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Completed

NCT Number: NCT00550459

Effects of Titrated Oral Tolvaptan 15-60 mg Once Daily (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.

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Key information

Conditions

Hyponatremia Metabolic Diseases Nutritional and Metabolic Diseases Water-Electrolyte Imbalance

Age range

50 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Sarah. S. Olelewe, MD, Hawthorne, California, United States

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About this study

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).

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Tolvaptan

Drug

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

Other names: OPC-41061

Placebo

Drug

Placebo tablet given once daily for 21 days

Primary outcomes

  1. Change From Baseline in the Neurocognitive Composite Score of Speed Domains (NCS-SD; Sum of All Correct Speed Domain Z-Scores)

    Time frame: baseline and Day 22

    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

Secondary outcomes

  1. Change From Baseline to Day 22 in the Individual Neurocognitive Domains Included in the Primary Endpoint: Reaction Time in Computer Tests

    Time frame: baseline and Day 22

    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

  2. Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Psychomotor Speed Via Morse Tapping Test

    Time frame: baseline and Day 22

    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

  3. 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

    Time frame: baseline and Day 22

    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

  4. Change From Baseline in Overall Neurocognitive Composite Score

    Time frame: baseline and Day 22

    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

  5. Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)

    Time frame: baseline and Day 22

    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

  6. Change From Baseline in Postural Stability Test

    Time frame: baseline and Day 22

    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

  7. Change From Baseline in Serum Sodium; ITT Population

    Time frame: Baseline and Day 22

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

  8. Number of Patients With Vital Sign Abnormalities: Blood Pressure

    Time frame: 28 days

    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)

  9. Number of Patients With Vital Sign Abnormalities: Pulse Rate

    Time frame: 28 days

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

  10. Number of Patients With Vital Sign Abnormalities: Body Weight

    Time frame: 28 days

    Incidence of clinically significant body weight change post-baseline (defined as change upward or downward of >=7%)

  11. Number of Patients With Vital Sign Abnormalities: Body Temperature

    Time frame: 28 days

    Incidence of potentially clinically significant changes in body temperature post-baseline (defined as an increase of >=1.1 to >=38.3 degrees Celsius)

  12. Number of Patients With Hematology Laboratory Abnormalities: Hemoglobin

    Time frame: 28 days

    Incidence of clinically significant hemoglobin abnormalities post-baseline (normal range=11.8-16.8 g/dL)

  13. Number of Patients With Hematology Laboratory Abnormalities: Activated Partial Thromboplastin Time (aPTT)

    Time frame: 28 days

    Incidence of potentially clinically significant Activated Partial Thromboplastin Time (aPTT) levels post-baseline (normal range=22-34 seconds)

  14. Number of Patients With Hematology Laboratory Abnormalities: Lymphocytes

    Time frame: 28 days

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

  15. Number of Patients With Hematology Laboratory Abnormalities: Neutrophils

    Time frame: 28 days

    Incidence of potentially clinically significant neutrophil count post-baseline (normal range=1.8-8 thousands/microliter)

  16. Number of Patients With Serum Chemistry Laboratory Abnormalities: Blood Urea Nitrogen (BUN)

    Time frame: 28 days

    Incidence of potentially clinically significant BUN levels post-baseline (normal range=7-30 mg/dL)

  17. Number of Patients With Serum Chemistry Laboratory Abnormalities: Uric Acid

    Time frame: 28 days

    Incidence of potentially clinically significant uric acid levels post-baseline (normal range=4-8.5 mg/dL)

  18. Number of Patients With Serum Chemistry Laboratory Abnormalities: Cholesterol

    Time frame: 28 days

    Incidence of potentially clinically significant cholesterol levels post-baseline (normal range=0-199 mg/dL)

  19. Number of Patients With Serum Chemistry Laboratory Abnormalities: Glucose

    Time frame: 28 days

    Incidence of potentially clinically significant glucose levels post-baseline (normal range=70-125 mg/dL)

  20. Number of Patients With Serum Chemistry Laboratory Abnormalities: Magnesium

    Time frame: 28 days

    Incidence of potentially clinically significant magnesium levels post-baseline (normal range=1.2-2 mEq/L)

  21. Number of Patients With Electrocardiogram (ECG) Abnormalities: QT >500 Milliseconds (Msec)

    Time frame: 28 days

    Incidence of potentially clinically significant ECG abnormalities (QT>500 msec) post-baseline

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

    Time frame: 28 days

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

  23. Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcB Increase 30-60 Msec

    Time frame: 28 days

    Incidence of potentially clinically significant ECG abnormalities (QTcB increase 30-60 msec)

  24. Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcF Increase 30-60 Msec

    Time frame: 28 days

    Incidence of potentially clinically significant ECG abnormalities (QTcF increase 30-60 msec post-baseline)

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

    Time frame: 28 days

    Incidence of potentially clinically significant ECG abnormalities: ST Segment

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

    Time frame: 28 days

    Incidence of potentially clinically significant ECG abnormalities: T wave

  27. Number of Patients With Electrocardiogram (ECG) Abnormalities: Right Bundle Branch Block (RBBB), Left Bundle Branch Block (LBBB), Myocardial Infarction (MI)

    Time frame: 28 days

    Incidence of potentially clinically significant ECG abnormalities: Right bundle branch block (RBBB), Left bundle branch block (LBBB), myocardial infarction (MI)

  28. Number of Patients With Electrocardiogram (ECG) Abnormalities: Arrhythmia

    Time frame: 28 days

    Incidence of potentially clinically significant ECG abnormalities: arrhythmia

Sponsors and collaborators

Lead sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc.

Industry

Collaborators

  • Otsuka Pharmaceutical Co., Ltd.

Registry information

Official study title

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

Acronym: INSIGHT

Important dates

Study start
2007
Primary completion
2009
Study completion
2009
First posted
Oct 29, 2007
Registry last updated
Apr 28, 2011

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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