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Phase 3
A phase 3 clinical trial included 753 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and patients on renin-angiotensin system blockers. Patients were randomized (1:1:1:1:1) to ZS-9 (1.25g, 2.5g, 5g or 10g) or placebo three times daily for 48 hours (acute phase), after which those with potassium levels ≤4.9 mmol/L (normokalemic) were either re-randomized 1:1 to the same dose of ZS-9 or placebo once daily; placebo-treated patients were re-randomized to ZS-9 1.25g or 2.5g once daily for Day 3-15 (extended phase).

ZS-9 produced a significant dose-dependent reduction in potassium when given three times daily for 48 hours during the acute phase. Subgroup analyses showed that 10g ZS-9 was effective in decreasing serum potassium during the acute phase, regardless of baseline potassium level or use of renin-angiotensin system blockers (yes/no). 542 patients achieved normokalemia in the acute phase. During the extended phase, patients receiving 5g and 10g ZS-9 maintained normokalemia, whereas those receiving placebo generally returned to hyperkalemia. Subgroup analyses of extended phase data showed that 10g ZS-9 was effective in maintaining normokalemia regardless of starting potassium level, glomerular filtration rate, chronic kidney disease status (yes/no), congestive heart failure status (yes/no), use of renin-angiotensin system blockers (yes/no), and diabetes mellitus status (yes/no). 10g ZS-9 was also shown to significantly increase urinary pH and serum bicarbonate, and reduce blood urea nitrogen (compared with placebo), suggesting ZS-9 may improve acid-base balance in patients with hyperkalemia. The overall incidence of adverse events (including gastrointestinal adverse events) associated with ZS-9 was similar to placebo both the acute and extended phase.