The role of sodium zirconium cyclosilicate in uptitrating spironolactone in patients with heart failure with reduced ejection fraction and at high-risk for hyperkalemia

JRCT ID: jRCTs031220568

Registered date:13/01/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Hyperkalemia
• Date of first enrollment: 13/01/2023
• Target sample size: 266
• Study type: Interventional

Intervention(s)

- Name of the drug (generic name and trade name): sodium zirconium cyclosilicate hydrate (SZC), Lokelma.
- Route of administration, dosage, and administration period. The usual starting dose for adults is 10 g suspended in water and orally administered three times a day for 2 days. Thereafter, a dose of 5 g suspended in water is orally administered once a day.

Outcome(s)

Primary Outcome

The primary endpoint is the achievement of spironolactone 50 mg/day at the end of the double-blind period and without use of rescue therapy* for hypokalemia or hyperkalemia at any time during the double-blind period.
*Definition of rescue therapy
1) Rescue treatment for hyperkalemia
Calcium gluconate
Glucose-insulin therapy
Potassium adsorbent other than SZC
Dialysis therapy
2) Rescue treatment for hypokalemia
Potassium replacement therapy (oral or intravenous)

The numerator is the number of patients who achieved the above criteria (i.e., responder), and the denominator is the number of patients who were randomly allocated. The patient who meets the following conditions is classified as a non-responder.
- Patients who discontinued study treatment (SZC/placebo) or withdrew from study participation during the double-blind period.

Secondary Outcome

- Achievement of a potassium level of >5.5 mEq/L in the double-blind period
- Time to first use of rescue therapy and/or MRA dose reduction for hyperkalemia in the double-blind period
- Changes in spironolactone dose over double-blind period
- Achievement of target dose of ACE inhibitors and other GDMT, including ARBs and ARNi [target dose (per day) for lisinopril (10 mg), enalapril (10 mg), candesartan (8 mg), and sacubitril/valsartan 400 mg]
- Achievement a target dose of 50% or higher of other GDMT, including beta-blockers [target dose (per day) for carvedilol (20 mg) and bisoprolol (5 mg)], ACE inhibitors, ARBs, and ARNi
- Change in KCCQ, PGIC, NYHA class
- Change in eGFR, NT-proBNP, urinary Na, K, Cl, Cr, BUN, and UACR

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: <= 90age old
• Gender: Both

Include criteria

(1) Individuals who have been briefed on the nature of the study and provided written informed consent to participate in the study
(2) Aged 20 to 90 years old
(3) Left ventricular ejection fraction of less than 50%
(4) Estimated glomerular filtration rate (eGFR) of 15-45 mL/min/1.73 m2
(5) Potassium level exceeds 5.0 mEq/L
(6) Spironolactone has been introduced at 12.5-37.5 mg
(7) NT-proBNP level of more than 400 pg/mL (if the patient had a history of hospitalization for heart failure)
(8) NT-proBNP level of more than 600 pg/mL (if the patient had no history of heart failure hospitalization)
(9) Currently taking a beta-blocker and either an ACE inhibitor/ARB/ARNi (regardless of dose), unless contraindicated

Exclude criteria

(1) Heart failure due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy, or organic valvular disease
(2) Renal artery stenosis
(3) Chronic dialysis (hemodialysis, peritoneal dialysis)
(4) Use of NSAIDs within 1 week and/or inability to discontinue
(5) QT prolongation; QTc (f) >550 msec
(6) Symptomatic bradycardia without pacemaker or concomitant symptomatic II (Mobitz type 2) or III degree AV block
(7) History of drug-induced QT prolongation with drug discontinuation
(8) Congenital long QT syndrome
(9) Use of lactulose, rifaximin, or other non-absorbable antibiotics for hyperammonemia
(10) Use of resin (sevelamer acetate, sodium polystyrene sulfonate, etc.), calcium acetate, calcium carbonate, or lanthanum carbonate within 7 days prior to the first dose of the study drug
(11) Patients who are pregnant or lactating or those who wish to become pregnant during the study period
(12) Use of potassium-lowering drugs other than study drugs (calcium polystyrene sulfonate, sodium polystyrene sulfonate)
(13) Patients who are already taking over 50 mg of spironolactone
(14) Symptomatic or uncontrolled atrial fibrillation despite treatment or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
(15) Patients who are judged to be unsuitable for enrollment by the principal investigator or sub-investigator

Related Information

• Primary Sponsor: Kida Keisuke
• Source(s) of Monetary Support: AstraZeneca K.K.