title: Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study.
abstract: BACKGROUND
  Current management of autosomal dominant polycystic kidney disease (ADPKD) is focused on treating disease complications, not on slowing cyst development or preventing progression to kidney failure. Tolvaptan, a selective vasopressin V2 (vasopressin 2) receptor antagonist, has been proved to inhibit kidney cyst growth and preserve kidney function in multiple animal models of polycystic kidney disease. The TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) 3-4 Study will examine the long-term effectiveness and safety of tolvaptan in patients with ADPKD. We report baseline characteristics and revised power calculations for the trial.
  
  
  METHODS
  A prospective, 3-year, multicenter, double-blind, placebo-controlled trial of tolvaptan, a selective V2 receptor antagonist. Primary outcome is total kidney volume percentage of change from baseline for tolvaptan relative to placebo. Secondary outcome parameters include time to ADPKD-associated complications (kidney function decrease, blood pressure control, renal pain, and albuminuria) and safety end points.
  
  
  METHODS
  This trial includes patients with ADPKD with relatively preserved kidney function (baseline estimated creatinine clearance ≥60 mL/min), aged 50 years or younger, and with total kidney volume measured using magnetic resonance imaging ≥750 mL.
  
  
  METHODS
  Administration of placebo or tolvaptan, dose titrated to tolerance.
  
  
  RESULTS
  Number of subjects enrolled and baseline characteristics.
  
  
  METHODS
  Total kidney volume, kidney function, albuminuria, kidney pain, and vital signs.
  
  
  RESULTS
  1,445 patients with ADPKD were enrolled between March 2007 and January 2009. Preliminary baseline median total kidney volume was 1.46 L, and estimated creatinine clearance was 105 ± 34 mL/min. A prespecified blinded sample-size recalculation at two-thirds enrollment confirmed the likely power of the study to detect 20% differences from placebo in the primary and key secondary end points at P < 0.05.
  
  
  CONCLUSIONS
  This is a preselected ADPKD population chosen for its risk of progression to kidney failure and may not represent the general ADPKD population. If study results are positive with regard to the primary end point, positive effects on other secondary clinical outcomes will be required to assess overall benefit.
  
  
  CONCLUSIONS
  This randomized trial is the largest clinical study of a proposed ADPKD intervention to date. It targets patients with ADPKD with early disease who are projected to have rapid cyst growth and accelerated outcomes. Blockade of vasopressin V2 receptor is hypothesized to inhibit cyst growth, thereby delaying additional adverse clinical outcomes.
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA. torres.vicente@mayo.edu
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Esther
authors.initials: E
authors.lastname: Meijer
authors.forename: Kyongtae T
authors.initials: KT
authors.lastname: Bae
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.forename: Olivier
authors.initials: O
authors.lastname: Devuyst
authors.forename: Ron T
authors.initials: RT
authors.lastname: Gansevoort
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.forename: Eiji
authors.initials: E
authors.lastname: Higashihara
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Perrone
authors.forename: Holly B
authors.initials: HB
authors.lastname: Krasa
authors.forename: John J
authors.initials: JJ
authors.lastname: Ouyang
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
mesh_terms: D000293:Adolescent; D000328:Adult; D000419:Albuminuria / Q000139:chemically induced; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D019468:Disease Management; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000139:chemically induced; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy* / Q000503:physiopathology; D011446:Prospective Studies; D017483:Receptors, Vasopressin / Q000502:physiology; D000077602:Tolvaptan; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D017483:Receptors, Vasopressin; D000077602:Tolvaptan