Efficacy and Safety of Tenapanor in Patients with Hyperphosphatemia Receiving Maintenance Hemodialysis: A Randomized Phase 3 Trial

Abstract

Background: Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport.

Methods: In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group.

Results: Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action.

Conclusions: Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.

Keywords: NHE3; hemodialysis; hyperphosphatemia; phosphate; tenapanor.

Graphical abstract

Figure 1.

Study design. ^aPatients initially receiving tenapanor 30 mg twice a day were allowed to down-titrate weekly (stepwise 30 → 20 → 15 → 10 → 3 mg twice a day) during the first 4 weeks of the RTP, on the basis of gastrointestinal tolerability. Mean final dose of tenapanor in this group at the end of the RTP was 24.4 mg twice a day for the safety and ITT analysis sets, and 22.8 mg twice a day for the secondary efficacy analysis set. ^bOne patient did not receive any dose of study drug and was excluded from analyses. ^cThe study was initiated on January 20, 2016 as an 8-week randomized dose range–finding study; the RWP was added to the protocol in an amendment dated March 3, 2016, when 22 patients were enrolled. Patients randomized to tenapanor in the RWP remained on their previous dose from the RTP. Mean exposure during the RTP was 48 days in all three treatment groups, and during the RWP was 26 days for patients receiving placebo and 27 days for patients receiving tenapanor. bid, twice daily.

Figure 2.

Patient flow. ^aOne patient discontinued before receiving a dose of study drug and was excluded from the analyses. bid, twice daily; GI, gastrointestinal.

Figure 3.

Tenapanor significantly decreased serum phosphate levels in patients with hyperphosphatemia receiving maintenance hemodialysis. Data presented are for the change in serum phosphate during the RTP and the RWP for (A) the ITT analysis set and (B) the efficacy (responder) analysis set. Line graph data are mean±SD. Bar chart data are LSM change (95% CI) in serum phosphate concentration and error bars show SEM, from an analysis of covariance with treatment and pooled investigator sites as factors and baseline (left) or end of 8-week RTP (right) serum phosphate concentration as a covariate. Data in (B) are shown for the responder population, defined as all patients with a reduction in serum phosphate concentration of at least 1.2 mg/dl during the RTP. The analyses used a patient’s last study center visit as the end point visit; there may be apparent discrepancies in patient numbers between figure panels if patients did not visit the study center after the first visit of each period (i.e., had no end point visit for the RTP/RWP). *P<0.001 versus baseline. bid, twice daily; 95% CI, 95% confidence interval; LSM, least squares mean.

Figure 4.

Mean bowel movement frequency increased with tenapanor treatment, but remained within the normal range for healthy individuals. Data presented are for (A) bowel movement frequency and (B) stool consistency during the RTP and the RWP. Data are mean±SD. BSFS scores are weekly averages. bid, twice daily; BSFS, Bristol Stool Form Scale.