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

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.

Study Overview

• Status: Terminated
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Sodium Zirconium Cyclosilicate; Drug: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 182
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Belo Horizonte, Brazil, 30140 062
    • Research Site
  • Belo Horizonte, Brazil, 30150-240
    • Research Site
  • Brasillia, Brazil, 70200-730
    • Research Site
  • Campina Grande do Sul, Brazil, 83430000
    • Research Site
  • Campinas, Brazil, 13060-080
    • Research Site
  • Curitiba, Brazil, 80010-030
    • Research Site
  • Marília, Brazil, 17515000
    • Research Site
  • Porto Alegre, Brazil, 90020090
    • Research Site
  • Rio de Janeiro, Brazil, 20241-180
    • Research Site
  • Santo Andre, Brazil, 09090-790
    • Research Site
  • Sao Paulo, Brazil, 05403-000
    • Research Site
  • São José do Rio Preto, Brazil, 15090-000
    • Research Site
  • Uberlandia, Brazil, 38411-186
    • Research Site
  • Votuporanga, Brazil, 15500-003
    • Research Site
• Bulgaria
  • Plovdiv, Bulgaria, 4003
    • Research Site
  • Shumen, Bulgaria, 9700
    • Research Site
  • Sofia, Bulgaria, 1202
    • Research Site
  • Sofia, Bulgaria, 1407
    • Research Site
  • Sofia, Bulgaria, 1527
    • Research Site
• Canada
  • Quebec, Canada, G1V 4G5
    • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Research Site
    • Saint-Charles-Borromee, Quebec, Canada, J6E 6J2
      • Research Site
    • Trois-Rivieres, Quebec, Canada, G8Z 3R9
      • Research Site
• Hungary
  • Baja, Hungary, 6500
    • Research Site
  • Budapest, Hungary, 1122
    • Research Site
  • Budapest, Hungary, 1051
    • Research Site
  • Budapest, Hungary, 1096
    • Research Site
  • Budapest, Hungary, 1106
    • Research Site
  • Budapest, Hungary, 1204
    • Research Site
  • Hatvan, Hungary, 3000
    • Research Site
  • Kecskemét, Hungary, 6000
    • Research Site
  • Miskolc, Hungary, 3529
    • Research Site
  • Nyíregyháza, Hungary, 4400
    • Research Site
  • Pécs, Hungary, 7623
    • Research Site
  • Szentes, Hungary, 6600
    • Research Site
• Poland
  • Chorzów, Poland, 41-500
    • Research Site
  • Gdańsk, Poland, 80-952
    • Research Site
  • Legnica, Poland, 59-220
    • Research Site
  • Poznań, Poland, 60-848
    • Research Site
  • Rzeszów, Poland, 35-055
    • Research Site
  • Tczew, Poland, 83-110
    • Research Site
• Romania
  • Brasov, Romania, 500283
    • Research Site
  • Bucuresti, Romania, 042122
    • Research Site
  • Cluj Napoca, Romania, 400001
    • Research Site
  • Craiova, Romania, 200642
    • Research Site
  • Sibiu, Romania, 550245
    • Research Site
  • Tg Mures, Romania, 540143
    • Research Site
• Russian Federation
  • Aramil, Russian Federation, 624002
    • Research Site
  • Ekaterinburg, Russian Federation, 620039
    • Research Site
  • Krasnoyarsk, Russian Federation, 660062
    • Research Site
  • Moscow, Russian Federation, 121552
    • Research Site
  • Novosibirsk, Russian Federation, 630055
    • Research Site
  • Perm, Russian Federation, 614000
    • Research Site
  • Ryazan, Russian Federation, 390039
    • Research Site
  • Saint Petersburg, Russian Federation, 191015
    • Research Site
  • Tver, Russian Federation, 170036
    • Research Site
  • Yaroslavl, Russian Federation, 150062
    • Research Site
• Slovakia
  • Brezno, Slovakia, 97742
    • Research Site
  • Lucenec, Slovakia, 984 01
    • Research Site
  • Presov, Slovakia, 080 01
    • Research Site
  • Svidnik, Slovakia, 08901
    • Research Site
• United States
  • California
    • National City, California, United States, 91950
      • Research Site
    • Stanford, California, United States, 94305
      • Research Site
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Research Site
  • Florida
    • Miami, Florida, United States, 33133
      • Research Site
    • New Smyrna Beach, Florida, United States, 32169
      • Research Site
    • Port Charlotte, Florida, United States, 33952
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Research Site
  • Louisiana
    • Alexandria, Louisiana, United States, 71301
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Research Site
  • Michigan
    • Flint, Michigan, United States, 48504
      • Research Site
  • New York
    • Brooklyn, New York, United States, 11204
      • Research Site
  • Pennsylvania
    • Wyomissing, Pennsylvania, United States, 19610
      • Research Site
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Research Site
  • Texas
    • El Paso, Texas, United States, 79935
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 150 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium Zirconium Cyclosilicate (ZS); Powder for oral suspension	Drug: Sodium Zirconium Cyclosilicate; Oral use for approximately 3 months; Other Names: ZS; Lokelma
Placebo Comparator: Placebo; Powder for oral suspension	Drug: Placebo; Oral use for approximately 3 months; Other Names: PBO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	RAASi treatment categories: No, or less than target dose, angiotensin converting enzyme inhibitors (ACEi)/ angiotensin receptor blockers (ARB)/ angiotensin receptor/ neprolysin inhibitors (ARNI) and no mineralocorticoid receptor antagonist (MRA);; ACEi/ARB/ARNI at target dose and no MRA;; MRA at less than target dose;; MRA at target dose. Missing values at 3 months were imputed using a multiple imputation approach with 10000 imputations. The imputation model included RAASi category at 3 months as the outcome variable and the following covariates: RAASi category, local lab-K, eGFR and systolic blood pressure measured at the last visit before the 3 months (starting with the randomisation visit) when all the covariates' data were available.	At the end of the treatment visit (Month 3)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Who Experienced Adverse Events (AEs) During the Study	An AE is the development of any untoward medical occurrence in a patient or clinical study patient administered an investigational product (IP) and which does not necessarily have a causal relationship with the IP. An AE can be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of an IP. A serious adverse event (SAE) is an AE occurring during any study phase, that fulfils one or more of the following criteria: Results in death;; Is immediately life-threatening;; Requires in-patient 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 patient or may require medical treatment to prevent one of the outcomes listed above.	From Day 1 of treatment up to the end of the follow-up period (Week 17)
Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters	The number of patients who experienced clinically important abnormalities in clinical laboratory assessments as assessed by the Investigator are presented. Clinically important abnormalities in clinical laboratory parameters were reported as AEs. Clinical laboratory assessments included clinical chemistry, haematology and urinalysis performed at the central laboratory.	From Day 1 of treatment up to the end of the follow-up period (Week 17)
Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements	The number of patients who experienced clinically important abnormalities in vital signs assessments as assessed by the Investigator are presented. Clinically important abnormalities in vital signs measurements were reported as AEs. Vital signs assessments included weight, pulse, and systolic and diastolic blood pressure measurements.	From Day 1 of treatment up to the end of the follow-up period (Week 17)
Number of Patients Who Experienced Clinically Significant Changes in Electrocardiogram (ECG) Measurements	The number of patients who experienced clinically significant changes in ECG measurements as assessed by the Investigator are presented. Clinically important abnormalities in ECG measurements were reported as AEs. 12-lead ECGs were obtained using a digital ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT (using QT interval corrected by Fredericia's algorithm) intervals.	From Day 1 of treatment up to the end of the follow-up period (Week 17)
Number of Patients Who Experienced Low and High S-K Levels	The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. Patients with S-K levels < 3.5 mmol/L were considered to have low S-K levels. Patients with S-K levels > 5.0 mmol/L were considered to have high S-K levels.	From Day 1 of treatment up to the end of the follow-up period (Week 17)
Number of Events of Low and High S-K Levels	The S-K levels used for this analysis were based on the measurements obtained by the central laboratory. Patients with S-K levels < 3.5 mmol/L were considered to have had an event of low S-K levels. Patients with S-K levels > 5.0 mmol/L were considered to have had an event of high S-K levels.	From Day 1 of treatment up to the end of the follow-up period (Week 17)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Investigators: Principal Investigator: Jean-Claude Tardif, Montreal Heart Institute 5000 Belanger Street, Montreal, PQ Canada H1T1C8

Publications and helpful links

Helpful Links

• redacted CSR synopsis
• redacted SAP
• redacted CSP

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2018
• Primary Completion (Actual): May 22, 2020
• Study Completion (Actual): May 22, 2020

Study Registration Dates

• First Submitted: March 29, 2018
• First Submitted That Met QC Criteria: May 9, 2018
• First Posted (Actual): May 22, 2018

Study Record Updates

• Last Update Posted (Actual): June 15, 2021
• Last Update Submitted That Met QC Criteria: May 20, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Heart Failure; Chronic Heart Failure; Hyperkalaemia
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: D9484C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No