Original Investigation
Hypertension and Acid-Base/Electrolyte Disorders
Tolvaptan and Neurocognitive Function in Mild to Moderate Chronic Hyponatremia: A Randomized Trial (INSIGHT)

https://doi.org/10.1053/j.ajkd.2015.12.024Get rights and content

Background

This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia.

Study Design

Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study.

Setting & Participants

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.

Intervention

Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15 mg/d, with titration to 30 or 60 mg/d based on change in serum sodium concentration and tolerance.

Outcomes

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).

Limitations

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.

Section snippets

Study Design

The Investigation of the Neurocognitive Impact of Sodium Improvement in Geriatric Hyponatremia: Efficacy and Safety of Tolvaptan (INSIGHT) was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, titration-to-effect trial (Table S1, available as online supplementary material). The trial consisted of a 30-day screening period, 21-day treatment period, and 7-day posttreatment period (Fig 1A). During the screening period, attempts were made to identify and eliminate the

Patients

In all, 57 men and women were enrolled at 16 US sites in September 2007 to March 2009; a total of 53 patients were analyzed for efficacy (26 tolvaptan and 27 placebo), and 57, for safety (29 tolvaptan and 28 placebo; Fig 2). The 2 patient groups were relatively well matched for relevant baseline characteristics (Table 1). Compared with normative values from age-matched individuals, patients in this trial at baseline had significantly impaired cognitive performance on measures of correct choice

Discussion

This trial demonstrated the effects of oral tolvaptan on correction of serum sodium concentrations to the normal range in adult patients with mild hyponatremia and the effects of this correction on measures of cognition, gait, and bone metabolism. Compared with normative values from age-matched individuals, study participants had impaired cognitive performance at baseline on measures of correct choice and speed of choice, impaired postural and gait stability, and reduced SF-12 physical

Acknowledgements

The INSIGHT Investigators are Otis Barnum, Natchitoches Hospital; Karthikeya Devireddy, KD Medical Group Inc; Howard Ellison, Rockdale Medical Research Associates; Miguel Franco, Memorial Clinical Associates; Francis Goldstein, Carolina Research Associates; Terrence C. Hack, Primary Care Cardiology Research Inc; Kianoosh Kaveh, Coastal Nephrology Associates Research Center; Ali Khojasteh, Columbia Comprehensive Care Clinic; John LaFata, Progressive Clinical Research; Michael J. Lillestol,

References (32)

  • S.A. Jamal et al.

    Hyponatremia and fractures: findings from the Osteoporotic Fractures in Men Study

    J Bone Miner Res

    (2015)
  • C. Kruse et al.

    Hyponatremia and osteoporosis: insights from the Danish National Patient Registry

    Osteoporos Int

    (2015)
  • R.L. Usala et al.

    Hyponatremia is associated with increased osteoporosis and bone fractures in a large US health system population

    J Clin Endocrinol Metab

    (2015)
  • R.W. Schrier et al.

    Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia

    N Engl J Med

    (2006)
  • T. Berl et al.

    Oral tolvaptan is safe and effective in chronic hyponatremia

    J Am Soc Nephrol

    (2010)
  • P.M. Simpson et al.

    The Cognitive Drug Research computerised assessment system for demented patients: a validation study

    Int J Geriatr Psychiatry

    (1991)
  • Cited by (0)

    Trial registration: www.ClinicalTrials.gov; study number: NCT00550459.

    A list of the INSIGHT Investigators appears in the Acknowledgements.

    View full text