Table 1.

Summary of clinical trials with oral potassium binders

Clinical trial	Number of participants & dosage	Study population	Study type	Duration	Primary endpoints	Acute serum K+ findings	Limitations
Sodium polystyrene sulfonate
Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD [18] Lepage et al.	33 patients total; 16 assigned to SPS treatment group (30 g/day) and 17 assigned to placebo group	Adult patients in ambulatory setting with chronic kidney disease and baseline serum K+ of 5.0–5.9 mEq/L	Double-blind, randomized clinical controlled trial	7 days	Comparison of serum K+ between groups from baseline to day 7 (after final treatment dose)	Decreased serum K+ levels by a mean of 1.25 mEq/L (SD: ± 0.56) in SPS group compared to 0.21 mEq/L (SD: ± 0.29) in placebo group over 7-day period; difference of -1.04 mEq/L (95% CI, -1.37 to -0.71); P < 0.001	Small sample size; serum K+ of > 5.9 mEq/L was excluded; limited to 2 blood draws for serum K+ (day 0 and day 7) hence, unable to detect efficacy in acute setting
Patiromer
Patiromer for Treatment of Hyperkalemia in the Emergency Department: A Pilot Study [19] Rafique et al.	30 patients total; 15 assigned to standard of care group, 15 assigned to patiromer group receiving single, 25.2 g dose	Adult emergency room patients with end-stage renal disease and baseline serum K+  ≥ 6.0 mEq/L	Single-center, randomized, open-label pilot study	6 h	Difference in serum K+ between SOC group and treatment group at 6 h	Decreased serum K+ within 2 h of the patiromer-treated group (single-dose 25.2 g) compared to the SOC group (5.91 mEq/L vs. 6.51 mEq/L respectively; P < 0.009); no differences shown at 6 h	Small sample size
Patiromer Induces Rapid and Sustained Potassium Lowering in Patients with Chronic Kidney Disease and Hyperkalemia [13] Bushinsky et al.	25 patients in single treatment group receiving 8.4 g/dose, 4 doses total	Adult patients hospitalized with serum K+ of 5.5–6.5 mEq/L; majority with chronic kidney disease and all taking at least one RAAS inhibitor	Multicenter, international, phase I, open-label, single-arm study conducted at 5 sites in Europe	72-h K+/Na+ restricted diet phase followed by 48-h treatment phase and outpatient follow-up phase	Mean change in serum K+ from baseline until 48 h after initial dose	Decreased serum K+ of 0.21 mEq/L within 7 h of initial treatment compared to baseline (95% CI, -0.35 to -0.07) P = 0.004. Significant reductions occurred at all assessment points from 7–48 h P ≤ 0.004 at 10 h, P ≤ 0.001 at 12–48 h	Lack of comparative placebo control and small sample size. Those with abnormal electrocardiograph readings related to hyperkalemia were excluded
Sodium zirconium cyclosilicate
Emergency Potassium Normalization Treatment Including Sodium Zirconium Cyclosilicate: A Phase II, Randomized, Double-blind, Placebo-controlled Study (ENERGIZE) [16] Peacock et al.	62 patients total; 29 assigned to SZC group (10 g, up to 3 doses); 33 assigned to placebo group	Adult patients admitted to the emergency room with baseline serum K+ of ≥ 5.8 mEq/L	Multicenter, international, randomized, double-blind, placebo-controlled, parallel-group, phase II study conducted at 33 sites in Denmark, Italy, Russia, and the United States	10-h treatment period followed by a single follow-up visit 7 days later	Mean change in serum K+ from baseline until 4 h after initial dose	Greater reduction in baseline serum K+ within SZC treatment group compared to placebo group –0.72 (0.12) versus –0.36 (0.11) mEq/L (least squares mean difference –0.35 mmol/L; 95% CI = –0.68 to –0.02)	Missing lab values of serum K+ at 4 h for substantial amount of patients; small sample size of patients (N = 62); enrolled; high withdrawal rate (30.2% treatment group and 43.2% placebo group)
Sodium Zirconium Cyclosilicate in Hyperkalemia [20] Packham et al.	754 patients assigned to 4 different SZC treatment groups (1.5 g, 2.5 g, 5 g, 10 g) or placebo group	Adult patients in the ambulatory setting with baseline serum K+ of 5.0 – 6.5 mEq/L	Multicenter, two-stage, randomized, double-blind, phase III study conducted at 65 sites in United States, Australia, and South Africa	Initial phase of 48 h, followed by a 12-day maintenance phase	Exponential rate of change in mean serum K+ at 48 h and between-group difference of serum K+ post 48 h during maintenance phase	Mean reduction of serum K+ with single dose of 10 g SZC within 1 h was 0.11 mEq/L compared to 0.01 mEq/L in placebo group (95% CI, -0.05 to 0.07)	Patients with serum K+ of > 6.5 mEq/L and those with abnormal electrocardiograph readings related to hyperkalemia were excluded; hospitalized patients were excluded
Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients with Hyperkalemia – the HARMONIZE Randomized Clinical Trial [21] Kosiborod et al.	258 patients assigned to 10 g SZC treatment group (open-label phase) followed by randomization to 3 different SZC dosage groups (5, 10, or 15 g) or placebo (28-day phase)	Adult patients in the ambulatory setting with baseline serum K+ of ≥ 5.1 mEq/L	Phase III, randomized, double-blind, placebo-controlled trial conducted at 44 sites in United States, Australia, and South Africa	Initial open-label phase of 48 h, followed by a randomized 28-day phase	Difference of mean serum K+ levels between 3 different SZC treatment groups and placebo group	Decreased serum K+ of 0.2 mEq/L within 1 h of single 10 g dose of SZC compared to baseline (95% CI, -0.3 to -0.2) P < 0.001. At 2 and 4 h after initial dose, mean change in serum K+ was -0.4 mEq/L (95% CI, -0.5 to -0.4 and -0.5 mEq/L (95% CI, -0.6 to -0.5); P < 0.001 for each time point	Hospitalized patients and those with severe arrythmias were excluded
A Phase 2 Study on the Treatment of Hyperkalemia in Patients with Chronic Kidney Disease Suggests that the Selective Potassium Trap, ZS-9, is Safe and Efficient [22] Ash et al.	90 patients total; 60 assigned to 3 different SZC dosage groups (0.3, 3, or 10 g); 30 assigned to placebo group	Adult patients with stage 3 chronic kidney disease and baseline serum K+ of 5.0–6.0 mEq/L	Phase II, randomized, double-blind, placebo-controlled trial conducted at 9 sites in the United States	48 h	Rate of serum K+ decline within the first 48 h	Decreased serum K+ of 0.11 mEq/L from baseline at 1 h following initial dose in 10 g SZC group compared to placebo (P = 0.02)	Small sample size of patients; serum K+ of > 6.0 mEq/L was excluded