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: 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.
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.affiliation: Division of Nephrology, Section of Nephrology, University of Chicago, Chicago, IL, USA.
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.affiliation: Department of Medicine, Division of Nephrology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Perrone
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Dandurand
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
authors.affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD, USA.
authors.forename: Jaime D
authors.initials: JD
authors.lastname: Blais
mesh_terms: D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy*; D011379:Prognosis; D061665:Time-to-Treatment; D000077602:Tolvaptan / Q000627:therapeutic use*
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan