Clinical trial NCT03532009: Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Heart Failure
Keywords: Heart Failure
Chronic Heart Failure
Hyperkalaemia
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2018-05-22
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Maximum age (years): 150
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

Primary outcomes:
measure: Percentage of Patients Receiving Different Categories of RAASi Treatments at Month 3
timeFrame: At the end of the treatment visit (Month 3)
Secondary outcomes:
Other outcomes:
measure: Number of Patients Who Experienced Adverse Events (AEs) During the Study
timeFrame: From Day 1 of treatment up to the end of the follow-up period (Week 17)
measure: Number of Patients Who Experienced Clinically Important Abnormalities in Clinical Laboratory Parameters
timeFrame: From Day 1 of treatment up to the end of the follow-up period (Week 17)
measure: Number of Patients Who Experienced Clinically Important Abnormalities in Vital Signs Measurements
timeFrame: From Day 1 of treatment up to the end of the follow-up period (Week 17)
measure: Number of Patients Who Experienced Clinically Significant Changes in Electrocardiogram (ECG) Measurements
timeFrame: From Day 1 of treatment up to the end of the follow-up period (Week 17)
measure: Number of Patients Who Experienced Low and High S-K Levels
timeFrame: From Day 1 of treatment up to the end of the follow-up period (Week 17)
measure: Number of Events of Low and High S-K Levels
timeFrame: From Day 1 of treatment up to the end of the follow-up period (Week 17)
Locations:
city: National City
country: United States
facility: Research Site
state: California
city: Stanford
country: United States
facility: Research Site
state: California
city: Waterbury
country: United States
facility: Research Site
state: Connecticut
city: Miami
country: United States
facility: Research Site
state: Florida
city: New Smyrna Beach
country: United States
facility: Research Site
state: Florida
city: Port Charlotte
country: United States
facility: Research Site
state: Florida
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Alexandria
country: United States
facility: Research Site
state: Louisiana
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Flint
country: United States
facility: Research Site
state: Michigan
city: Brooklyn
country: United States
facility: Research Site
state: New York
city: Wyomissing
country: United States
facility: Research Site
state: Pennsylvania
city: Rapid City
country: United States
facility: Research Site
state: South Dakota
city: El Paso
country: United States
facility: Research Site
state: Texas
city: Belo Horizonte
country: Brazil
facility: Research Site
city: Belo Horizonte
country: Brazil
facility: Research Site
city: Brasillia
country: Brazil
facility: Research Site
city: Campina Grande do Sul
country: Brazil
facility: Research Site
city: Campinas
country: Brazil
facility: Research Site
city: Curitiba
country: Brazil
facility: Research Site
city: Marília
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Rio de Janeiro
country: Brazil
facility: Research Site
city: Santo Andre
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: São José do Rio Preto
country: Brazil
facility: Research Site
city: Uberlandia
country: Brazil
facility: Research Site
city: Votuporanga
country: Brazil
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Shumen
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Saint-Charles-Borromee
country: Canada
facility: Research Site
state: Quebec
city: Trois-Rivieres
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Baja
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Hatvan
country: Hungary
facility: Research Site
city: Kecskemét
country: Hungary
facility: Research Site
city: Miskolc
country: Hungary
facility: Research Site
city: Nyíregyháza
country: Hungary
facility: Research Site
city: Pécs
country: Hungary
facility: Research Site
city: Szentes
country: Hungary
facility: Research Site
city: Chorzów
country: Poland
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Legnica
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Rzeszów
country: Poland
facility: Research Site
city: Tczew
country: Poland
facility: Research Site
city: Brasov
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Cluj Napoca
country: Romania
facility: Research Site
city: Craiova
country: Romania
facility: Research Site
city: Sibiu
country: Romania
facility: Research Site
city: Tg Mures
country: Romania
facility: Research Site
city: Aramil
country: Russian Federation
facility: Research Site
city: Ekaterinburg
country: Russian Federation
facility: Research Site
city: Krasnoyarsk
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Novosibirsk
country: Russian Federation
facility: Research Site
city: Perm
country: Russian Federation
facility: Research Site
city: Ryazan
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Tver
country: Russian Federation
facility: Research Site
city: Yaroslavl
country: Russian Federation
facility: Research Site
city: Brezno
country: Slovakia
facility: Research Site
city: Lucenec
country: Slovakia
facility: Research Site
city: Presov
country: Slovakia
facility: Research Site
city: Svidnik
country: Slovakia
facility: Research Site
Study officials:
affiliation: Montreal Heart Institute 5000 Belanger Street, Montreal, PQ Canada H1T1C8
name: Jean-Claude Tardif
role: PRINCIPAL_INVESTIGATOR
References: