A Randomized Trial of Tenapanor and Phosphate Binders as a Dual-Mechanism Treatment for Hyperphosphatemia in Patients on Maintenance Dialysis (AMPLIFY)

Significance Statement In patients receiving maintenance dialysis, strategies for managing hyperphosphatemia are only moderately effective. In this 4-week randomized trial involving 236 patients experiencing hyperphosphatemia despite phosphate binder use, tenapanor (a small molecule that inhibits paracellular phosphate absorption) significantly reduced serum phosphorus concentration from baseline, compared with placebo, when used with phosphate binders as a dual-mechanism treatment. A significantly larger proportion of patients randomized to tenapanor plus binder achieved a serum phosphorus concentration <5.5 mg/dl at all time points compared with placebo plus binder. Few patients discontinued tenapanor because of diarrhea (the most frequently reported adverse event) or other adverse events. These findings indicate that evaluation of long-term safety and efficacy of this dual-mechanism treatment of hyperphosphatemia is merited. Background Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action—tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders—is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis. Methods This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5–10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4. Results Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (−0.84 versus −0.19 mg/dl, P <0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively. Conclusions A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone. Clinical Trial registry name and registration number: AMPLIFY, NCT03824587