Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: Sodium Zirconium Cyclosilicate; Placebo
Intervention description: Oral use for approximately 3 months; Oral use for approximately 3 months
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 182.0
Sex: All
Minimum age: 18 Years
Maximum age: 150 Years
Healthy volunteers: No
Keywords: Heart Failure; Chronic Heart Failure; Hyperkalaemia

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.
    

Eligibility criteria:

        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, MRA and beta blocker should have been stable for ≥4 weeks.
             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 once a day (QD) or
             25 mg every other day (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:

               1. eGFR 20-44 ml/min/1.73m2 by CKD-EPI and local lab-K 4.0-5.5 mmol/L inclusive, or

               2. eGFR 45-59 ml/min/1.73m2 by CKD-EPI and local lab-K 5.1-5.5 mmol/L inclusive, or

               3. 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.

          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 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.

          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. 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.

         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.

         21. Subjects with a family history of long QT syndrome, presence of cardiac arrhythmias or
             conduction defects that require immediate treatment, or a QTc (corrected QT interval)
             of ≥550 msec.