only scheduled visits). In addition, a graph showing mean S-K values over time (only 
scheduled visits) with SD per treatment group will be presented.
4.5
Analysis of safety variables
Whenever “during treatment” is used in tabulations of safety data, the treatment period is 
considered to continue up to (and including) the date of last dose of study drug plus 1 day.
4.5.1
Adverse events
Summaries of adverse events will primarily include all events with a start date on or after the 
first dose. However, some of the tables (an overall summary of AEs and a summary by SOC 
and PT) will also be replicated for “during treatment” time period. 
Adverse events for non-randomized subjects will be presented separately, in the form of a 
listing.


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Number and percentage of subjects with events will be tabulated per treatment group by 
preferred term and system organ class. Adverse events will also be summarized by 
intensity/severity and separately, by causality/relatedness (as determined by the investigator). 
Serious AEs, AEs leading to discontinuation of IP will be summarized in a generally similar 
manner. Adverse events, SAEs, AEs leading to death, and AEs leading to IP discontinuation 
will be summarized for each treatment group as applicable. 
Number and percentage of subjects with fluid overload/oedema related events will in addition 
be presented separately. Fluid overload/oedema related events will be defined by the 
following MedDRA terms: Fluid overload, Fluid retention, Generalised oedema, 
Hypervolaemia, Localised oedema, Oedema, Oedema peripheral, Peripheral swelling.
4.5.2
Laboratory safety variables
All summaries of clinical chemistry/haematology variables collected for the purpose of safety 
evaluation will be based on samples analyzed at the central laboratory, and presented in SI 
units.
Laboratory data, including eGFR, will be summarized by presenting shift tables using normal 
ranges (baseline to most extreme value during treatment), and by presenting summary 
statistics of observed and change from baseline values (n, mean, SD, median, quartiles, 
minimum and maximum). Changes outside pre-specified criteria will be listed and 
summarized. For eGFR, the shift table will be based on the intervals <15, 15 to <30, 30 to 
<45, 45 to <60, 60 to <90 and ≥90 ml/min/1.73m2.
The incidence of clinically notable lab abnormalities will be summarized by presenting data 
on subjects with potential Hy’s law.
4.5.3
Vital signs
Vital sign data will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital sign abnormalities will be 
summarized by presenting a shift table of vital sign measurements classified by the 
investigator as clinically significant or not, baseline to minimum and maximum values during
treatment. Measurements not marked as clinically significant will be assumed to be judged 
normal, while clinically significant are judged to be abnormal.
4.5.4
ECGs
ECG intervals (PR, QRS, QT and QTc) will be summarized by presenting summary statistics 
of observed and change from baseline values. Fridericia's correction will be used for QTc. The 
incidence of clinically notable ECG abnormalities will be summarized. QTc values falling 
outside pre-defined criteria will be tabulated, during treatment and during study.


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4.5.5
S-K
Number and percentage of subjects with central lab S-K < 3.5 mmol/L, <3.0 mmol/L and < 
<2.5 mmol/, as well as those with > 5.0 mmol/L , >5.5 mmol/L >6.0 mmol/L and >6.5 
mmol/L during the study (i.e. treatment period and follow-up) will be presented per treatment 
group. The denominator will be the total number of subjects in the Safety analysis set per 
treatment group.
All available samples, including unscheduled samples, will be included in above calculations.
4.5.6
Other
Duration of exposure (days) will be presented descriptively, and exposure over time will be 
presented in a figure. Actual exposure, by dose, will be tabulated. Summaries of dosing 
pattern (average daily dose, number and frequency of dose titrations) during the study will
also be presented.
Both exposure and actual exposure will be listed.
4.6
Analysis of demographics and baseline characteristics 
Demographics and subject characteristics, relevant medical history, medications at the time of 
randomization and subject disposition will be summarized by treatment group using frequency 
and percentages (for categorical variables) and descriptive statistics of n, mean, standard 
deviation, minimum, median, and maximum (for continuous variables) using the Full analysis 
set.
4.7
Analysis of concomitant and baseline medication
Baseline medication is defined as medication with at least one dose taken before date of 
randomization and with no stop date before date of randomization. 
Concomitant medications are defined as medications taken post randomization, including the 
randomization day.
The frequency of baseline and concomitant medication, including RAASi medications, will be 
presented per ATC class and treatment group using the Full analysis set. Separate tables will 
be created for RAASi and non-RAASi medications.
Summaries of restricted concomitant medications that were started or ongoing after 
randomization will also be presented. Restricted medications will be identified in eCRF data 
based on ATC codes (and drug code, if needed). Restricted concomitant medications include
the medications listed in Table 2.


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Subject receiving restricted concomitant medications will not be excluded from any statistical 
analyses.
4.8
Other
Study drug compliance (%) will be presented descriptively, including mean, standard 
deviation (SD), median, quartiles and 5% and 95% percentiles.
4.9
COVID-19 related analyses
To assess the degree of missingness for the study, number of patients attending the different 
study visits, as well as number of patients still on treatment, will be tabulated, for visits 
occurring after the start of the pandemic, defined as the 11th of March 2020. Visit type for 
such visits will be tabulated and listed. COVID-19 related protocol deviations (both important 
and non-important) will be tabulated and listed. In addition, a summary table illustrating the 
study disruptions that could be attributable to COVID-19, where e.g. the number of subjects in 
the study at the start of the pandemic is displayed, per treatment group, will be provided.
5
INTERIM ANALYSES
Not applicable.
5.1
Data Monitoring Committee (DMC)
An independent data monitoring committee (also called a Safety Review Committee) will be 
utilized for this study. The responsibilities of the Safety Review Committee will be specified 
in a Safety Review Committee charter.
6
CHANGES OF ANALYSIS FROM PROTOCOL
Not applicable.
7
REFERENCES
Green et al 2000
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and Evaluation of the Kansas 
City Cardiomyopathy Questionnaire: A New Health Status Measure for Heart Failure. J Am 
Coll Cardiol. 2000 Apr; 35(5):1245-55.
Levey at al 2009
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW,
Eggers P, VanLente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009
May 5; 150(9):604-12


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Li et al 1991
Li K, Meng X, Raghunathan T, Rubin D. Significance levels from repeated p-values with 
multiply-imputed data. Statistica Sinica, 1(1), 65-92. 
Ratitch et al 2013
Ratitch B, Lipkovich I, O’Kelly M. Combining Analysis Results from Multiply Imputed 
Categorical Data
Spertus et al 2005
Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM, Jones P, McCullough 
PA, Pina I, Tooley J, Weintraub WS, Rumsfeld JS; Cardiovascular Outcomes Research 
Consortium. Monitoring clinical changes in patients with heart failure: a comparison of 
methods. Am Heart J. 2005 Oct;150(4):707-15.
Vasudevan et al 2017
Vasudevan A, Jazi HH, Won JI, Ball T, Patankar GR, Sarmast SA, Shin HJ, McCullough PA. 
Proc (Bayl Univ Med Cent). 2017 Apr; 30(2):139-142.
8
APPENDIX
8.1
Restricted concomitant medications


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Table 2
Restricted concomitant medications
Class of drug
Drugs
ATC codes
Potassium binders
Polystyrene sulphonate, patiromer, 
zirconium cyclosilicate
V03AE01
V03AE09
V03AE10
Potassium supplements
A12BA
8.2
KCCQ scoring instructions
There are 10 summary scores within the KCCQ, which are calculated as follows:
1.  Physical Limitation
•
Code responses to each of Questions 1a-f as follows: 
Extremely limited = 1
Quite a bit limited = 2
Moderately limited = 3
Slightly limited = 4
Not at all limited = 5
Limited for other reasons or did not do = <missing value>
•
If at least three of Questions 1a-f are not missing, then compute
Physical Limitation Score = 100*[(mean of Questions 1a-f actually answered) – 1]/4
(see footnote at end of this document for explanation of meaning of “actually answered”)
2.  Symptom Stability
•
Code the response to Question 2 as follows: 
Much worse = 1
Slightly worse = 2
Not changed = 3
Slightly better = 4
Much better = 5
I’ve had no symptoms over the last 2 weeks = 3
•
If Question 2 is not missing, then compute
Symptom Stability Score = 100*[(Question 2) – 1]/4


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3.  Symptom Frequency
•
Code responses to Questions 3, 5, 7 and 9 as follows: 
Question 3
Every morning = 1
3 or more times a week but not every day = 2
1-2 times a week = 3
Less than once a week = 4
Never over the past 2 weeks = 5


KCCQ Scoring Instructions / 2
© Copyright 2000 – 2003 John Spertus MD MPH
Rev. 3/27/01
3.  Symptom Frequency (cont.)
Questions 5 and 7
All of the time = 1
Several times a day = 2
At least once a day = 3
3 or more times a week but not every day = 4
1-2 times a week = 5
Less than once a week = 6
Never over the past 2 weeks = 7
Question 9
Every night = 1
3 or more times a week but not every day = 2
1-2 times a week = 3
Less than once a week = 4
Never over the past 2 weeks = 5
•
If at least two of Questions 3, 5, 7 and 9 are not missing, then compute: 
S3 = [(Question 3) – 1]/4
S5 = [(Question 5) – 1]/6
S7 = [(Question 7) – 1]/6
S9 = [(Question 9) – 1]/4
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9)
4.  Symptom Burden
•
Code responses to each of Questions 4, 6 and 8 as follows: 
Extremely bothersome = 1
Quite a bit bothersome = 2
Moderately bothersome = 3
Slightly bothersome = 4
Not at all bothersome = 5
I’ve had no swelling/fatigue/shortness of breath = 5
•
If at least one of Questions 4, 6 and 8 is not missing, then compute
Symptom Burden Score = 100*[(mean of Questions 4, 6 and 8 actually answered) – 1]/4
5.  Total Symptom Score
= mean of the following available summary scores: 
Symptom Frequency Score
Symptom Burden Score


KCCQ Scoring Instructions / 3
© Copyright 2000 – 2003 John Spertus MD MPH
Rev. 3/27/01
6.  Self-Efficacy
•
Code responses to Questions 10 and 11 as follows: 
Question 10
Not at all sure = 1
Not very sure = 2
Somewhat sure = 3
Mostly sure = 4
Completely sure = 5
Question 11
Do not understand at all = 1
Do not understand very well = 2
Somewhat understand = 3
Mostly understand = 4
Completely understand = 5
•
If at least one of Questions 10 and 11 is not missing, then compute
Self-Efficacy Score = 100*[(mean of Questions 10 and 11 actually answered) – 1]/4
7.  Quality of Life
•
Code responses to Questions 12, 13 and 14 as follows: 
Question 12
It has extremely limited my enjoyment of life = 1
It has limited my enjoyment of life quite a bit = 2
It has moderately limited my enjoyment of life = 3
It has slightly limited my enjoyment of life = 4
It has not limited my enjoyment of life at all = 5
Question 13
Not at all satisfied = 1
Mostly dissatisfied = 2
Somewhat satisfied = 3
Mostly satisfied = 4
Completely satisfied = 5
Question 14
I felt that way all of the time = 1
I felt that way most of the time = 2
I occasionally felt that way = 3
I rarely felt that way = 4
I never felt that way = 5


KCCQ Scoring Instructions / 4
© Copyright 2000 – 2003 John Spertus MD MPH
Rev. 3/27/01
7.  Quality of Life (cont.)
•
If at least one of Questions 12, 13 and 14 is not missing, then compute
Quality of Life Score = 100*[(mean of Questions 12, 13 and 14 actually answered) – 1]/4
8.  Social Limitation
•
Code responses to each of Questions 15a-d as
follows: Severely limited = 1
Limited quite a bit = 2
Moderately limited = 3
Slightly limited = 4
Did not limit at all = 5
Does not apply or did not do for other reasons = <missing value>
•
If at least two of Questions 15a-d are not missing, then compute
Social Limitation Score = 100*[(mean of Questions 15a-d actually answered) – 1]/4
9.  Overall Summary Score
= mean of the following available summary
scores: Physical Limitation Score
Total Symptom
Score Quality of
Life Score Social
Limitation Score
10. Clinical Summary Score
= mean of the following available summary
scores: Physical Limitation Score
Total Symptom Score
Note: references to “means of questions actually answered” imply the following.
If there are n questions in a scale, and the subject must answer m to score the scale, but the
subject answers only n-i, where n-i >= m, calculate the mean of those questions as
(sum of the responses to those n-i questions) / (n-i)
not
(sum of the responses to those n-i questions) / n
If doing these calculations seems like too much trouble, consider using one of our tools –
available at www.cvoutcomes.org:


KCCQ Scoring Instructions / 5
© Copyright 2000 – 2003 John Spertus MD MPH
Rev. 3/27/01
SAS or SPSS code
Excel spreadsheets
Web data services


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