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

• Status: Recruiting
• Trial end date: 2024-06-30
• Target enrollment: 0
• Participant gender: All

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=230)

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 (at least 4 weeks)

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.

Primary Outcome Measure:

Whether a patient maintains MRA at a dose ≥ 25 mg daily and S-K level in the normal range (3.5-5.0 mmol/L) at the end of study, without rescue therapy due to hyperkalemia at any point during the randomization phase.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Michael Fu
• Collaborators: AstraZeneca; Göteborg University

Criteria

Inclusion Criteria:

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.

Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this study. Under no circumstances can there be exceptions to this rule.

Inclusion criteria

For inclusion in the study subjects should fulfil the following criteria:

1. Obtain signed informed consent prior to any study specific procedures

2. >18 yrs, irrespective of sex

3. LVEF ≤ 40%, with echocardiography within last 2 years

4. NYHA II-IV

5. Stable heart failure as judged by local Investigator. Patients may be en-rolled as an outpatient or in-hospital at, or close to, the time of hospital dis-charge

6. On optimal treatment with GDMT (Guideline-Directed Medical Treatment including ACE/ARB/ARNI and beta blockers) as per physician´s judgement

7. AND one of followings:

(1) Prior hyperkalemia due to MRA therapy and current S-K ≤ 5.0 mmol/L; (2) Risk of hyperkalemia as indicated by eGFR 30-45 ml/min/1.73m2 and S-K 4.5-5.0 mmol/L; (3) Mild hyperkalemia (S-K 5.1-5.5 mmol/L) and MRA below target dose (target doses for spironolactone: 25-50 mg daily, and for eplerenone: 50 mg daily)

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

• S-K 4.5-5.0 mmol/L and GFR < 45 mL/min/1,73 m2

Note: All S-K related limits in this protocol concern serum measurements. In Sweden it is plasma that is analyzed, which makes 4.8 mmol/l (plasma) equivalent to 5.0 mmol/L(serum)

Exclusion Criteria:

Subjects should not enter the study if any of the following exclusion criteria are ful-filled:

1. Symptomatic hypotension (< 90/60 mmHg)

2. eGFR < 30 ml/min/1,73 m2 (modified MDRD formula)

3. HF due to restrictive cardiomyopathy, hypertrophic (obstructive) cardio-myopathy or primary valvular disease

4. Current/recent (within 3 months) hospitalization due to myocardial infarc-tion, unstable angina pectoris, coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), or other interven-tions (valvular repair/replacement, cardiac transplantation or implantation of a ventricular assistance device)

5. Ongoing or planned dialysis

6. Prior history of hypersensitivity (other than hyperkalemia) to a MRA, or SZC

7. Advanced malignancy requiring treatment

8. History of QT prolongation associated with other medications that required discontinuation of that medication.

9. Congenital long QT syndrome.

10. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymp-tomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted

11. QTc(f) > 550 msec

12. Currently pregnant (confirmed with positive pregnancy test) or planned pregnancy or breast-feeding

13. Can not sign informed consent.