search
Back to results

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

Primary Purpose

Heart Failure, Hyperkalemia

Status
Recruiting
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Sodium zirconium cyclosilicate
Placebo
Sponsored by
Michael Fu
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Heart Failure focused on measuring Mineralocorticoid receptor antagonists, Sodium Zirconium Cyclosilicate (SZC), Heart failure with reduced ejection fraction, Treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Sahlgrenska University Hospital-Ostra HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

SZC + MRA treated heart failure patients

Placebo + MRA treated heart failure patients

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
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.
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

Full Information

First Posted
February 25, 2021
Last Updated
October 12, 2023
Sponsor
Michael Fu
Collaborators
AstraZeneca, Göteborg University
search

1. Study Identification

Unique Protocol Identification Number
NCT04789239
Brief Title
OPtimizing Aldosterone Receptor Antagonist Therapy by Sodium Zirconium Cyclosilicate in Heart Failure
Acronym
OPRA-HF
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

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 1, 2021 (Actual)
Primary Completion Date
December 30, 2024 (Anticipated)
Study Completion Date
December 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Michael Fu
Collaborators
AstraZeneca, Göteborg University

4. Oversight

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
Data Monitoring Committee
Yes

5. 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=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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Hyperkalemia
Keywords
Mineralocorticoid receptor antagonists, Sodium Zirconium Cyclosilicate (SZC), Heart failure with reduced ejection fraction, Treatment

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
230 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
SZC + MRA treated heart failure patients
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo + MRA treated heart failure patients
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Sodium zirconium cyclosilicate
Other Intervention Name(s)
Lokelma
Intervention Description
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
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Treatment with the same dose of placebo medicine as they would have received had they been treated with the interventional drug (SZC).
Primary Outcome Measure Information:
Title
Optimization of MRA usage by Sodium Zirconium Cyclosilicate in HFrEF
Description
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.
Time Frame
180 days during randomization phase
Secondary Outcome Measure Information:
Title
Maintainance of MRA-dose by Sodium Zirconium Cyclosilicate
Description
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
Time Frame
180 days during randomization phase
Title
The impact of MRA-optimization on quality of life by Sodium Zirconium Cyclosilicate
Description
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.
Time Frame
180 days during randomization phase
Title
The impact of MRA-optimization on symptomatic relief by Sodium Zirconium Cyclosilicate
Description
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
Time Frame
180 days during randomization
Other Pre-specified Outcome Measures:
Title
The safety of Sodium Zirconium Cyclosilicate
Description
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)
Time Frame
180 days during randomization phase

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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: Obtain signed informed consent prior to any study specific procedures >18 yrs. LVEF ≤ 40% within past 2 years (including recovered EF later on). NYHA II-IV. On optimal treatment including ACE/ARB/ARNI, beta blockers, SGLT2 inhibitor, as per physician´s judgement. Suboptimal treatment with MRA (defined as: no use or ≤ 25 mg daily) And one of following: 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 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) 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: Symptomatic hypotension (< 90/60 mmHg) eGFR < 30 ml/min/1,73 m2 (modified MDRD formula) HF due to restrictive cardiomyopathy, hypertrophic (obstructive) cardio-myopathy or primary valvular disease 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) Ongoing or planned dialysis Prior history of hypersensitivity (other than hyperkalemia) to a MRA, or SZC Advanced malignancy requiring treatment History of QT prolongation associated with other medications that required discontinuation of that medication. Congenital long QT syndrome. Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymp-tomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted QTc(f) > 550 msec Currently pregnant (confirmed with positive pregnancy test) or planned pregnancy or breast-feeding Can not sign informed consent.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Fu, Professor
Phone
0046313421000
Ext
34850
Email
michael.fu@gu.se
First Name & Middle Initial & Last Name or Official Title & Degree
Erik Thunström, asso. prof
Phone
0046313421000
Email
erik.thunstrom@vgregion.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Fu, Professor
Organizational Affiliation
Sahlgrenska University Hospital, Sweden
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sahlgrenska University Hospital-Ostra Hospital
City
Gothenburg
ZIP/Postal Code
41650
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michael LX Fu, MD
Phone
0046313421000
Ext
34850
Email
michael.fu@gu.se
First Name & Middle Initial & Last Name & Degree
Erik Thunström, MD
Phone
0046313421000
Email
erik.thunstrom@vgregion.se
First Name & Middle Initial & Last Name & Degree
Carmen Basic, MD
First Name & Middle Initial & Last Name & Degree
Erik Thunström, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.

Learn more about this trial

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

We'll reach out to this number within 24 hrs