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

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

Detailed Description
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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).

Official Title
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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

Conditions
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Hyponatremia

Intervention / Treatment
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* Drug: Tolvaptan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br>Placebo tablet given once a day for 21 days | Drug: Placebo<br>* Placebo tablet given once daily for 21 days<br>|
| Active Comparator: 2<br>Tolvaptan 15 mg-60 mg tablet given once a day for 21 days. | Drug: Tolvaptan<br>* 15-60 mg oral tablet given once a day for 21 days.<br>* Other names: OPC-41061;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Neurocognitive Composite Score of Speed Domains (NCS-SD; Sum of All Correct Speed Domain Z-Scores) | Change from baseline to Day 22 in sum of all speed domain Z-scores:Reaction Time (Simple=recognize yes 50 times;Choice=recognize yes or no 50 times;Digit Vigilance=match 45 digits);Psychomotor Speed (Morse Tapping=tap button for 30 seconds with right & left hands);Processing Speed (Rapid Visual Information Processing=detect consecutive sequences of 3 odd or 3 even digits;Numeric Working Memory=recognize numbers from series of 5 digits among 30;Word Recognition=remember 15 prior learned words from 30 total;results age-matched to healthy controls from Cognitive Drug Research normative data | baseline and Day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 22 in the Individual Neurocognitive Domains Included in the Primary Endpoint: Reaction Time in Computer Tests | Change from baseline in the individual neurocognitive domains Z-score for Reaction Time in Computer Tests (simple reaction time test, choice reaction time test, digit vigilance test); ITT population | baseline and Day 22 | 
| Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Psychomotor Speed Via Morse Tapping Test | Change from baseline to Day 22 in the individual neurocognitive domains Z-score for Psychomotor Speed (mean tap rate of Morse tapping test); ITT population | baseline and Day 22 | 
| Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Processing Speed of Rapid Visual Information Processing Test, Numeric Working Memory Test, and Word Recognition Test | Change from baseline to Day 22 in the individual neurocognitive domains Z-score for Processing Speed of Rapid Visual Information Processing Test, Numeric Working Memory Test, and Word Recognition Test; ITT population | baseline and Day 22 | 
| Change From Baseline in Overall Neurocognitive Composite Score | Change from Baseline to Day 22 in the overall Neurocognitive Composite Score (NCS)comprising the sum of 7 neurocognitive domain Z-scores (Reaction Time, Psychomotor Speed, Processing Speed, Continuity of Attention, Working Memory/Executive Functions, Quality of Episodic Verbal Memory, and Postural Stability); ITT population | baseline and Day 22 | 
| Change From Baseline in Gait Test (Timed Get-Up-and-Go Test) | Change from baseline to Day 22 in Gait Test (Timed Get-Up-and-Go Test=time it takes for a seated subject to rise from a chair, walk 3 meters, walk around an object and return to sit in chair. Values: under 10 sec (no difficulties), 10 to 20 sec (starting to have balance difficulty), over 30 sec (at high risk for falls and dependent in most activities of daily living and mobility); test assesses risk to elderly subjects of falling and higher scores in seconds indicate higher risk of falling; ITT population | baseline and Day 22 | 
| Change From Baseline in Postural Stability Test | Change from baseline to Day 22 in Postural Stability Test Z-score (This test measures gross motor control. The ability to stand upright without moving is assessed using the SWAY meter that is modeled on the Wright Ataxiameter. A cord from the meter is attached to the subject who is required to stand as still as possible with feet apart and eyes closed for 1 minute. The test is then repeated with eyes open for 1 minute. The outcomes of these tests are combined and measured as a movement Z-score. Higher result=better postural stability); ITT population | baseline and Day 22 | 
| Change From Baseline in Serum Sodium; ITT Population | Change from Baseline to Day 22 in Serum Sodium; ITT population | Baseline and Day 22 | 
| Number of Patients With Vital Sign Abnormalities: Blood Pressure | Incidence of abnormal systolic & diastolic blood pressure values post-baseline (abnormal systolic values: >=180 mmHg + increase of >=20 mmHg, <= 90 mmHg + decrease >=20 mmHg; abnormal diastolic values: >=105 mmHg+increase of >=15 mmHg, <=50 mmHg + decrease of >= 15 mmHg) | 28 days | 
| Number of Patients With Vital Sign Abnormalities: Pulse Rate | Incidence of abnormal pulse rate post-baseline [abnormal values: >=120 beats per minute (bpm) + increase of >=15 bpm; <=50 bpm + decrease of >=15 bpm] | 28 days | 
| Number of Patients With Vital Sign Abnormalities: Body Weight | Incidence of clinically significant body weight change post-baseline (defined as change upward or downward of >=7%) | 28 days | 
| Number of Patients With Vital Sign Abnormalities: Body Temperature | Incidence of potentially clinically significant changes in body temperature post-baseline (defined as an increase of >=1.1 to >=38.3 degrees Celsius) | 28 days | 
| Number of Patients With Hematology Laboratory Abnormalities: Hemoglobin | Incidence of clinically significant hemoglobin abnormalities post-baseline (normal range=11.8-16.8 g/dL) | 28 days | 
| Number of Patients With Hematology Laboratory Abnormalities: Activated Partial Thromboplastin Time (aPTT) | Incidence of potentially clinically significant Activated Partial Thromboplastin Time (aPTT) levels post-baseline (normal range=22-34 seconds) | 28 days | 
| Number of Patients With Hematology Laboratory Abnormalities: Lymphocytes | Incidence of potentially clinically significant lymphocyte count post-baseline (normal range = 16-46%) | 28 days | 
| Number of Patients With Hematology Laboratory Abnormalities: Neutrophils | Incidence of potentially clinically significant neutrophil count post-baseline (normal range=1.8-8 thousands/microliter) | 28 days | 
| Number of Patients With Serum Chemistry Laboratory Abnormalities: Blood Urea Nitrogen (BUN) | Incidence of potentially clinically significant BUN levels post-baseline (normal range=7-30 mg/dL) | 28 days | 
| Number of Patients With Serum Chemistry Laboratory Abnormalities: Uric Acid | Incidence of potentially clinically significant uric acid levels post-baseline (normal range=4-8.5 mg/dL) | 28 days | 
| Number of Patients With Serum Chemistry Laboratory Abnormalities: Cholesterol | Incidence of potentially clinically significant cholesterol levels post-baseline (normal range=0-199 mg/dL) | 28 days | 
| Number of Patients With Serum Chemistry Laboratory Abnormalities: Glucose | Incidence of potentially clinically significant glucose levels post-baseline (normal range=70-125 mg/dL) | 28 days | 
| Number of Patients With Serum Chemistry Laboratory Abnormalities: Magnesium | Incidence of potentially clinically significant magnesium levels post-baseline (normal range=1.2-2 mEq/L) | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: QT >500 Milliseconds (Msec) | Incidence of potentially clinically significant ECG abnormalities (QT>500 msec) post-baseline | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: QRS Interval | Incidence of potentially clinically significant ECG abnormalities involving QRS interval (change > 100 msec) | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcB Increase 30-60 Msec | Incidence of potentially clinically significant ECG abnormalities (QTcB increase 30-60 msec) | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcF Increase 30-60 Msec | Incidence of potentially clinically significant ECG abnormalities (QTcF increase 30-60 msec post-baseline) | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: ST Segment | Incidence of potentially clinically significant ECG abnormalities: ST Segment | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: T Wave | Incidence of potentially clinically significant ECG abnormalities: T wave | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: Right Bundle Branch Block (RBBB), Left Bundle Branch Block (LBBB), Myocardial Infarction (MI) | Incidence of potentially clinically significant ECG abnormalities: Right bundle branch block (RBBB), Left bundle branch block (LBBB), myocardial infarction (MI) | 28 days | 
| Number of Patients With Electrocardiogram (ECG) Abnormalities: Arrhythmia | Incidence of potentially clinically significant ECG abnormalities: arrhythmia | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyponatremia, Cognitive, Neurological Function, Elderly