Effects of Titrated Oral Tolvaptan 15-60 mg Once Daily (QD) on Cognitive and Neurological Function in Elderly Hyponatremic Patients

A Pilot, Phase 3B, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of the Effects of Titrated Oral Tolvaptan 15, 30, or 60 mg QD on Cognitive and Neurological Function in Elderly Hyponatremic Patients

Demonstrate an improvement in the composite scores of validated neurocognitive tests in elderly subjects with chronic sub-clinical (i.e., asymptomatic) hyponatremia.

Subjects will be randomized, with stratification by baseline sodium <130 or ≥ 130 mEq/L[mmol/L] to receive either tolvaptan 15 mg tablet or matching placebo tablet at doses of 15, 30 or 60 mg for 21 days. During this period, fluid restrictions should be loosened or suspended, until the subject's response to therapy can be evaluated, typically over the first few days of therapy. Fluid restriction may be reinstituted at any time in subjects whose sodium fails to improve or worsens with study therapy. A forced-titration up to 60 mg of study drug by day 3 to 7 will be based on the subject's serum sodium Subjects entering the study with a serum sodium concentration less than 130 mEq/L[mmol/L] may be fluid restricted if necessary at the discretion of the Investigator. Subjects should be monitored closely during the first 24 hours of treatment for dosing titration. The total dosing duration will be up to 21 days (plus 3 day treatment window). Subjects will return to the clinic on Day 22 (+3 days) for assessments and will complete a follow-up visit on Day 28 (+2 days).

Inclusion Criteria:

• Women and men 50 years of age or older.
• Serum Sodium ≥123 and ≤ 134 mEq/L [mmol/L]at screening and baseline.
• Subjects with serum sodium concentrations ≥118 and ≤122 mEq/L[mmol/L] at screening and baseline may be entered into the trial based on consultation and approval from the study medical monitor.

Exclusion Criteria:

• Conditions or history which may present a safety concern to the subject or their offspring or extreme susceptibility to hypotension with sudden fluid loss (aquaresis).
• Hyponatremia that is acute, easily reversible, artifactual, or due to a condition not associated with vasopressin excess or likely to respond to aquaretic therapy.
• Conditions associated with an independent imminent risk of morbidity and mortality.
• Conditions which may confound the assessment of endpoints, history of poor compliance, participation in a clinical trial believed by the PI or Sponsor likely to confound endpoint assessments.
• Conditions which may confound primary endpoints of cognitive function.