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Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure (PRIORITIZE HF)

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ClinicalTrials.gov Identifier: NCT03532009
Recruitment Status : Suspended (The recruitment has been tentatively stopped while an amendment is written. Recruitment will be restarted after approval of the amendment.)
First Posted : May 22, 2018
Last Update Posted : August 16, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Sodium Zirconium Cyclosilicate Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : June 26, 2018
Estimated Primary Completion Date : October 12, 2020
Estimated Study Completion Date : October 12, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Zirconium

Arm Intervention/treatment
Experimental: Sodium Zirconium Cyclosilicate (ZS)
Powder for oral suspension
Drug: Sodium Zirconium Cyclosilicate
Oral use for approximately 3 months
Other Name: ZS; Lokelma

Placebo Comparator: Placebo
Powder for oral suspension
Drug: Placebo
Oral use for approximately 3 months
Other Name: PBO




Primary Outcome Measures :
  1. Proportion of subjects in the following categories: • 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 [ Time Frame: Approximately 3 months ]

    To determine if there is a difference between ZS and placebo in RAAS blockade treatment.

    Note: ACEi=angiotensinogen converting enzyme inhibitors; ARB=angiotensin receptor blockers; ARNI=angiotensin receptor blocker and neprolysin inhibitors; MRA=mineralocorticoid receptor antagonists




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 150 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03532009


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Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Jean-Claude Tardif Montreal Heart Institute 5000 Belanger Street, Montreal, PQ Canada H1T1C8

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03532009     History of Changes
Other Study ID Numbers: D9484C00001
First Posted: May 22, 2018    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by AstraZeneca:
Heart Failure
Chronic Heart Failure
Hyperkalaemia

Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases