Evaluation of Sodium Zirconium Cyclosilicate Efficacy in Managing Hyperkalemia in Chronic Kidney Disease Patients: A Phase III Randomized Clinical Trial
- Trial ID
- 2024-517631-43-00
- Protocol
- KEEP-ON
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase III, multicenter, open-label, randomized clinical trial is to evaluate the efficacy of **Sodium Zirconium Cyclosilicate** (SZC), marketed as Lokelma, in managing **hyperkalemia** in patients with chronic kidney disease (CKD) who are not on dialysis. The study aims to analyze the proportion of patients achieving serum potassium (sK) levels of less than 5.5 mEq/L with SZC compared to the discontinuation of renin-angiotensin-aldosterone system inhibitors (RAASi) and/or mineralocorticoid receptor antagonists (MRA). This is clinically relevant as maintaining optimal sK levels is crucial in preventing complications associated with hyperkalemia, which can be life-threatening in CKD patients.
Participants
The clinical trial involves participants diagnosed with **hyperkalemia** in the context of chronic kidney disease (CKD), specifically targeting those not on dialysis. The study population includes both male and female subjects, aged 18 years and older, with no vulnerable populations selected. Participants are required to have serum potassium levels between 5.5-6.5 mEq/L at the selection visit and 5.0-6.5 mEq/L at the randomization visit. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants are expected to be receiving standard care for heart failure, including RAASi and/or MRA treatment, which should have been stable for at least four weeks at maximum tolerated doses. Female participants of childbearing potential must have a negative pregnancy test and adhere to strict contraceptive measures throughout the study and for three months following the last dose of Sodium zirconium cyclosilicate (SZC). The trial does not focus on any specific lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is a **Phase III**, multicenter, open-label, randomized study designed to evaluate the efficacy of **sodium zirconium cyclosilicate** (Lokelma) compared to the standard of care in managing **hyperkalemia** in patients with chronic kidney disease (CKD). The trial will involve a parallel-group, non-inferiority design, and will include patients with CKD not on dialysis, specifically those with cardiorenal syndrome. The primary objective is to analyze the proportion of patients achieving serum potassium levels of less than 5.5 mEq/L with sodium zirconium cyclosilicate versus the discontinuation or downtitration of RAASi and/or MRA. The trial is expected to run from November 28, 2022, to January 5, 2026, with a maximum treatment period of 60 days for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit where eligibility criteria are assessed, including serum potassium levels between 5.5-6.5 mEq/L. Following successful screening, participants will be randomized and commence treatment. The randomization visit will confirm serum potassium levels between 5.0-6.5 mEq/L. Subsequent follow-up visits will occur at 7, 30, 60, and 90 days to monitor serum potassium levels and assess the primary endpoint, which is the percentage of patients achieving serum potassium levels of less than 5.5 mEq/L at three or all timepoints. The end-of-study visit will conclude the participant's involvement, ensuring all safety and efficacy data are collected.
Participant involvement is expected to last up to 90 days, with the possibility of early termination if adverse events occur or if the participant withdraws consent. The trial will adhere to ethical standards, requiring informed consent from all participants or their legal representatives before any study-specific procedures. Female participants of childbearing potential must use acceptable contraception methods throughout the study and for three months after the last dose of sodium zirconium cyclosilicate. The trial is classified as low intervention, as all medications involved are approved and will be prescribed according to clinical practice guidelines.
Treatment
The clinical trial involves the administration of **Lokelma**, a pharmaceutical product containing the active substance **sodium zirconium cyclosilicate**. Lokelma is provided in two formulations: a 5 g and a 10 g powder for oral suspension. The pharmaceutical form is an oral suspension, and the route of administration is oral. The maximum daily dose for both formulations is 10 g, with a total maximum treatment period of 60 days. The product is manufactured by AstraZeneca AB and is authorized for use in the European Union. The active substance, sodium zirconium cyclosilicate, is of chemical origin and functions as a cation exchanger, which is relevant for its role in managing hyperkalemia in patients with chronic kidney disease (CKD).
In this trial, Lokelma is compared to the standard-of-care therapy, which involves the discontinuation of renin-angiotensin-aldosterone system inhibitors (RAASi) and/or mineralocorticoid receptor antagonists (MRA) in patients with hyperkalemia and non-dialysis CKD. The trial aims to evaluate the efficacy of Lokelma in achieving serum potassium levels of less than 5.5 mEq/L. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The trial is designed as a Phase III, multicenter, open-label, randomized clinical trial.
Efficacy
The efficacy of Sodium Zirconium Cyclosilicate (Lokelma) in managing **hyperkalemia** in patients with chronic kidney disease (CKD) will be assessed in a Phase III, multicenter, open-label, randomized clinical trial. The primary endpoint for evaluating efficacy is the percentage of patients achieving serum potassium levels of less than 5.5 mEq/L at three or all timepoints (7, 30, 60, or 90 days) after a follow-up period of 90 days in both the treatment and control groups. This endpoint will be measured using laboratory tests to determine serum potassium levels at specified intervals throughout the study duration.
Inclusion and Exclusion 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).
- Over 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 28 Nov 2022 | 78 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lokelma 5 g powder for oral suspension | Test | POWDER FOR ORAL SUSPENSION | ORAL | 10 | 60 | PRD5996144 |
Lokelma 10 g powder for oral suspension | Test | POWDER FOR ORAL SUSPENSION | ORAL | 10 | 60 | PRD5995720 |