Tolvaptan in patients with autosomal dominant polycystic kidney disease

Abstract

Background: The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function.

Methods: In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.

Results: Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).

Conclusions: Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).

Figure 1. Patient Enrollment and Outcomes

We screened 2122 patients, of whom 1445 were randomly assigned to receive either tolvaptan or placebo. Overall, 1157 patients (80.1%) completed the 3-year trial. The primary efficacy analysis included 1307 of the 1445 patients (90.4%), the key secondary efficacy analysis included all 1445 (100%), and the key secondary safety analysis included 1444 (99.9%). MRI denotes magnetic resonance imaging.

Figure 2. Effect of Tolvaptan on the Annual Slopes of Total Kidney Volume and Kidney function

The slopes of the growth in total kidney volume in the intention-to-treat population during the 3-year treatment period are shown, with individual patient data included in the slope calculations; 6 outliers of the 1315 data points in the placebo group and 3 outliers of the 2370 data points in the tolvaptan group are not shown. The ratio of the geometric mean was 0.97 (95% CI, 0.97 to 0.98; P<0.001) (Panel A). The forest plot of the treatment effect according to baseline subgroups was based on the between-group difference in the slopes, with the variance approximated by means of the delta method under the assumption of independence between the slopes. Horizontal bars indicate 95% confidence intervals (Panel B). The slopes of kidney function were estimated with the use of the reciprocal of the serum creatinine level in the intention-to-treat population during the treatment period, and individual patient data were included in the slope calculations; 19 outliers of 4759 data points in the placebo group and 16 outliers of 8564 data points in the tolvaptan group are not shown. The annual difference in slope was 1.202 (mg per milliliter)⁻¹ per year (95% CI, 0.62 to 1.78; P<0.001) (Panel C). The forest plot of the treatment effect for kidney function according to the baseline subgroups was based on the difference in the annual change in slope (with 95% confidence intervals) of the reciprocal of the serum creatinine level (Panel D).

Figure 3. Effect of Tolvaptan on the Time to Multiple Events Associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Panel A shows the hazard ratios for the secondary end point of ADPKD-related events with tolvaptan as compared with placebo for the secondary composite end point and its component events. There were fewer events per 100 person-years of follow-up in the tolvaptan group than in the placebo group, with a hazard ratio of 0.87 (95% CI, 0.78 to 0.97). Horizontal bars indicate 95% confidence intervals. Panel B shows the cumulative hazard of multiple events of ADPKD progression, Panel C the cumulative hazard of worsening kidney function, and Panel D the cumulative hazard of clinically significant kidney pain.