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.

Abstract

Background:

In TEMPO 3:4, the vasopressin V2 receptor antagonist tolvaptan slowed total kidney volume (TKV) growth and estimated glomerular filtration rate (eGFR) decline relative to placebo.

Methods:

TEMPO 4:4 was designed to provide an additional 2 years of data on the long-term safety and efficacy of tolvaptan in subjects completing TEMPO 3:4. The objective was to assess the disease-modifying effects of tolvaptan on TKV and eGFR end-points including change from baseline over the combined duration of TEMPO 3:4 and TEMPO 4:4, and non-inferiority of slopes during TEMPO 4:4.

Results:

Of the 1445 subjects randomized to TEMPO 3:4, 871 (60.3%) enrolled in TEMPO 4:4. Percent changes in TKV from TEMPO 3:4 baseline to TEMPO 4:4 Month 24 were 29.9% and 31.6% (prior tolvaptan versus prior placebo, P = 0.38). 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 (P = 0.04). Slopes of TKV growth during TEMPO 4:4 were higher in early- versus delayed-treatment groups (6.16% versus 4.96% per year, P = 0.05). Analysis of secondary eGFR endpoints demonstrated a persistent effect on eGFR (3.15 mL/min/1.73 m2, P < 0.001), and non-inferiority in eGFR slopes. The safety profile on exposure to tolvaptan in TEMPO 4:4 was similar to that in TEMPO 3:4.

Conclusions:

The results of TEMPO 4:4 support a sustained disease-modifying effect of tolvaptan on eGFR. The lack of a sustained treatment difference on TKV may be accounted for by limitations of the trial design, including loss of randomization and baseline imbalances ensuing TEMPO 3:4. The safety profile was similar to that observed in TEMPO 3:4.

• Authors: Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Ronald D Perrone, Ann Dandurand, John Ouyang, Frank S Czerwiec, Jaime D Blais, TEMPO 4:4 Trial Investigators
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 33 Issue 3 Pg. 477-489 (03 01 2018) ISSN: 1460-2385 [Electronic] England
• PMID: 28379536 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.

Chemical References

• Antidiuretic Hormone Receptor Antagonists
• Benzazepines
• Tolvaptan

Topics

• Adult
• Antidiuretic Hormone Receptor Antagonists (therapeutic use)
• Benzazepines (therapeutic use)
• Female
• Glomerular Filtration Rate
• Humans
• Male
• Polycystic Kidney, Autosomal Dominant (drug therapy)
• Prognosis
• Time-to-Treatment
• Tolvaptan (therapeutic use)