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

Heart Failure Clinical Trial

— PRIORITIZE HF  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03532009
• Other study ID #: D9484C00001
• Status: Terminated
• Phase: Phase 2
• Start date: June 26, 2018
• Est. completion date: May 22, 2020

Study information

• Verified date: May 2021
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 182
• Est. completion date: May 22, 2020
• Est. primary completion date: May 22, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 150 Years

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Sodium Zirconium Cyclosilicate
Oral use for approximately 3 months
• Placebo
Oral use for approximately 3 months

Locations

Country	Name	City	State
Brazil	Research Site	Belo Horizonte
Brazil	Research Site	Belo Horizonte
Brazil	Research Site	Brasillia
Brazil	Research Site	Campina Grande do Sul
Brazil	Research Site	Campinas
Brazil	Research Site	Curitiba
Brazil	Research Site	Marília
Brazil	Research Site	Porto Alegre
Brazil	Research Site	Rio de Janeiro
Brazil	Research Site	Santo Andre
Brazil	Research Site	São José do Rio Preto
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Uberlandia
Brazil	Research Site	Votuporanga
Bulgaria	Research Site	Plovdiv
Bulgaria	Research Site	Shumen
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Quebec
Canada	Research Site	Saint-Charles-Borromee	Quebec
Canada	Research Site	Trois-Rivieres	Quebec
Canada	Research Site	Vancouver	British Columbia
Hungary	Research Site	Baja
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Hatvan
Hungary	Research Site	Kecskemét
Hungary	Research Site	Miskolc
Hungary	Research Site	Nyíregyháza
Hungary	Research Site	Pécs
Hungary	Research Site	Szentes
Poland	Research Site	Chorzów
Poland	Research Site	Gdansk
Poland	Research Site	Legnica
Poland	Research Site	Poznan
Poland	Research Site	Rzeszów
Poland	Research Site	Tczew
Romania	Research Site	Brasov
Romania	Research Site	Bucuresti
Romania	Research Site	Cluj Napoca
Romania	Research Site	Craiova
Romania	Research Site	Sibiu
Romania	Research Site	Tg Mures
Russian Federation	Research Site	Aramil
Russian Federation	Research Site	Ekaterinburg
Russian Federation	Research Site	Krasnoyarsk
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Perm
Russian Federation	Research Site	Ryazan
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Tver
Russian Federation	Research Site	Yaroslavl
Slovakia	Research Site	Brezno
Slovakia	Research Site	Lucenec
Slovakia	Research Site	Presov
Slovakia	Research Site	Svidnik
United States	Research Site	Alexandria	Louisiana
United States	Research Site	Boston	Massachusetts
United States	Research Site	Brooklyn	New York
United States	Research Site	El Paso	Texas
United States	Research Site	Flint	Michigan
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Miami	Florida
United States	Research Site	National City	California
United States	Research Site	New Smyrna Beach	Florida
United States	Research Site	Port Charlotte	Florida
United States	Research Site	Rapid City	South Dakota
United States	Research Site	Stanford	California
United States	Research Site	Waterbury	Connecticut
United States	Research Site	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Brazil,  Bulgaria,  Canada,  Hungary,  Poland,  Romania,  Russian Federation,  Slovakia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)
Other	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)
Other	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)
Other	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)
Other	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)
Other	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)
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.	At the end of the treatment visit (Month 3)

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