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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00550459

Acronym

INSIGHT

Enrollment

Registered

2007-10-29

Start date

2007-08-31

Completion date

2009-03-31

Last updated

2011-04-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hyponatremia

Keywords

Hyponatremia, Cognitive, Neurological Function, Elderly

Brief summary

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

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).

Interventions

DRUGTolvaptan

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

DRUGPlacebo

Placebo tablet given once daily for 21 days

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

50 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline in the Neurocognitive Composite Score of Speed Domains (NCS-SD; Sum of All Correct Speed Domain Z-Scores)	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

Measure	Time frame	Description
Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Psychomotor Speed Via Morse Tapping Test	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
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	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
Change From Baseline in Overall Neurocognitive Composite Score	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
Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)	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
Change From Baseline in Postural Stability Test	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
Change From Baseline in Serum Sodium; ITT Population	Baseline and Day 22	Change from Baseline to Day 22 in Serum Sodium; ITT population
Number of Patients With Vital Sign Abnormalities: Blood Pressure	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)
Number of Patients With Vital Sign Abnormalities: Pulse Rate	28 days	Incidence of abnormal pulse rate post-baseline \[abnormal values: \>=120 beats per minute (bpm) + increase of \>=15 bpm; \<=50 bpm + decrease of \>=15 bpm\]
Number of Patients With Vital Sign Abnormalities: Body Weight	28 days	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	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)
Number of Patients With Hematology Laboratory Abnormalities: Hemoglobin	28 days	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)	28 days	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	28 days	Incidence of potentially clinically significant lymphocyte count post-baseline (normal range = 16-46%)
Change From Baseline to Day 22 in the Individual Neurocognitive Domains Included in the Primary Endpoint: Reaction Time in Computer Tests	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
Number of Patients With Serum Chemistry Laboratory Abnormalities: Blood Urea Nitrogen (BUN)	28 days	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	28 days	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	28 days	Incidence of potentially clinically significant cholesterol levels post-baseline (normal range=0-199 mg/dL)
Number of Patients With Serum Chemistry Laboratory Abnormalities: Glucose	28 days	Incidence of potentially clinically significant glucose levels post-baseline (normal range=70-125 mg/dL)
Number of Patients With Serum Chemistry Laboratory Abnormalities: Magnesium	28 days	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)	28 days	Incidence of potentially clinically significant ECG abnormalities (QT\>500 msec) post-baseline
Number of Patients With Electrocardiogram (ECG) Abnormalities: QRS Interval	28 days	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	28 days	Incidence of potentially clinically significant ECG abnormalities (QTcB increase 30-60 msec)
Number of Patients With Electrocardiogram (ECG) Abnormalities: QTcF Increase 30-60 Msec	28 days	Incidence of potentially clinically significant ECG abnormalities (QTcF increase 30-60 msec post-baseline)
Number of Patients With Electrocardiogram (ECG) Abnormalities: ST Segment	28 days	Incidence of potentially clinically significant ECG abnormalities: ST Segment
Number of Patients With Electrocardiogram (ECG) Abnormalities: T Wave	28 days	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)	28 days	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	28 days	Incidence of potentially clinically significant ECG abnormalities: arrhythmia
Number of Patients With Hematology Laboratory Abnormalities: Neutrophils	28 days	Incidence of potentially clinically significant neutrophil count post-baseline (normal range=1.8-8 thousands/microliter)

Countries

United States

Participant flow

Recruitment details

16 United States (US) sites/clinics; first subject signed informed consent on 9/11/07; last subject's final visit on 12/16/08

Participants by arm

Arm	Count
Placebo Placebo tablet given once daily for 21 days	28
Tolvaptan (15-60 mg) Tolvaptan tablet 15-60 mg given once daily for 21 days	29
Total	57

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	2
Overall Study	Withdrawal by Subject	1	1

Baseline characteristics

Characteristic	Tolvaptan (15-60 mg)	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	23 Participants	22 Participants	45 Participants
Age, Categorical Between 18 and 65 years	6 Participants	6 Participants	12 Participants
Age Continuous	71.1 years STANDARD_DEVIATION 10.2	71.3 years STANDARD_DEVIATION 9.7	71.2 years STANDARD_DEVIATION 9.9
Region of Enrollment United States	29 participants	28 participants	57 participants
Sex: Female, Male Female	15 Participants	19 Participants	34 Participants
Sex: Female, Male Male	14 Participants	9 Participants	23 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	13 / 28	17 / 29
serious Total, serious adverse events	1 / 28	2 / 29

Outcome results

Primary

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

Population: Analysis based upon observed cases (OC).

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in the Neurocognitive Composite Score of Speed Domains (NCS-SD; Sum of All Correct Speed Domain Z-Scores)	0.20 Z-score	Standard Deviation 0.61
Tolvaptan (15-60 mg)	Change From Baseline in the Neurocognitive Composite Score of Speed Domains (NCS-SD; Sum of All Correct Speed Domain Z-Scores)	0.39 Z-score	Standard Deviation 0.49

Comparison: Analysis of covariance (ANCOVA) with factors of treatment,disease severity (\<130mEq/L \[mmol/L\] or ≥130mEq/L \[mmol/L\] at baseline),age (\<65, ≥65 to \<75,and ≥75 years) (factor with 6 Degrees of Freedom), and covariate baseline used to fit primary endpoint using the intent-to-treat (ITT) dataset. Estimated treatment effect and its 95% confidence interval (CI) provided under the model with p-value. A 2-sided alpha (0.05) applied to the primary analysis. Primary analysis based on observed cases (OC).p-value: 0.0895% CI: [-0.03, 0.5]ANCOVA

Secondary

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

Population: ITT population with OC

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)	1.06 Seconds	Standard Deviation 5.63
Tolvaptan (15-60 mg)	Change From Baseline in Gait Test (Timed Get-Up-and-Go Test)	-0.43 Seconds	Standard Deviation 1.54

Comparison: 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.p-value: 0.2395% CI: [-4.02, 1]ANCOVA

Secondary

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

Population: ITT population with OC

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Overall Neurocognitive Composite Score	0.19 Z-score	Standard Deviation 0.39
Tolvaptan (15-60 mg)	Change From Baseline in Overall Neurocognitive Composite Score	0.30 Z-score	Standard Deviation 0.39

Secondary

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

Population: ITT population with LOCF (this group includes missing values)

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Postural Stability Test	1.3 Z-score	Standard Deviation 4.68
Tolvaptan (15-60 mg)	Change From Baseline in Postural Stability Test	-0.35 Z-score	Standard Deviation 2.33

Secondary

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

Population: ITT population with OC

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in Serum Sodium; ITT Population	2.23 mEq/L	Standard Deviation 3.51
Tolvaptan (15-60 mg)	Change From Baseline in Serum Sodium; ITT Population	7.04 mEq/L	Standard Deviation 3.39

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

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

Population: ITT population with OC

Arm	Measure	Value (MEAN)	Dispersion
Placebo	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	0.24 Z-score	Standard Deviation 0.75
Tolvaptan (15-60 mg)	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	0.48 Z-score	Standard Deviation 0.91

Secondary

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

Population: ITT population with OC

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Psychomotor Speed Via Morse Tapping Test	0.04 Z-score	Standard Deviation 0.36
Tolvaptan (15-60 mg)	Change From Baseline in the Individual Neurocognitive Domains Included in the Primary Endpoint: Psychomotor Speed Via Morse Tapping Test	0.31 Z-score	Standard Deviation 0.46

Secondary

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

Population: ITT population with OC

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Change From Baseline to Day 22 in the Individual Neurocognitive Domains Included in the Primary Endpoint: Reaction Time in Computer Tests	0.21 Z-score	Standard Deviation 0.86
Tolvaptan (15-60 mg)	Change From Baseline to Day 22 in the Individual Neurocognitive Domains Included in the Primary Endpoint: Reaction Time in Computer Tests	0.33 Z-score	Standard Deviation 0.41

Secondary