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

NCT03532009 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: D9484C00001
• Study Type: interventional
• Target: 182
• Locations: 9 countries
• Sites: 76

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.

Conditions

Heart Failure

Keywords

Heart Failure; Chronic Heart Failure; Hyperkalaemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• 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)

• 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)

• 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)

Study Arms (2)

Sodium Zirconium Cyclosilicate (ZS)

EXPERIMENTAL

Powder for oral suspension

Drug: Sodium Zirconium Cyclosilicate

Placebo

PLACEBO COMPARATOR

Powder for oral suspension

Drug: Placebo

Interventions

Sodium Zirconium Cyclosilicate DRUG

Oral use for approximately 3 months

Also known as: ZS; Lokelma

Sodium Zirconium Cyclosilicate (ZS)

Placebo DRUG

Oral use for approximately 3 months

Also known as: PBO

Placebo

Eligibility Criteria

• Age: 18 Years - 150 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
• 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.
• Subject must be ≥18 years of age inclusive, at the time of signing the informed consent form.
• 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.
• 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%).
• 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.
• 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:
• eGFR 20-44 ml/min/1.73m2 by CKD-EPI and local lab-K 4.0-5.5 mmol/L inclusive, or
• eGFR 45-59 ml/min/1.73m2 by CKD-EPI and local lab-K 5.1-5.5 mmol/L inclusive, or
• 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.
• Women of childbearing potential must have a negative pregnancy test during screening (before first dose of IP) performed locally.

You may not qualify if:

• HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease.
• 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.
• 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.
• 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.
• Previous cardiac transplantation or implantation of a ventricular assistance device (VAD) or similar device, or transplantation or implantation expected after randomization.
• Symptomatic bradycardia or second (Mobitz type 2) or third-degree heart block without a pacemaker.
• Symptomatic hypotension or systolic blood pressure (BP) \<95 mmHg on 2 consecutive measurements.
• Receiving dialysis or anticipated by the investigator to require dialysis therapy within 3 months.
• 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.
• Addison's disease or other causes of hypoaldosteronism.
• Known hypersensitivity to ZS.
• 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.
• Active malignancy requiring treatment.
• MRA therapies that are mainly investigational and/or are not widely available as an oral dosing formulation (eg, canrenoate and finerenone) are excluded.
• 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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (76)

Research Site

National City, California, 91950, United States

Location

Research Site

Stanford, California, 94305, United States

Location

Research Site

Waterbury, Connecticut, 06708, United States

Location

Research Site

Miami, Florida, 33133, United States

Location

Research Site

New Smyrna Beach, Florida, 32169, United States

Location

Research Site

Port Charlotte, Florida, 33952, United States

Location

Research Site

Indianapolis, Indiana, 46260, United States

Location

Research Site

Alexandria, Louisiana, 71301, United States

Location

Research Site

Boston, Massachusetts, 02115, United States

Location

Research Site

Flint, Michigan, 48504, United States

Location

Research Site

Brooklyn, New York, 11204, United States

Location

Research Site

Wyomissing, Pennsylvania, 19610, United States

Location

Research Site

Rapid City, South Dakota, 57701, United States

Location

Research Site

El Paso, Texas, 79935, United States

Location

Research Site

Belo Horizonte, 30140 062, Brazil

Location

Research Site

Belo Horizonte, 30150-240, Brazil

Location

Research Site

Brasillia, 70200-730, Brazil

Location

Research Site

Campina Grande do Sul, 83430000, Brazil

Location

Research Site

Campinas, 13060-080, Brazil

Location

Research Site

Curitiba, 80010-030, Brazil

Location

Research Site

Marília, 17515000, Brazil

Location

Research Site

Porto Alegre, 90020090, Brazil

Location

Research Site

Rio de Janeiro, 20241-180, Brazil

Location

Research Site

Santo André, 09090-790, Brazil

Location

Research Site

São José do Rio Preto, 15090-000, Brazil

Location

Research Site

São Paulo, 05403-000, Brazil

Location

Research Site

Uberlândia, 38411-186, Brazil

Location

Research Site

Votuporanga, 15500-003, Brazil

Location

Research Site

Plovdiv, 4003, Bulgaria

Location

Research Site

Shumen, 9700, Bulgaria

Location

Research Site

Sofia, 1202, Bulgaria

Location

Research Site

Sofia, 1407, Bulgaria

Location

Research Site

Sofia, 1527, Bulgaria

Location

Research Site

Vancouver, British Columbia, V5Z 1M9, Canada

Location

Research Site

Montreal, Quebec, H1T 1C8, Canada

Location

Research Site

Québec, Quebec, G1V 4G5, Canada

Location

Research Site

Saint-Charles-Borromée, Quebec, J6E 6J2, Canada

Location

Research Site

Trois-Rivières, Quebec, G8Z 3R9, Canada

Location

Research Site

Baja, 6500, Hungary

Location

Research Site

Budapest, 1051, Hungary

Location

Research Site

Budapest, 1096, Hungary

Location

Research Site

Budapest, 1106, Hungary

Location

Research Site

Budapest, 1122, Hungary

Location

Research Site

Budapest, 1204, Hungary

Location

Research Site

Hatvan, 3000, Hungary

Location

Research Site

Kecskemét, 6000, Hungary

Location

Research Site

Miskolc, 3529, Hungary

Location

Research Site

Nyíregyháza, 4400, Hungary

Location

Research Site

Pécs, 7623, Hungary

Location

Research Site

Szentes, 6600, Hungary

Location

Research Site

Chorzów, 41-500, Poland

Location

Research Site

Gdansk, 80-952, Poland

Location

Research Site

Legnica, 59-220, Poland

Location

Research Site

Poznan, 60-848, Poland

Location

Research Site

Rzeszów, 35-055, Poland

Location

Research Site

Tczew, 83-110, Poland

Location

Research Site

Brasov, 500283, Romania

Location

Research Site

Bucharest, 042122, Romania

Location

Research Site

Cluj-Napoca, 400001, Romania

Location

Research Site

Craiova, 200642, Romania

Location

Research Site

Sibiu, 550245, Romania

Location

Research Site

Tg Mures, 540143, Romania

Location

Research Site

Aramil, 624002, Russia

Location

Research Site

Krasnoyarsk, 660062, Russia

Location

Research Site

Moscow, 121552, Russia

Location

Research Site

Novosibirsk, 630055, Russia

Location

Research Site

Perm, 614000, Russia

Location

Research Site

Ryazan, 390039, Russia

Location

Research Site

Saint Petersburg, 191015, Russia

Location

Research Site

Tver', 170036, Russia

Location

Research Site

Yaroslavl, 150062, Russia

Location

Research Site

Yekaterinburg, 620039, Russia

Location

Research Site

Brezno, 97742, Slovakia

Location

Research Site

Lučenec, 984 01, Slovakia

Location

Research Site

Prešov, 080 01, Slovakia

Location

Research Site

Svidník, 08901, Slovakia

Location

Related Publications (1)

• Tardif JC, Rouleau J, Chertow GM, Al-Shurbaji A, Lisovskaja V, Gustavson S, Zhao Y, Bouabdallaoui N, Desai AS, Chernyavskiy A, Evsina M, Merkely B, McMurray JJV, Pfeffer MA. Potassium reduction with sodium zirconium cyclosilicate in patients with heart failure. ESC Heart Fail. 2023 Apr;10(2):1066-1076. doi: 10.1002/ehf2.14268. Epub 2022 Dec 23.

  PMID: 36564955 DERIVED

Related Links

• redacted CSR synopsis
• redacted SAP
• redacted CSP

MeSH Terms

Conditions

Heart Failure; Hyperkalemia

Interventions

sodium zirconium cyclosilicate

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Water-Electrolyte Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

The study was paused from May to October 2019 to undergo a major protocol amendment. The study was also prematurely terminated due to the COVID-19 pandemic resulting in a reduced sample size and a high premature treatment discontinuation rate.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: Study Information Center

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Jean-Claude Tardif

  Montreal Heart Institute 5000 Belanger Street, Montreal, PQ Canada H1T1C8

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2018
• First Posted: May 22, 2018
• Study Start: June 26, 2018
• Primary Completion: May 22, 2020
• Study Completion: May 22, 2020
• Last Updated: June 15, 2021
• Results First Posted: June 15, 2021

Record last verified: 2021-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

US (14); RO (6); RU (10); BU (5); PL (6); SL (4); HU (12); BR (14); CA (5)