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

• ClinicalTrials.gov Identifier: NCT04789239
• Recruitment Status: Recruiting
• First Posted: March 9, 2021
• Last Update Posted: September 22, 2021
• Sponsor: Michael Fu
• Collaborators: AstraZeneca; Göteborg University
• Information provided by (Responsible Party): Michael Fu, Sahlgrenska University Hospital, Sweden

Study Description

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=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.

Condition or disease	Intervention/treatment	Phase
Heart Failure; Hyperkalemia	Drug: Sodium zirconium cyclosilicate; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 230 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

A multicenter, 1:1 randomized, placebo-controlled, double-blinded study in Sweden of 230 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).

• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description

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.

• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 1, 2021
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: June 30, 2024

Arms and Interventions

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 Name: 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).

Outcome Measures

Primary Outcome Measures :

1. Optimization of MRA usage by Sodium Zirconium Cyclosilicate in HFrEF [ Time Frame: 180 days during randomization phase ]

   The efficacy will be assessed by difference in the proportion of patients who may or may not maintain 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.

   Subjects who require rescue therapy because of hyperkalemia are considered as "failures" even if they will be able to continue in the study.

   Temporary hyperkalemia secondary to dehydration or other temporary predisposing factors during study as per physician´s judgement should not be regarded as "fail-ure".

   A subject with Optimization success MUST meet with 3 criteria:

   1. Subjects who are able to maintain MRA at a daily dose ≥ 25 mg in the End of Study
   2. AND in the normal range of S-K (3.5-5.0 mmol/L) in the End of Study
   3. AND without experiencing rescue therapy due to hyperkalemia at any time throughout the study

Secondary Outcome Measures :

1. Maintainance of MRA-dose by Sodium Zirconium Cyclosilicate [ Time Frame: 180 days during randomization phase ]
   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
2. The impact of MRA-optimization on quality of life by Sodium Zirconium Cyclosilicate [ Time Frame: 180 days during randomization phase ]
   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.
3. The impact of MRA-optimization on symptomatic relief by Sodium Zirconium Cyclosilicate [ Time Frame: 180 days during randomization ]

   Symptomatic relief is evaluated by a composite of change either in NYHA or Lickert Scale as prespecified below:

   1. change in the NYHA functional classifi-cation (I-IV) with higher class indicating more symptomatic and physical limita-tions, or
   2. change in the 5-point Likert scale (5PLS) with higher score indicating the worst possible shortness of breath

Other Outcome Measures:

1. The safety of Sodium Zirconium Cyclosilicate [ Time Frame: 180 days during randomization phase ]

   The difference in safety between two groups is assessed by percent of occurrence of any following prespecified safety endpoints (during the randomization phase):

   1. Patient with S-K <3.0 mmol/l (yes/no)
   2. Patient with S-K ≥6.0 mmol/l (yes/no)
   3. Patient in need of rescue therapy be-cause of hyperkalemia (yes/no)
   4. Patient with fluid retention (general edema, peripheral edema, unrelated to heart failure) (yes/no)
   5. Patient with gastrointestinal events such as constipation, diarrhea, abdominal pain, nausea or vomiting) (yes/no)
   6. Patient with any AE, SAE or DAE (yes/no)

Eligibility Criteria

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

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.

Contacts and Locations

Contacts

Contact: Michael Fu, Professor; 0046313421000 ext 34850; michael.fu@gu.se

Contact: Erik Thunström, asso. prof; 0046313421000; erik.thunstrom@vgregion.se

Locations

Sweden

Sahlgrenska University Hospital-Ostra Hospital; Recruiting

Gothenburg, Sweden, 41650

Contact: Michael LX Fu, MD 0046313421000 ext 34850 michael.fu@gu.se

Contact: Erik Thunström, MD 0046313421000 erik.thunstrom@vgregion.se

Sub-Investigator: Carmen Basic, MD

Sub-Investigator: Erik Thunström, MD

Sponsors and Collaborators

Michael Fu

AstraZeneca

Göteborg University

Investigators

• Principal Investigator: Michael Fu, Professor; Sahlgrenska University Hospital, Sweden

More Information

• Responsible Party: Michael Fu, Professor, MD, PhD, FESC, Sahlgrenska University Hospital, Sweden
• ClinicalTrials.gov Identifier: NCT04789239
• Other Study ID Numbers: ESR-19-20262
• First Posted: March 9, 2021
• Last Update Posted: September 22, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol; Informed Consent Form (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.

• 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

Keywords provided by Michael Fu, Sahlgrenska University Hospital, Sweden:

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

Additional relevant MeSH terms:

Heart Failure; Hyperkalemia; Heart Diseases; Cardiovascular Diseases; Water-Electrolyte Imbalance; Metabolic Diseases