OPtimizing Aldosterone Receptor Antagonist Therapy by Sodium Zirconium Cyclosilicate in Heart Failure

NCT04789239 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: ESR-19-20262
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 2

Brief Summary

Mineralocorticoid receptor antagonists (MRA) is one of cornerstones in the treatment of heart failure with reduced ejection fraction (HFrEF). However, MRA has been extremely under-used globally. The main reason for this seems to be increased risk of hyperkalemia in individuals on MRA. Theoretically, by limiting the risk of hyperkalemia it could thus be possible to optimize MRA therapy. This is studied in this randomized controlled trial in which it is investigated whethere adding a potassium-binder in combination with MRA treatment prevent hyperkalemia to a greater extent than only using MRA. The specific aim of this study is to demonstrate the efficacy and safety of Sodium Zirconium Cyclosilicate (SZC) in optimizing MRA in symptomatic patients with HFrEF. A multicenter, randomized, placebo-controlled, double-blinded study in Sweden (n=110) The study consists of 2 phases: 1) open-label run-in within maximum 2 months, where all are treated with SZC to test tolarability, and 2) a 1:1 randomized, double-blinded and placebo-controlled treatment during 6 months. The open-label phase, in turn, consists of three periods: run-in (1 - 2 weeks), correc-tion (maximum 72 hours) and maintenance (4-7 weeks). In addition, post-randomization phase, all patients will be followed by 3 visits (Follow-Up 1, 2 and 3) at 1, 2 and 4 weeks after End of Study (EOS) / End of Treatment (EOT) (which comes first) for further control of kalium and creatinine levels and documentation of current MRA use incl dose. Sodium Zirconium Cyclosilicate (SZC) (Lokelma)®, 5 g, 10 g, orally, is an approved drug in Sweden. For correction of hyperkalemia, the recommended starting dose is 10 g, three times daily. Once normokalemia has been achieved, the maintenance reg-imen should be started with 5 g once daily. The dose can be titrated up to 10 g once daily or lowered to 5 g once every other day as needed, to maintain a normal level of potassium. Primary Objective: To demonstrate the efficacy of Sodium Zirconium Cyclosilicate (SZC) on optimiz-ing MRA in HFrEF, SZC vs Placebo. Outcome measure: Whether a patient maintains MRA either at a dose ≥ 25 mg daily (for those without MRA at base-line) or a dose increase by 25 mg daily (for those with MRA ≤ 25 mg daily at baseline) and K level in the normal range (3.5-5.0 mmol/L) at the end of study, without rescue therapy due to hy-perkalemia at any point during the randomization phase.

Conditions

Heart Failure; Hyperkalemia

Keywords

Mineralocorticoid receptor antagonists; Sodium Zirconium Cyclosilicate (SZC); Heart failure with reduced ejection fraction; Treatment

Outcome Measures

Primary Outcomes (1)

• Optimization of MRA usage by Sodium Zirconium Cyclosilicate in HFrEF

  Outcome Measure: Whether a patient maintains MRA either at a dose ≥ 25 mg daily (for those without MRA at base-line) or a dose increase by 25 mg daily (for those with MRA ≤ 25 mg daily at baseline) and K level in the normal range (3.5-5.0 mmol/L) at the end of study, without rescue therapy due to hy-perkalemia at any point during the randomization phase.

  180 days during randomization phase

Secondary Outcomes (3)

• Maintainance of MRA-dose by Sodium Zirconium Cyclosilicate

  180 days during randomization phase

• The impact of MRA-optimization on quality of life by Sodium Zirconium Cyclosilicate

  180 days during randomization phase

• The impact of MRA-optimization on symptomatic relief by Sodium Zirconium Cyclosilicate

  180 days during randomization

Other Outcomes (1)

• The safety of Sodium Zirconium Cyclosilicate

  180 days during randomization phase

Study Arms (2)

SZC + MRA treated heart failure patients

EXPERIMENTAL

Optimal dose of SZC, which is an approved drug for hyperkalemia in Sweden. The subject is treat with 5 mg daily however it can be reduced to once every second day, or inreased to as much as as 10 mg daily, depending on measured potassium levels. This is combined with a mineralcorticoid receptor antagonist (spironolacton or eplerenon), 25 mg or 50 mg depending on what dose they could tolerate.

Drug: Sodium zirconium cyclosilicate

Placebo + MRA treated heart failure patients

PLACEBO COMPARATOR

The subject is treat with placebo drug, 5 mg once daily, however it can be reduced to once every second day, or increased to as much as as 10 mg daily, depending on measured potassium levels. This is combined with the dose of mineralcorticoid receptor antagonist (spironolacton or eplerenon) 25 mg or 50 mg depending on what dose they could tolerate.

Other: Placebo

Interventions

Sodium zirconium cyclosilicate DRUG

SZC is an approved drug in Sweden and subsidized for patients with chronic kidney disease in stages 3 to 5, with or without chronic heart failure, for whom treatment with Resonium is not suitable and for patients with chronic heart failure without con-comitant chronic kidney disease

Also known as: Lokelma

SZC + MRA treated heart failure patients

Placebo OTHER

Treatment with the same dose of placebo medicine as they would have received had they been treated with the interventional drug (SZC).

Placebo + MRA treated heart failure patients

Eligibility Criteria

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

You may qualify if:

• Recruiting will take place mainly from specialist care at University hospitals or Province hospitals in Sweden. But some of patients might have simultaneous follow-up at primary care as well.

You may not qualify if:

• Obtain signed informed consent prior to any study specific procedures
• \>18 yrs.
• LVEF ≤ 40% within past 2 years (including recovered EF later on).
• NYHA II-IV.
• On optimal treatment including ACE/ARB/ARNI, beta blockers, SGLT2 inhibitor, as per physician´s judgement.
• Suboptimal treatment with MRA (defined as: no use or ≤ 25 mg daily)
• And one of following:
• Prior hyperkalemia (S-K\> 5.0 mmol/L or P-K\> 4.8 mmol/L\*) during MRA treat-ment within last 24 months, and current S-K ≤ 5.0 or P-K ≤ 4.8 mmol/L
• Current S-K 4.5-5.0 mmol/L or P-K 4.3-4.8 mmol/L, and potential risk of hyper-kalemia as indicated by eGFR 30-45 ml/min/1,73 m2 (modified MDRD formula)
• Current S-K 5.1-5.9 mmol/L or P-K 4.9-5.7 mmol/L
• Corresponding plasma K (P-K) level is 0.2 mmol lower than serum K(S-K) (The Nordic Reference Interval Project).
• Depending on the S-K status during screening, patients are divided into two groups before treatment initiation /run-in:
• Group 1: Patients who are hyperkalemic (S-K 5.1 - 5.5 mmol/L measured within last 2 weeks)
• Group 2: Patients who are normokalemic (S-K 3.5 - 5.0 mmol/L) during screening but are at a high risk of developing hyperkalemia associated with MRA initiation / increase. Namely, one (or both) of the following:
• Prescription of MRA within last 12 months and documented hyperkalemia after MRA prescription

Sponsors & Collaborators

• Michael Fu: lead
• AstraZeneca: collaborator
• Göteborg University: collaborator

Study Sites (2)

Section of Cardiology, Sahlgrenska University Hospital-Östra Hospital

Gothenburg, Västra Götalanddsregion, 41650, Sweden

Location

Sahlgrenska University Hospital-Ostra Hospital

Gothenburg, 41650, Sweden

Location

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

Study Officials

• Michael Fu, Professor

  Sahlgrenska University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: For the 2nd part of study, ie randomized treatment, it is double-blinded with blinding for subjects, endpoint assessors and study personnel. Pharmacy is responsible for masking of differences in appearance, smell and taste, and also packaging and label-ling to ensure blinding. Individual treatment codes, indicating the treatment randomisation for each random-ised subject, will be available to Pharmacy where the personnel are independent to the study evaluation. The treatment code should not be broken except in medical emergencies when the appropriate management of the subject requires knowledge of the treatment randomisation. The Investigator documents and reports the action to PI, without revealing the treatment given to subject to the PI.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, MD, PhD, FESC

Model Details: A multicenter, 1:1 randomized, placebo-controlled, double-blinded study in Sweden of 110 heart failure patients with reduced ejection fraction. This study consists of 2 phases: 1) open-label run-in within maximum 2 months, and 2) randomized, double-blinded and placebo-controlled treatment during 6 months. The open-label phase, in turn, consists of three periods: run-in (1 - 2 weeks), correction (maximum 72 hours) and maintenance (at least 4 weeks). After the open-label run-in phase, upon randomization (1:1 ratio to receive investigational product (IP), either Sodium Zirconium Cyclosilicate (SZC) or placebo, in a blinded manner), SZC will be switched to investigational drug (IP) but with the same dose individually as for SZC before randomization (pre-randomization dose).

Study Record Dates

• First Submitted: February 25, 2021
• First Posted: March 9, 2021
• Study Start: September 1, 2021
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: July 4, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: We will share the study protocol once a manuscript relating to results of the trial is published in a peer-reviewed medical journal.
• Access Criteria: Researchers that ask for access to the study information, were the intention is to evaluate the study and were the anonymity of the study participants is not jeopardized will all be considered for access.

Locations

SE (2)