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Nephrol Dial Transplant. 2018 Mar 1;33(3):477-489. doi: 10.1093/ndt/gfx043.

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.

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Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
Division of Nephrology, Section of Nephrology, University of Chicago, Chicago, IL, USA.
Division of Nephrology, Cliniques Universitaires St Luc, Université catholique de Louvain Medical School, Brussels, Belgium.
Institute of Physiology, Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.
Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Medicine, Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.



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.


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.


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.


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.

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