Multicenter Study of Long-Term Safety of Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

Abstract

Background and objectives: Tolvaptan slows kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4, 2-year extension to TEMPO 3:4 (TEMPO 4:4), and 1-year Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, aquaretic adverse events were common. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurred in all three studies. Three patients met Hy Law criteria (ALT or AST more than three times and total bilirubin more than two times the upper limit of normal) for severe drug-induced liver injury (two in TEMPO 3:4 and one in TEMPO 4:4). In REPRISE, liver enzyme monitoring frequency was increased to monthly, with no Hy Law cases. A long-term, phase 3 safety study has further characterized tolvaptan safety.

Design, setting, participants, & measurements: Subjects who completed TEMPO 4:4, REPRISE, or other tolvaptan trials could enroll in this prospective, multinational, open-label safety study. Assessments included monthly liver enzyme testing during the first 18 months of tolvaptan exposure and every 3 months thereafter.

Results: Among 1803 subjects, median tolvaptan exposure during the extension was 651 days (interquartile range, 538-924), and cumulative exposure (extension and previous trials) was ≤11 years. Subjects entering from REPRISE placebo experienced more aquaretic adverse events compared with subjects from TEMPO 4:4 or REPRISE tolvaptan (i.e., patients with prior long-term tolvaptan exposure). Liver enzyme elevations also occurred more frequently in subjects from REPRISE placebo. Percentages experiencing ALT ≥3/≥5/ ≥10/≥20 times the upper limit of normal were 3.2%/2.1%/0.9%/0.7%, respectively, in subjects from REPRISE placebo and 0.6%-1.1%/0.0%-0.1%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. Percentages experiencing AST ≥3/ ≥5/≥10/≥20 times the upper limit of normal were 6.9%/3.8%/2.3%/0.8%, respectively, in subjects from REPRISE placebo and 0.9%-2.0%/0.0%-1.0%/0%/0%, respectively, in those from REPRISE tolvaptan and TEMPO 4:4. No Hy Law cases occurred.

Conclusions: No new safety signals emerged during this long-term extension. Monthly liver function testing for the first 18 months of treatment appeared to enable effective detection and management of transaminase elevations.

Clinical trial registry name and registration number: Open Label Extension of TEMPO 3:4, NCT02251275.

Keywords: ADPKD; cystic kidney; tolvaptan.

Graphical abstract

Figure 1.

Potential cumulative duration of tolvaptan exposure in subjects entering the long-term extension from the Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease (REPRISE) and the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 4:4 trials. All subjects in REPRISE had a brief (5-week) tolvaptan run-in period at the start of that study, and those randomized to the REPRISE placebo arm received placebo for 12 months and reinitiated tolvaptan in the long-term extension. Subjects from the tolvaptan arm of REPRISE had approximately \raster="CJASN_10250620_wc_f1"13 months of previous exposure, and those entering from TEMPO 3:4 (tolvaptan arm)/TEMPO 4:4 had up to 5 years of previous exposure.

Figure 2.

Exposure to tolvaptan during the extension trial by previous trial participation. *Entered the long-term extension directly from TEMPO 3:4 or NOCTURNE (n=9; four from TEMPO 3:4 tolvaptan, two from NOCTURNE tolvaptan, and three from TEMPO 3:4 placebo).

Figure 3.

Frequencies of common aquaretic adverse events by prior trial participation.

Figure 4.

Patients with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations by laboratory value threshold in the long-term extension, shown by prior trial participation. Denominators are the numbers of subjects with greater than or equal to one postbaseline measurement for the given laboratory test. Data from nine subjects entering from other trials are not shown. AST measurements were not required by protocol at the monthly visits, and as a result, the percentage of AST elevations might have been affected by selection bias.