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

Abstract

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.

Keywords: FGF23; NHE3 dialysis; hyperphosphatemia; phosphate binders; phosphate uptake; phosphorus; tenapanor.

Figure 1.

Overview of patient flow through the trial. The safety population set included all randomized patients who received at least one dose of treatment. The FAS included all randomized patients who had at least one postbaseline serum phosphorus measurement during the trial. Baseline was defined as the measurement collected at day 1 (randomization). If this value was missing, the last measurement before the first dose of study drug was used. BIND, binder; PBO, placebo; TEN, tenapanor.

Figure 2.

LS mean change in serum phosphorus concentration from baseline at week 4 (primary end point, FAS). Mean baseline serum phosphorus was 6.9 mg/dl for the PBO + BIND group and 6.7 mg/dl for the TEN + BIND group. Baseline was defined as the measurement collected at day 1. If this value was missing, the last measurement before the first dose of study drug was used. Data are LS mean change (95% confidence interval) in serum phosphorus concentration, P value, and SEM from a mixed effects model for repeated measures. BIND, binder; PBO, placebo; TEN, tenapanor.

Figure 3.

Change in serum phosphorus concentration from baseline over time to week 4 (FAS). Mean baseline serum phosphorus was 6.9 mg/dl for the PBO + BIND group and 6.7 mg/dl for the TEN + BIND group. Baseline was defined as the measurement collected at day 1. If this value was missing, the last measurement before the first dose of study drug was used. Data are LS mean change in serum phosphorus concentration, P value, and SEM from a mixed effects model for repeated measures. BIND, binder; PBO, placebo; TEN, tenapanor. *P<0.001 versus placebo.

Figure 4.

Proportion of patients achieving serum phosphorus below 5.5 mg/dl at weeks 1–4 (± SEM; FAS). The P value was obtained from the Cochran–Mantel–Haenszel test adjusting for type of binder and serum phosphorus concentration before randomization (<7.5 or ≥7.5 mg/dl). BIND, binder; PBO, placebo; TEN, tenapanor. *P<0.001 versus placebo; **P<0.01 versus placebo.

Figure 5.

Relative change from baseline at week 4 in concentrations of iFGF23 and cFGF23 (FAS). Mean baseline iFGF23 (SD) was 15,436.9 (16,804.2) pg/ml for the PBO + BIND group and 14,032.4 (15,729.8) pg/ml for the TEN + BIND group. Mean baseline cFGF23 (SD) was 24,108.0 (26,238.8) RU/ml for the PBO + BIND group and 22,203.7 (25,068.6) RU/ml for the TEN + BIND group. Relative change from baseline at week 4 was derived as “week 4 value/baseline value –1.” Baseline was defined as the measurement collected at day 1. If this value was missing, the last measurement before the first dose of study drug was used. The P values come from an analysis of covariates model with the natural logarithm of “week 4 value/baseline value” as the dependent variable and serum phosphorus level before randomization (<7.5 or ≥7.5 mg/dl) and treatment as factors. BIND, binder; PBO, placebo; RU, relative unit; TEN, tenapanor.