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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 110
- 试验地点
- 2
- 主要终点
- Optimization of MRA usage by Sodium Zirconium Cyclosilicate in HFrEF
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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 hyper-kalemia 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)
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Sodium zirconium cyclosilicate (Drug)
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.
干预措施: Placebo (Other)
结局指标
主要结局
Optimization of MRA usage by Sodium Zirconium Cyclosilicate in HFrEF
时间窗: 180 days during randomization phase
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.
次要结局
- Maintainance of MRA-dose by Sodium Zirconium Cyclosilicate(180 days during randomization phase)
- The impact of MRA-optimization on quality of life by Sodium Zirconium Cyclosilicate(180 days during randomization phase)
- The impact of MRA-optimization on symptomatic relief by Sodium Zirconium Cyclosilicate(180 days during randomization)
研究者
Michael Fu
Professor, MD, PhD, FESC
Sahlgrenska University Hospital