Clinical trial NCT04789239: OPtimizing Aldosterone Receptor Antagonist Therapy by Sodium Zirconium Cyclosilicate in Heart Failure
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Heart Failure
Hyperkalemia
Keywords: Mineralocorticoid receptor antagonists
Sodium Zirconium Cyclosilicate (SZC)
Heart failure with reduced ejection fraction
Treatment
Lead sponsor: Sahlgrenska University Hospital
Sponsor class: OTHER
Collaborators: name: AstraZeneca
name: Göteborg University
First posted: 2021-03-09
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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).
Primary purpose: TREATMENT

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.

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.

Eligibility 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.
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 hyper-kalemia 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.

Primary outcomes:
measure: Optimization of MRA usage by Sodium Zirconium Cyclosilicate in HFrEF
timeFrame: 180 days during randomization phase
Secondary outcomes:
measure: Maintainance of MRA-dose by Sodium Zirconium Cyclosilicate
timeFrame: 180 days during randomization phase
measure: The impact of MRA-optimization on quality of life by Sodium Zirconium Cyclosilicate
timeFrame: 180 days during randomization phase
measure: The impact of MRA-optimization on symptomatic relief by Sodium Zirconium Cyclosilicate
timeFrame: 180 days during randomization
Other outcomes:
measure: The safety of Sodium Zirconium Cyclosilicate
timeFrame: 180 days during randomization phase
Locations:
city: Gothenburg
country: Sweden
facility: Section of Cardiology, Sahlgrenska University Hospital-Östra Hospital
state: Västra Götalanddsregion
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital-Ostra Hospital
Study officials:
affiliation: Sahlgrenska University Hospital
name: Michael Fu, Professor
role: PRINCIPAL_INVESTIGATOR
References: