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

Otsuka Pharmaceutical Development & Commercialization, Inc.57 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Hyponatremia

Interventions

TolvaptanDRUG

15-60 mg oral tablet given once a day for 21 days.

PlaceboDRUG

Placebo tablet given once daily for 21 days

Eligibility

Sex: ALLMin age: 50 Years

Medical Language ↔ Plain English

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.

Locations (12)

Sarah. S. Olelewe, MD

Hawthorne, California, United States

Progressive Clinical Research

Vista, California, United States

Pikes Peak Cardiology

Colorado Springs, Colorado, United States

Outcomes

Primary Outcomes

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

Time frame: baseline and Day 22

Secondary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: baseline and Day 22

Data from ClinicalTrials.gov

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Innovative Research of West FL

Largo, Florida, United States

Coastal Nephrology Assoc. Research Center

Punta Gorda, Florida, United States

Rockdale Medical Research Associates

Conyers, Georgia, United States

Otis Barnum, DO

Natchitoches, Louisiana, United States

Lillestol Research, LLC

Fargo, North Dakota, United States

Carolina Research Associates

Columbia, South Carolina, United States

Wayne O. Wells, MD

Lebanon, Tennessee, United States

...and 2 more locations

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

Time frame: 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

Time frame: 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

Time frame: baseline and Day 22

Change From Baseline in Serum Sodium; ITT Population

Change from Baseline to Day 22 in Serum Sodium; ITT population

Time frame: 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)

Time frame: 28 days

Number of Patients With Vital Sign Abnormalities: Pulse Rate

Incidence of abnormal pulse rate post-baseline \[abnormal values: \>=120 beats per minute (bpm) + increase of \>=15 bpm; \<=50 bpm + decrease of \>=15 bpm\]

Time frame: 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%)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 28 days

Number of Patients With Hematology Laboratory Abnormalities: Lymphocytes

Incidence of potentially clinically significant lymphocyte count post-baseline (normal range = 16-46%)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: 28 days

Number of Patients With Electrocardiogram (ECG) Abnormalities: QRS Interval

Incidence of potentially clinically significant ECG abnormalities involving QRS interval (change \> 100 msec)

Time frame: 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)

Time frame: 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)

Time frame: 28 days

Number of Patients With Electrocardiogram (ECG) Abnormalities: ST Segment

Incidence of potentially clinically significant ECG abnormalities: ST Segment

Time frame: 28 days

Number of Patients With Electrocardiogram (ECG) Abnormalities: T Wave

Incidence of potentially clinically significant ECG abnormalities: T wave

Time frame: 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)

Time frame: 28 days

Number of Patients With Electrocardiogram (ECG) Abnormalities: Arrhythmia

Incidence of potentially clinically significant ECG abnormalities: arrhythmia

Time frame: 28 days