OPtimizing Aldosterone Receptor Antagonist Therapy by Sodium Zirconium Cyclosilicate in Heart Failure (OPRA-HF)

OPtimizing Aldosterone Receptor Antagonist Therapy by Sodium Zirconium Cyclosilicate in Heart Failure - Efficacy and Safety of Sodium Zirconium Cyclosilicate in Optimizing Mineralocorticoid Receptor Antagonists Therapy in Heart Failure

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Hyperkalemia
• Intervention / Treatment: Drug: Sodium zirconium cyclosilicate; Other: Placebo

Detailed Description

Target subject population

Stable and symptomatic patients with chronic heart failure and LVEF ≤ 40% despite Guideline-Directed Medical Treatment (ACE/ARB/ARNI, beta blockers, SGLT2 inhibitor, MRA) at the discretion of physician´s judgement AND remaining suboptimal treatment of MRA

Duration of treatment

This study consists of 2 treatment phases: 1) Open-label Run-in, and 2) Randomized, pla-cebo-controlled, double-blinded treatment during 6 months. The Open-label phase, in turn, consists of three periods: up-titration (normally 1 - 2 weeks, or longer in some cases), Cor-rection (maximum up to 72 hours) and Maintenance (4-7 weeks)

Investigational product, dosage and mode of administration 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 regimen should be started with 5 g once daily. The dose can be adjusted up to 10 g once daily or lowered to 5 g once every other day as needed, to maintain a normal level of potassium.

• Study Type: Interventional
• Enrollment (Estimated): 230
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Fu, Professor; Phone Number: 34850 0046313421000; Email: michael.fu@gu.se
• Study Contact Backup: Name: Erik Thunström, asso. prof; Phone Number: 0046313421000; Email: erik.thunstrom@vgregion.se

Study Locations

• Sweden
  • Gothenburg, Sweden, 41650
    • Recruiting
    • Sahlgrenska University Hospital-Ostra Hospital
    • Contact: Michael LX Fu, MD; Phone Number: 34850 0046313421000; Email: michael.fu@gu.se
    • Contact: Erik Thunström, MD; Phone Number: 0046313421000; Email: erik.thunstrom@vgregion.se
    • Sub-Investigator: Carmen Basic, MD
    • Sub-Investigator: Erik Thunström, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.
3. LVEF ≤ 40% within past 2 years (including recovered EF later on).
4. NYHA II-IV.
5. On optimal treatment including ACE/ARB/ARNI, beta blockers, SGLT2 inhibitor, as per physician´s judgement.
6. Suboptimal treatment with MRA (defined as: no use or ≤ 25 mg daily)

7. And one of following:

   1. 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
   2. Current S-K 4.5-5.0 mmol/L or P-K 4.3-4.8 mmol/L, and potential risk of hy-perkalemia as indicated by eGFR 30-45 ml/min/1,73 m2 (modified MDRD formula)

   3. 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
  • 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SZC + MRA treated heart failure patients; 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; 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; Other Names: Lokelma
Placebo Comparator: Placebo + MRA treated heart failure patients; 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; Treatment with the same dose of placebo medicine as they would have received had they been treated with the interventional drug (SZC).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maintainance of MRA-dose by Sodium Zirconium Cyclosilicate	Measuring whether a patient is able to maintain at least the same MRA dose at the end of study as at the point of randomization without receiving rescue therapy. SZC vs Placebo	180 days during randomization phase
The impact of MRA-optimization on quality of life by Sodium Zirconium Cyclosilicate	Quality of life is measured by KCCQ (the Kansas City Cardiomyopathy Questionnaire): a change in the clinical summary score ( from 0 to 100) with higher scores indicating fewer symptoms and physical limitations, end of study vs at the point of randomizaiton.	180 days during randomization phase
The impact of MRA-optimization on symptomatic relief by Sodium Zirconium Cyclosilicate	Symptomatic relief is evaluated by a composite of change either in NYHA or Lickert Scale as prespecified below: change in the NYHA functional classifi-cation (I-IV) with higher class indicating more symptomatic and physical limita-tions, or; change in the 5-point Likert scale (5PLS) with higher score indicating the worst possible shortness of breath	180 days during randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The safety of Sodium Zirconium Cyclosilicate	The difference in safety between two groups is assessed by percent of occurrence of any following prespecified safety endpoints (during the randomization phase): Patient with S-K <3.0 mmol/l (yes/no); Patient with S-K ≥6.0 mmol/l (yes/no); Patient in need of rescue therapy be-cause of hyperkalemia (yes/no); Patient with fluid retention (general edema, peripheral edema, unrelated to heart failure) (yes/no); Patient with gastrointestinal events such as constipation, diarrhea, abdominal pain, nausea or vomiting) (yes/no); Patient with any AE, SAE or DAE (yes/no)	180 days during randomization phase

Collaborators and Investigators

• Sponsor: Michael Fu
• Collaborators: Göteborg University; AstraZeneca
• Investigators: Principal Investigator: Michael Fu, Professor, Sahlgrenska University Hospital, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Estimated): December 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: February 25, 2021
• First Submitted That Met QC Criteria: March 4, 2021
• First Posted (Actual): March 9, 2021

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 12, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Treatment; Mineralocorticoid receptor antagonists; Sodium Zirconium Cyclosilicate (SZC); Heart failure with reduced ejection fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Water-Electrolyte Imbalance; Heart Failure; Hyperkalemia
• Other Study ID Numbers: ESR-19-20262

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data with approved ethical permission. All requests will be evaluated but this does not mean all requests will be shared.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No