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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
History of Changes
Results First Received: August 5, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Hyponatremia
Interventions: Drug: Tolvaptan
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
16 United States (US) sites/clinics; first subject signed informed consent on 9/11/07; last subject's final visit on 12/16/08

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Placebo Placebo tablet given once daily for 21 days
Tolvaptan (15-60 mg) Tolvaptan tablet 15-60 mg given once daily for 21 days

Participant Flow:   Overall Study
    Placebo     Tolvaptan (15-60 mg)  
STARTED     28     29  
COMPLETED     27     26  
NOT COMPLETED     1     3  
Adverse Event                 0                 2  
Withdrawal by Subject                 1                 1  



  Baseline Characteristics
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Reporting Groups
  Description
Placebo Placebo tablet given once daily for 21 days
Tolvaptan (15-60 mg) Tolvaptan tablet 15-60 mg given once daily for 21 days
Total Total of all reporting groups

Baseline Measures
    Placebo     Tolvaptan (15-60 mg)     Total  
Number of Participants  
[units: participants]
 		  28     29     57  
Age  
[units: participants]
 		     
<=18 years     0     0     0  
Between 18 and 65 years     6     6     12  
>=65 years     22     23     45  
Age  
[units: years]
Mean ± Standard Deviation 		  71.3  ± 9.7     71.1  ± 10.2     71.2  ± 9.9  
Gender  
[units: participants]
 		     
Female     19     15     34  
Male     9     14     23  
Region of Enrollment  
[units: participants]
 		     
United States     28     29     57  



  Outcome Measures
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1.  Primary:   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 ]
  Show Outcome Measure 1

2.  Secondary:   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 ]
  Show Outcome Measure 2

3.  Secondary:   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 ]
  Show Outcome Measure 3

4.  Secondary:   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 ]
  Show Outcome Measure 4

5.  Secondary:   Change From Baseline in Overall Neurocognitive Composite Score   [ Time Frame: baseline and Day 22 ]
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6.  Secondary:   Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)   [ Time Frame: baseline and Day 22 ]
  Hide Outcome Measure 6

Measure Type Secondary
Measure Title Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)
Measure Description 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  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
ITT population with OC

Reporting Groups
  Description
Placebo Placebo tablet given once daily for 21 days
Tolvaptan (15-60 mg) Tolvaptan tablet 15-60 mg given once daily for 21 days

Measured Values
    Placebo     Tolvaptan (15-60 mg)  
Number of Participants Analyzed  
[units: participants]
 		  26     23  
Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)  
[units: Seconds]
Mean ± Standard Deviation 		  1.06  ± 5.63     -0.43  ± 1.54  


Statistical Analysis 1 for Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.23
Median Difference (Final Values) [4] -1.51
Standard Deviation ± 3.53
95% Confidence Interval ( -4.02 to 1.00 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Per-protocol, secondary endpoints were ordered in 5 tiers and were to be analyzed only when at least 1 of the endpoints in the previous tier was significant. As the primary endpoint was not statistically significant, the analyses of subsequent secondary endpoint tiers are presented for exploratory purposes only.
[2] Other relevant information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  ANCOVA with factors of treatment, disease severity, age, and severity by age interaction, and baseline as covariate. The estimated treatment and its 95% CI were provided under the model along with the p-value.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   Change From Baseline in Postural Stability Test   [ Time Frame: baseline and Day 22 ]
  Show Outcome Measure 7

8.  Secondary:   Change From Baseline in Serum Sodium; ITT Population   [ Time Frame: Baseline and Day 22 ]
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9.  Secondary:   Number of Patients With Vital Sign Abnormalities: Blood Pressure   [ Time Frame: 28 days ]
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10.  Secondary:   Number of Patients With Vital Sign Abnormalities: Pulse Rate   [ Time Frame: 28 days ]
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11.  Secondary:   Number of Patients With Vital Sign Abnormalities: Body Weight   [ Time Frame: 28 days ]
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12.  Secondary:   Number of Patients With Vital Sign Abnormalities: Body Temperature   [ Time Frame: 28 days ]
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13.  Secondary:   Number of Patients With Hematology Laboratory Abnormalities: Hemoglobin   [ Time Frame: 28 days ]
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14.  Secondary:   Number of Patients With Hematology Laboratory Abnormalities: Activated Partial Thromboplastin Time (aPTT)   [ Time Frame: 28 days ]
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15.  Secondary:   Number of Patients With Hematology Laboratory Abnormalities: Lymphocytes   [ Time Frame: 28 days ]
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16.  Secondary:   Number of Patients With Hematology Laboratory Abnormalities: Neutrophils   [ Time Frame: 28 days ]
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17.  Secondary:   Number of Patients With Serum Chemistry Laboratory Abnormalities: Blood Urea Nitrogen (BUN)   [ Time Frame: 28 days ]
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18.  Secondary:   Number of Patients With Serum Chemistry Laboratory Abnormalities: Uric Acid   [ Time Frame: 28 days ]
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19.  Secondary:   Number of Patients With Serum Chemistry Laboratory Abnormalities: Cholesterol   [ Time Frame: 28 days ]
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20.  Secondary:   Number of Patients With Serum Chemistry Laboratory Abnormalities: Glucose   [ Time Frame: 28 days ]
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21.  Secondary:   Number of Patients With Serum Chemistry Laboratory Abnormalities: Magnesium   [ Time Frame: 28 days ]
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22.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: QT >500 Milliseconds (Msec)   [ Time Frame: 28 days ]
  Show Outcome Measure 22

23.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: QRS Interval   [ Time Frame: 28 days ]
  Show Outcome Measure 23

24.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcB Increase 30-60 Msec   [ Time Frame: 28 days ]
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25.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcF Increase 30-60 Msec   [ Time Frame: 28 days ]
  Show Outcome Measure 25

26.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: ST Segment   [ Time Frame: 28 days ]
  Show Outcome Measure 26

27.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: T Wave   [ Time Frame: 28 days ]
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28.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: Right Bundle Branch Block (RBBB), Left Bundle Branch Block (LBBB), Myocardial Infarction (MI)   [ Time Frame: 28 days ]
  Show Outcome Measure 28

29.  Secondary:   Number of Patients With Electrocardiogram (ECG) Abnormalities: Arrhythmia   [ Time Frame: 28 days ]
  Show Outcome Measure 29


  Serious Adverse Events
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  Other Adverse Events
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Pilot study powered only for serum Na+ improvements. Trial lacked sufficient power to detect changes in neurocognitive test scores and SF-12 and HDS outcomes.  


Results Point of Contact:  
Name/Title: Frank Czerwiec, MD, PhD; Sr. Director, Global Clinical Development
Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
phone: (240) 683-3523
e-mail: frank.czerwiec@otsuka.com


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