Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

Abstract

Background: Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition.

Methods: This multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 μg/day or 240 μg/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method.

Results: Regarding the primary endpoint, statistical superiority of TRK-100STP 240 μg over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 μg, at both doses, and at 240 μg, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated.

Conclusions: Although the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels.

Trial registration: NCT02480751. June 21, 2015.

Figures

Fig. 1

Summary of study design

Fig. 2

Inclusion and exclusion cliteria

Fig. 3

Patient dispositiona. aCONSORT 2010 flow diagram was provided as Additional file 1. * The number of the patients who were excluded during the Run-in period (n = 279) was calculated by adding the number of the patients who dropped out during the Run-in period (n = 278) and the patient who was excluded before the initiation of the study treatment (n = 1). ** Ten patients whose SCr values measured less than three points after Week 4 of the Treatment period were excluded from 112 patients randomized. As a results, 102 patients (32 patients in the 120 μg group, 36 patients in the 240 μg group and 34 patients in the placebo group) were included in the full analysis set (FAS). *** If there were multiple reasons for discontinuation, the main reason was used for calculation

Fig. 4

Change in SCr during study period (SCr values of each group at R20 [Week 20 of the run-in period] were set as 100 %)

Fig. 5

Primary endpoint: Least square mean of the change in the 1/SCr time slope

Fig. 6

Mean ± SD of ratio of SCr (final evaluation point/W0 [week 0 of the treatment period]): As shown in Table 5, both the 120 μg and the 240 μg groups showed an inhibition of the increase in SCr ratios as compared with the placebo group (P = 0.0309, 0.0204, respectively), assessed by ANCOVA with the SCr (R20) as covariate

Fig. 7

Mean ± SD of changes in serum cystatin C (final evaluation point – R20): As shown in Table 6, the 120 μg group showed a tendency and the 240 μg group showed significant inhibition of the increase in change in serum cystatin C as compared with the placebo group (P = 0.0928, 0.0285, respectively), assessed by ANCOVA with the SCr (R20) as covariate