Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure

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.

Inclusion Criteria:

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 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 collection of
sample 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.

4. Subject must be ≥18 years of age inclusive, at the time of signing the informed
consent form.

5. Individuals with established documented diagnosis of symptomatic Heart Failure with
Reduced Ejection Fraction (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 and beta blocker should have been stable for ≥4 weeks.

8. Individuals at risk of developing hyperkalaemia during the study, as defined by

1. Estimated Glomerular Filtration Rate (eGFR) 20-44 ml/min/1.73m2 by Chronic Kidney
Disease Epidemiology Collaboration Equation (CKD-EPI) and i-STAT-K 4.6-5.5 mmol/L
inclusive or

2. eGFR 45-59 ml/min/1.73m2 by CKD-EPI and i-STAT-K 5.1-5.5 mmol/L inclusive, or

3. eGFR 45-59 ml/min/1.73m2 by CKD-EPI and i-STAT-K 4.8-5.0 mmol/L inclusive and a
documented history of S-K > 5.0 mmol/L, or

4. eGFR 45-59 ml/min/1.73m2 by CKD-EPI and i-STAT-K 4.8-5.0 mmol/L inclusive and
diabetes (type I or II)

9. Women of childbearing potential must have a negative pregnancy test during screening
(before first dose of IP) performed locally.

Exclusion Criteria:

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 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.

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.

14. Current treatment with MRA, including spironolactone, eplerenone, canrenone,
canrenoate, or finerenone, at any dose at enrolment.

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.

17. Participation in another clinical study with ZS at any time or treatment with any
investigational product (IP) during the last 3 months.

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.