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

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

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03532009

Acronym

PRIORITIZE HF

Enrollment

182

Registered

2018-05-22

Start date

2018-06-26

Completion date

2020-05-22

Last updated

2021-06-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure

Keywords

Heart Failure, Chronic Heart Failure, Hyperkalaemia

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

Interventions

DRUGSodium Zirconium Cyclosilicate

Oral use for approximately 3 months

DRUGPlacebo

Oral use for approximately 3 months

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 150 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	At the end of the treatment visit (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.

Other

Measure	Time frame	Description
Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters	From Day 1 of treatment up to the end of the follow-up period (Week 17)	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.
Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements	From Day 1 of treatment up to the end of the follow-up period (Week 17)	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.
Number of Patients Who Experienced Adverse Events (AEs) During the Study	From Day 1 of treatment up to the end of the follow-up period (Week 17)	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.
Number of Patients Who Experienced Low and High S-K Levels	From Day 1 of treatment up to the end of the follow-up period (Week 17)	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.
Number of Events of Low and High S-K Levels	From Day 1 of treatment up to the end of the follow-up period (Week 17)	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.
Number of Patients Who Experienced Clinically Significant Changes in Electrocardiogram (ECG) Measurements	From Day 1 of treatment up to the end of the follow-up period (Week 17)	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.

Countries

Brazil, Bulgaria, Canada, Hungary, Poland, Romania, Russia, Slovakia, United States

Participant flow

Recruitment details

This study was performed at 64 sites in 9 countries (Brazil, Bulgaria, Canada, Hungary, Poland, Romania, Russia, Slovakia, and the United States of America) between 26 June 2018 and 22 May 2020.

Pre-assignment details

Patients were randomised in a 1:1 ratio to receive sodium zirconium cyclosilicate (SZC) or placebo for 3 months while titrating renin-angiotensin aldosterone system inhibitor (RAASi) therapies. The study was prematurely terminated due to the COVID-19 pandemic resulting in a reduced sample size (182 randomised patients as opposed to the planned 280 patients).

Participants by arm

Arm	Count
Sodium Zirconium Cyclosilicate Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received SZC 10 g orally tid for 2 days followed by SZC 5 g qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received SZC 5 g orally qd for 3 months. SZC was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	92
Placebo Patients with S-K concentration \> 5.0 mmol/L at the last assessment before randomisation received placebo orally tid for 2 days followed by placebo qd for 3 months. Patients with S-K concentration ≤ 5.0 mmol/L at the last assessment before randomisation received placebo orally qd for 3 months. Placebo was up- or down- titrated depending on local laboratory S-K concentration at every study visit.	90
Total	182

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	1	1
Overall Study	Other	1	1
Overall Study	Withdrawal by Patient	0	2

Baseline characteristics

Characteristic	Sodium Zirconium Cyclosilicate	Placebo	Total
Age, Continuous	72.9 years STANDARD_DEVIATION 8.8	71.0 years STANDARD_DEVIATION 8.1	71.9 years STANDARD_DEVIATION 8.5
Age, Customized ≤ 17 years	0 Participants	0 Participants	0 Participants
Age, Customized 18 - 64 years	17 Participants	16 Participants	33 Participants
Age, Customized 65 - 84 years	65 Participants	69 Participants	134 Participants
Age, Customized ≥ 85 years	10 Participants	5 Participants	15 Participants
Estimated Glomerular Filtration Rate (eGFR)	40.0 Millilitre/minute/1.73 metre^2 STANDARD_DEVIATION 11	42.7 Millilitre/minute/1.73 metre^2 STANDARD_DEVIATION 11.5	41.3 Millilitre/minute/1.73 metre^2 STANDARD_DEVIATION 11.3
Ethnicity (NIH/OMB) Hispanic or Latino	15 Participants	14 Participants	29 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	77 Participants	76 Participants	153 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Left Ventricular Ejection Fraction (LVEF)	33.8 LVEF Percentage STANDARD_DEVIATION 5.8	33.9 LVEF Percentage STANDARD_DEVIATION 6.1	33.8 LVEF Percentage STANDARD_DEVIATION 6
New York Heart Association (NYHA) Functional Classification Class I	0 Participants	0 Participants	0 Participants
New York Heart Association (NYHA) Functional Classification Class II	61 Participants	57 Participants	118 Participants
New York Heart Association (NYHA) Functional Classification Class III	31 Participants	33 Participants	64 Participants
New York Heart Association (NYHA) Functional Classification Class IV	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	90 Participants	89 Participants	179 Participants
Sex: Female, Male Female	41 Participants	33 Participants	74 Participants
Sex: Female, Male Male	51 Participants	57 Participants	108 Participants
S-K Concentration ≤ 5.0 mmol/L	65 Participants	67 Participants	132 Participants
S-K Concentration > 5.0 mmol/L	27 Participants	23 Participants	50 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 91	1 / 90
other Total, other adverse events	16 / 91	7 / 90
serious Total, serious adverse events	14 / 91	10 / 90

Outcome results

Primary

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.

Time frame: At the end of the treatment visit (Month 3)

Population: All randomised patients with a non-missing value for the RAASi treatment category (after imputation) were included.

Arm	Measure	Group	Value (NUMBER)
Sodium Zirconium Cyclosilicate	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	No, or less than target dose ACEi/ARB/ARNI, no MRA	14.7 Percentage of Patients
Sodium Zirconium Cyclosilicate	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	ACEi/ARB/ARNI at target dose and no MRA	14.7 Percentage of Patients
Sodium Zirconium Cyclosilicate	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	MRA at less than target dose	14.2 Percentage of Patients
Sodium Zirconium Cyclosilicate	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	MRA at target dose	56.4 Percentage of Patients
Placebo	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	MRA at target dose	47.0 Percentage of Patients
Placebo	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	No, or less than target dose ACEi/ARB/ARNI, no MRA	13.5 Percentage of Patients
Placebo	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	MRA at less than target dose	24.5 Percentage of Patients
Placebo	Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3	ACEi/ARB/ARNI at target dose and no MRA	15.1 Percentage of Patients

Comparison: The p-value was obtained by pooling the p-values from Chi-square tests performed on individual data sets using the F-distribution and reflects a global test of no difference in distribution of patients in the respective categories between SZC and placebo groups. The null hypothesis was that there is no difference between SZC and placebo in the distribution of percentage of patients in the 4 RAASi treatment categories. The hypothesis was tested at a significance level of 5%.p-value: 0.426F-test

Other Pre-specified

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.

Time frame: From Day 1 of treatment up to the end of the follow-up period (Week 17)