Tolvaptan treatment has a sustained disease-modifying effect on estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD), but the effects of five compared to two years of treatment on total kidney volume (TKV) were not significantly different, according to a new study.
The open-label extension trial, TEMPO (Tolvaptan Efficacy and safety in Management of Polycystic kidney disease and its Outcomes) 4:4, provided an additional 2 years of data on the long-term safety and efficacy of tolvaptan on TKV and eGFR among patients completing the pivotal TEMPO 3:4 trial. In TEMPO 3:4, tolvaptan, a vasopressin V2 receptor antagonist, slowed TKV growth by 49.2% and eGFR decline by 26% compared with placebo.
Of 1445 patients randomized to TEMPO 3:4, 871 (60.3%) enrolled in TEMPO 4:4. The group included 557 patients who received prior tolvaptan (early-treated group) and 314 who received prior placebo (delayed-treated group) in TEMPO 3:4.
From TEMPO 3:4 baseline to TEMPO 4:4 Month 24, TKV increased by 29.9% in early-treated patients and 31.6% in delayed-treated patients, a between-group difference that was not statistically significant, Vicente E. Torres, MD, of Mayo Clinic in Rochester, Minnesota, and colleagues reported in a paper published online ahead of print in Nephrology Dialysis Transplantation. TKV increases in both early- and delayed-treated patients were less than the increase estimated to have occurred without treatment (approximately 40%). The inability to demonstrate that the early treatment advantage on TKV achieved during TEMPO 3:4 was maintained at the end of TEMPO 4:4 may be accounted for by randomization imbalances that developed in the transition from TEMPO 3:4 to TEMPO 4:4 and by the fact that the tolvaptan effect on TKV is greatest during the first year of treatment, according to the investigators. Adjusting for baseline covariates improved the TKV treatment difference at month 24 in TEMPO 4:4 from 1.70% to 4.15% between the groups, a statistically significant difference.
Slopes of TKV growth during TEMPO 4:4 were higher in early- versus delayed-treatment groups (6.16% vs 4.96% per year).
Data showed that the effect of tolvaptan on slowing renal function decline in TEMPO 3:4 was maintained for an additional 2 years in TEMPO 4:4. The eGFR slopes in TEMPO 4:4 were similar in early and delayed-treated patients (−3.26 and −3.14 mL/min/1.73 m2 per year, respectively) compared with placebo.
The tolvaptan safety profile in TEMPO 4:4 was similar to that in TEMPO 3:4, Dr Torres’ team reported.
Torres VE, Chapman AB, Devuyst O, et al. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Nephol Dial Transplant 2017; published online ahead of print.