Evaluation of Sodium Zirconium Cyclosilicate for Optimizing Mineralocorticoid Receptor Antagonist Therapy in Heart Failure with Reduced Ejection Fraction

The primary objective of the study is to demonstrate the **efficacy** and **safety** of **Sodium Zirconium Cyclosilicate (SZC)** in optimizing **mineralocorticoid receptor antagonists (MRA)** in symptomatic patients with **heart failure** with reduced ejection fraction (HFrEF). This is clinically relevant as optimizing MRA therapy can potentially improve outcomes in patients with heart failure, a condition associated with significant morbidity and mortality.

Secondary objectives include:

• Determining the efficacy of SZC compared to placebo in maintaining the achieved MRA dose after a run-in period.
• Assessing the impact of MRA optimization by SZC on quality of life parameters.
• Estimating the treatment persistency of the highest tolerable dose (25-50 mg daily) of MRA.
• Evaluating the safety and tolerability of SZC compared to placebo, as assessed by differences in pre-specified safety endpoints between the two groups.

The clinical trial involves participants diagnosed with **heart failure** with reduced ejection fraction (HFrEF), high-risk **hyperkalemia**, and suboptimal heart failure treatment. The study population includes adults over the age of 18, encompassing both male and female subjects. Participants are required to have a left ventricular ejection fraction (LVEF) of 40% or less, as determined by echocardiography within the last two years, and must be classified as New York Heart Association (NYHA) class II-IV. The trial does not include a vulnerable population. Participants are expected to be on optimal treatment regimens, including ACE/ARB/ARNI, beta blockers, and SGLT2 inhibitors, as per physician's judgment, but with suboptimal use of mineralocorticoid receptor antagonists (MRA). The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize stable heart failure status, either as outpatients or in-hospital at or near the time of discharge, and specific potassium levels indicating a risk of hyperkalemia. Lifestyle factors such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the efficacy and safety of **sodium zirconium cyclosilicate** in optimizing mineralocorticoid receptor antagonists (MRA) in patients with heart failure with reduced ejection fraction (HFrEF). This is a randomized, double-blind, placebo-controlled trial, conducted over an estimated duration from August 2021 to June 2026. Participants will be randomly assigned to receive either sodium zirconium cyclosilicate or a placebo, both administered orally. The trial aims to assess the ability of sodium zirconium cyclosilicate to maintain MRA at a dose of at least 25 mg daily, with potassium levels within the normal range, without the need for rescue therapy due to hyperkalemia.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, left ventricular ejection fraction (LVEF) ≤ 40%, and stable heart failure. Participants must also be on optimal treatment for heart failure and have a history or risk of hyperkalemia. Follow-up visits will be scheduled to monitor the efficacy and safety of the treatment, with assessments of MRA dose maintenance, quality of life parameters, and safety endpoints. The end-of-study visit will evaluate the primary and secondary endpoints, including treatment persistency and safety.

Participant involvement is expected to last up to six months, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial is categorized as a Phase 4 study, indicating it involves post-marketing surveillance to further assess the drug's effectiveness and safety in a broader patient population. The trial is considered low-intervention, as the investigational product is already authorized and used in clinical practice, posing minimal additional risk to participants.

The clinical trial involves the administration of **sodium zirconium cyclosilicate**, a chemical compound used to optimize mineralocorticoid receptor antagonists in patients with heart failure with reduced ejection fraction. The pharmaceutical form of sodium zirconium cyclosilicate is a powder for oral suspension, identified by the code PHF00170MIG. The maximum daily dose is 30 grams, with the same amount being the maximum total dose allowed. The treatment period is limited to a maximum of six months. The route of administration is oral, and the medication is not formulated for pediatric use. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

A **placebo** is also utilized in this study as a comparator treatment. The placebo is designed to match the sodium zirconium cyclosilicate in appearance and is provided in bulk unlabelled Amcor sachets, each containing a powder for oral suspension equivalent to 5 grams. The placebo is manufactured by Sharp Packaging Solutions in Allentown, US, with a shelf life of 60 months and storage conditions requiring it to be kept below 30°C. The placebo is administered orally, following the same dosing schedule as the active treatment, to maintain blinding and ensure the integrity of the trial results.

The efficacy of **Sodium Zirconium Cyclosilicate** (SZC) in optimizing mineralocorticoid receptor antagonists (MRA) in patients with heart failure with reduced ejection fraction (HFrEF) will be assessed through several endpoints. The primary endpoint is the difference in the proportion of patients who maintain an MRA dose of at least 25 mg daily or achieve a dose increase by 25 mg daily, with potassium levels remaining within the normal range (3.5-5.0 mmol/L) at the end of the study, without requiring rescue therapy for hyperkalemia during the randomization phase.

Secondary endpoints include evaluating the efficacy of SZC compared to placebo in maintaining the achieved MRA dose after the run-in period, assessing the impact of MRA optimization by SZC on quality of life parameters, and determining the estimated treatment persistency of the highest tolerable MRA dose (25-50 mg daily) between SZC and placebo. Additionally, the safety and tolerability of SZC will be evaluated by comparing the percentage differences in pre-specified safety endpoints between the two groups throughout the study.