Keeping RAASi Treatment With Optimal Potassium Control

Official title

Phase III, Multicenter, Open-label, Randomized Clinical Trial to Evaluate Efficacy of Sodium Zirconium Cyclosilicate (Lokelma) Compared to Standard of Care to Manage Hyperkalemia in Patients With Chronic Kidney Disease (CKD)

Overview

Phase III, multicenter, randomized, open-label, parallel-group, non-inferiority, phase III clinical trial comparing CSZ (Lokelma) vs. iSRAA discontinuation/reduction and/or ARM (standard treatment).

Detailed description

Hyperkalemia is a potentially life-threatening condition associated with ventricular arrhythmias and sudden cardiac arrest. It is common in patients with some comorbidities such as chronic kidney disease, congestive heart failure, cardiovascular disease, diabetes or liver disease. Most of these patients should receive drugs that block the renin angiotensin aldosterone system (RAASi) and mineralocorticoid receptor antagonists (MRA), that increase the risk of hyperkalemia.

For these reasons, relatively few patients receive maximum doses of RAASi / MRA. The dose and its usage decline following an hyperkalemia episode. However, RAASi / MRA discontinuation because of hyperkalemia, represents an undesirable clinical scenario, loosing their potential cardiorenal and nephroprotective benefit. Patients on submaximum doses or who discontinued RAASi / MRA have worse outcomes than patients on maximum doses.

In this study 78 adult patients will be randomized to one of two treatment arms to analyze the proportion of patients achieving sK of \< 5.5 mEq/L:

* Control group: they will have their treatment with iSRAA and/or ARM withdrawn or tapered, according to standard clinical practice. * Experimental group: treatment with iSRAA and/or ARM will be maintained and oral treatment with CSZ (Lokelma) will be added.

The study will be conducted in 3 periods:

* Patient selection (Visit 0). * Randomization (Visit 1). * Follow up (Visits 2-7).

All the patients randomized and completing the treatment assigned will be participating in the study for an stimated period of 90 ± 13 d. The clinical trial will be finalized when the last 90-day follow-up of the last patient included is performed.

Interventions

• Drug Sodium Zirconium Cyclosilicate
  The recommended starting dose of Lokelma is 10 g, administered three times a day. If, at any time during the study, sK is \> 6.5 mEq/L, treatment for acute hyperkalemia will be started following common clinical practice and local protocols, and investigator will consider RAASi / MRA withdrawal, or downtitration. In this case (confirmed sK \> 6.5 mEq/L despite the maximum SZC dose) patient will leave the IP and will be counted as a treatment failure. If sK is ≤ 3.0 mEq/L, discontinue SZC. The s

Primary outcome measures

• Percentage of patients achieving serum potassium < 5.5mEq/L at three or all timepoints (7, 30, 60 or 90 days) after follow up (90 days) in both groups. [Time frame: Through study completion, an average of 1 year]

Secondary outcome measures (5)

• Percentage of patients achieving serum potassium < 5 mEq/L at two of the four temporal points in both groups. [Time frame: Through study completion, an average of 1 year]
• Number of patients treated with SZC with reduction of serum potassium > 20% after baseline in each time point. [Time frame: Through study completion, an average of 1 year]
• Percentage of patients achieving serum potassium below 5, 5.5, 6, 6.5 mEq/L in each time point. [Time frame: Through study completion, an average of 1 year]
• Percentage of patients requiring additional treatments for hyperkalemia in both groups (potassium binding resins, adding or increasing loop diuretics, or discontinuation of RAASi and/or MRA in Lokelma group. [Time frame: Through study completion, an average of 1 year]
• Mean change in the urine albumin-to-creatinine ratio (UACR) at 90 days from baseline in patients treated with SZC compared to RAASi / MRA discontinuation or downtitration. [Time frame: Through study completion, an average of 1 year]

Eligibility criteria

Inclusion criteria

• Patients must present serum potassium levels of 5.5-6.5 mEq/L at patient selection visit (V0)
• Patients must present serum potassium levels of 5.0-6.5 mEq/L at randomization visit (V1).
• Provision of patient or legal representative informed consent prior to any study specific procedures.
• Individuals receiving background standard of care for HF and treated according to locally recognized guidelines. Specific treatment should include RAASi and/or MRA treatment at first consultation and at least should have been stable for ≥ 4 weeks at maximum tolerated doses.
• Patients with CKD not on dialysis (Stages 2-5: estimated glomerular filtration rate (eGFR) between 15-60 ml/min/1,73m2 or eGFR between 60-90 ml/min/ 1.73 m2 with albuminuria/creatinuria (> 30 mg/g) in the previous three months). The estimated GFR can be reported by the laboratory or calculated by the researcher with serum creatinine, age, and sex (CKD-EPI equation).
• 18 years at the time of signing ICF.
• Negative pregnancy test (urine or serum) for female subjects of childbearing potential.
• Female subjects must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time they sign ICF) and for 3 months after the last dose of SZC. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.

Exclusion criteria

• Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site).
• Previous enrollment or randomization in the present study.
• HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease.
• Current acute decompensated HF, hospitalization due to decompensated HF, myocardial infarction, unstable angina, stroke or transient ischemic attack within 12 weeks prior to enrollment.
• Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting or valvular repair/replacement within 12 weeks prior to enrollment or planned to undergo any of these operations after randomization).
• Implantation of a Cardiac Resynchronization Therapy (CRT) device or Implantable Cardioverter Defibrillator (ICD) within 12 weeks prior to enrollment or intent to perform atrial fibrillation ablation or to implant a CRT or ICD device.
• Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or transplantation or implantation expected after randomization
• Oropharingeal dysfunction that precludes normal swallow.
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method.
• Patients with amputated limbs or pacemaker devices will be excluded of bioimpedance analysis.
• Participation in another clinical study with an investigational product during the last 6 months.
• Patients with a known hypersensitivity to SZC or any of the excipients of the product.
• Treated with potassium binding resins such as sodium polystyrene sulfonate (SPS; e.g. Kayexalate®) or calcium polystyrene sulfonate (CPS; e.g. Resonium®) or the cation exchange polymer, patiromer sorbitex calcium (Veltassa®), within 7 days prior to the first dose of study drug.
• Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.
• Subjects with a family history of long QT syndrome, presence of cardiac arrhythmias or conduction defects that require immediate treatment, or a QTc (corrected QT interval) of ≥ 550 msec.
• History of QT prolongation associated with other medications that required discontinuation of that medications.
• Symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Spain · 5 centers

• Hospital General Universitario Dr. Balmis — Alicante
• Hospital Universitario Vall d'Hebrón — Barcelona
• Hospital Universitario 12 de Octubre — Madrid
• Hospital Clínico Universitario de Valencia — Valencia
• Hospital Universitario Doctor Peset — Valencia

Identifiers

NCT: NCT06578533 · KEEP-ON

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗