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

This study has been completed.
Sponsor:
Collaborator:
Otsuka Pharmaceutical Co., Ltd.
Information provided by:
Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:
NCT00550459
First received: October 25, 2007
Last updated: April 26, 2011
Last verified: April 2011
  Purpose

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


Condition Intervention Phase
Hyponatremia
Drug: Tolvaptan
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in Overall Neurocognitive Composite Score [ Time Frame: baseline and Day 22 ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in Gait Test (Timed Get-Up-and-Go Test) [ Time Frame: baseline and Day 22 ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in Postural Stability Test [ Time Frame: baseline and Day 22 ] [ Designated as safety issue: No ]
    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

  • Change From Baseline in Serum Sodium; ITT Population [ Time Frame: Baseline and Day 22 ] [ Designated as safety issue: No ]
    Change from Baseline to Day 22 in Serum Sodium; ITT population

  • Number of Patients With Vital Sign Abnormalities: Blood Pressure [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    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)

  • Number of Patients With Vital Sign Abnormalities: Pulse Rate [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of abnormal pulse rate post-baseline [abnormal values: >=120 beats per minute (bpm) + increase of >=15 bpm; <=50 bpm + decrease of >=15 bpm]

  • Number of Patients With Vital Sign Abnormalities: Body Weight [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of clinically significant body weight change post-baseline (defined as change upward or downward of >=7%)

  • Number of Patients With Vital Sign Abnormalities: Body Temperature [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant changes in body temperature post-baseline (defined as an increase of >=1.1 to >=38.3 degrees Celsius)

  • Number of Patients With Hematology Laboratory Abnormalities: Hemoglobin [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of clinically significant hemoglobin abnormalities post-baseline (normal range=11.8-16.8 g/dL)

  • Number of Patients With Hematology Laboratory Abnormalities: Activated Partial Thromboplastin Time (aPTT) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant Activated Partial Thromboplastin Time (aPTT) levels post-baseline (normal range=22-34 seconds)

  • Number of Patients With Hematology Laboratory Abnormalities: Lymphocytes [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant lymphocyte count post-baseline (normal range = 16-46%)

  • Number of Patients With Hematology Laboratory Abnormalities: Neutrophils [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant neutrophil count post-baseline (normal range=1.8-8 thousands/microliter)

  • Number of Patients With Serum Chemistry Laboratory Abnormalities: Blood Urea Nitrogen (BUN) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant BUN levels post-baseline (normal range=7-30 mg/dL)

  • Number of Patients With Serum Chemistry Laboratory Abnormalities: Uric Acid [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant uric acid levels post-baseline (normal range=4-8.5 mg/dL)

  • Number of Patients With Serum Chemistry Laboratory Abnormalities: Cholesterol [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant cholesterol levels post-baseline (normal range=0-199 mg/dL)

  • Number of Patients With Serum Chemistry Laboratory Abnormalities: Glucose [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant glucose levels post-baseline (normal range=70-125 mg/dL)

  • Number of Patients With Serum Chemistry Laboratory Abnormalities: Magnesium [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant magnesium levels post-baseline (normal range=1.2-2 mEq/L)

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: QT >500 Milliseconds (Msec) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities (QT>500 msec) post-baseline

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: QRS Interval [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities involving QRS interval (change > 100 msec)

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcB Increase 30-60 Msec [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities (QTcB increase 30-60 msec)

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcF Increase 30-60 Msec [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities (QTcF increase 30-60 msec post-baseline)

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: ST Segment [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities: ST Segment

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: T Wave [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities: T wave

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: Right Bundle Branch Block (RBBB), Left Bundle Branch Block (LBBB), Myocardial Infarction (MI) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities: Right bundle branch block (RBBB), Left bundle branch block (LBBB), myocardial infarction (MI)

  • Number of Patients With Electrocardiogram (ECG) Abnormalities: Arrhythmia [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Incidence of potentially clinically significant ECG abnormalities: arrhythmia


Enrollment: 57
Study Start Date: August 2007
Study Completion Date: March 2009
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 1
Placebo tablet given once a day for 21 days
Drug: Placebo
Placebo tablet given once daily for 21 days
Active Comparator: 2
Tolvaptan 15 mg-60 mg tablet given once a day for 21 days.
Drug: Tolvaptan
15-60 mg oral tablet given once a day for 21 days.
Other Name: OPC-41061

Detailed Description:

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).

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00550459

Locations
United States, California
Sarah. S. Olelewe, MD
Hawthorne, California, United States, 90250
Progressive Clinical Research
Vista, California, United States, 92083
United States, Colorado
Pikes Peak Cardiology
Colorado Springs, Colorado, United States, 80907
United States, Florida
Innovative Research of West FL
Largo, Florida, United States, 33770
Coastal Nephrology Assoc. Research Center
Punta Gorda, Florida, United States, 33950
United States, Georgia
Rockdale Medical Research Associates
Conyers, Georgia, United States, 30094
United States, Louisiana
Otis Barnum, DO
Natchitoches, Louisiana, United States, 71457
United States, North Dakota
Lillestol Research, LLC
Fargo, North Dakota, United States, 58106
United States, South Carolina
Carolina Research Associates
Columbia, South Carolina, United States, 29201
United States, Tennessee
Wayne O. Wells, MD
Lebanon, Tennessee, United States, 37087
United States, Texas
Memorial Clinical Associates
Houston, Texas, United States, 77043
United States, Virginia
Mitchell Rosner, MD
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Otsuka Pharmaceutical Co., Ltd.
Investigators
Principal Investigator: Joseph Verbalis, MD Georgetown University, Washington, DC, 20007 USA
  More Information

No publications provided

Responsible Party: Dorothee Oberdhan, Manager, Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT00550459     History of Changes
Other Study ID Numbers: 156-04-246, INSIGHT
Study First Received: October 25, 2007
Results First Received: August 5, 2010
Last Updated: April 26, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Hyponatremia
Cognitive
Neurological Function
Elderly

Additional relevant MeSH terms:
Hyponatremia
Metabolic Diseases
Water-Electrolyte Imbalance

ClinicalTrials.gov processed this record on October 22, 2014