title: Tolvaptan and Neurocognitive Function in Mild to Moderate Chronic Hyponatremia: A Randomized Trial (INSIGHT).
abstract: BACKGROUND
  This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia.
  
  
  METHODS
  Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study.
  
  
  METHODS
  57 men and women 50 years or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia (serum sodium concentration >120-<135 mEq/L) at 16 sites.
  
  
  METHODS
  Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15mg/d, with titration to 30 or 60mg/d based on change in serum sodium concentration and tolerance.
  
  
  RESULTS
  Primary: change from baseline in the neurocognitive composite score of speed domains. Secondary: changes from baseline in individual neurocognitive domain scores, overall neurocognitive composite score, gait and postural stability test results, and serum sodium concentrations.
  
  
  RESULTS
  Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P<0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04-0.51; P=0.03).
  
  
  CONCLUSIONS
  There were some imbalances between treatment groups in baseline neurocognitive function scores and some baseline test results were near normal, leaving little opportunity for improvement. Formal sample size calculations were not performed because this was a pilot study. The study population was small (n=57) and treatment was of short duration (3 weeks). The primary end point of the study was not significant; thus, subgroup analyses are subject to errors of multiplicity and should be regarded as hypothesis generating.
  
  
  CONCLUSIONS
  Tolvaptan was effective in reversing chronic hyponatremia, and this correlated with improvements in results of a variety of neurocognition tests, particularly rapid motor movements, which tended to reverse following return to a low baseline serum sodium concentration after treatment withdrawal.
authors.affiliation: Division of Endocrinology and Metabolism, Georgetown University, Washington, DC. Electronic address: verbalis@georgetown.edu.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Verbalis
authors.affiliation: Rockdale Medical Research Associates, Conyers, GA.
authors.forename: Howard
authors.initials: H
authors.lastname: Ellison
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD.
authors.forename: Mary
authors.initials: M
authors.lastname: Hobart
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD.
authors.forename: Holly
authors.initials: H
authors.lastname: Krasa
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD.
authors.forename: John
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc, Rockville, MD.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D065092:Antidiuretic Hormone Receptor Antagonists / Q000627:therapeutic use*; D001552:Benzazepines / Q000627:therapeutic use*; D002908:Chronic Disease; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007010:Hyponatremia / Q000150:complications* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D012720:Severity of Illness Index; D000077602:Tolvaptan
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan
keywords: Chronic hyponatremia; aquaresis; bone metabolism; bone resorption; cognition; gait; neurocognitive function; osteoporosis; postural stability; randomized controlled trial (RCT); serum sodium; tolvaptan; vasopressin receptor antagonist