@article{56b35158d32c4cd29b90ac9d143166f3,
title = "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 m 2, 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.",
keywords = "autosomal dominant polycystic kidney disease, chronic kidney disease, polycystin kidney disease, vasopressin, vasopressin v2 receptor antagonist",
author = "Torres, {Vicente E.} and Chapman, {Arlene B.} and Olivier Devuyst and Gansevoort, {Ron T.} and Perrone, {Ronald D.} and Ann Dandurand and John Ouyang and Czerwiec, {Frank S.} and Blais, {Jaime D.}",
note = "Funding Information: R.T.G., R.D.P., A.B.C., O.D. and V.E.T are members of the TEMPO 3:4 and 4:4 steering committee. J.B.D, F.S.C, A.D. and J.O are employees of Otsuka Pharmaceutical Development and Commercialization Inc. (Princeton, NJ, USA). V.E.T., O.D., A.B.C., R.T.G. and R.D.P. have received research funding from Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA); A.B.C. have received consultancy fees from Otsuka Pharmaceutical Development & Commercialization, Inc. Funding Information: The authors thank the patients involved in the TEMPO 3:4 Trial for their participation and contribution; the trial sub-investigators, radiologists, study coordinators and nurses; the trial managers, trial monitors, data managers, programmers and statisticians; the staff at the University of Wisconsin Statistical Data Analysis Center; and Dr K. Bae for assistance in the development of the imaging protocol. The authors want to acknowledge in memoriam the contributions of Dr Vincent H. Gattone 2nd for his insights into the connection between vasopressin and polycystic kidney disease, and of Mr Akihiko Otsuka and Dr Taro Iwamoto for their dedication to finding a treatment for ADPKD. The authors also thank David Norris, PhD (Ecosse Medical Communications, Falmouth, MA, USA) for editorial assistance provided during the preparation of this report. The study was funded by Otsuka Pharmaceutical Development and Commercialization, Inc. Publisher Copyright: {\textcopyright} 2017 The Author.",
year = "2018",
month = mar,
day = "1",
doi = "10.1093/ndt/gfx043",
language = "English (US)",
volume = "33",
pages = "477--489",
journal = "Proceedings of the European Dialysis and Transplant Association - European Renal Association. European Dialysis and Transplant Association - European Renal Association. Congress",
issn = "0931-0509",
publisher = "Oxford University Press",
number = "3",
}