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SENIOR: A Study to Compare Two Medications With an Inactive Medication and Look at the Effect on a Person's Mental Ability

Sponsor
Astellas Pharma Inc (Industry)
Overall Status
Completed
CT.gov ID
NCT01126424
Collaborator
(none)
26
Enrollment
3
Locations
3
Arms
8
Duration (Months)
8.7
Patients Per Site
1.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose is to compare solifenacin and oxybutynin with an inactive tablet and assess any potential effects on mental ability.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

All subjects will receive each intervention during the course of the study. Subjects will complete a 21-day washout period between treatment periods and following last treatment period.

Study Design

Study Type:
Interventional
Actual Enrollment :
26 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Official Title:
A Study to Compare the Cognitive Effect of Solifenacin 5mg Once-daily and Oxybutynin 5mg Twice-daily After Chronic Dosing Versus Placebo in Subjects 75 Years and Over With Mild Cognitive Impairment - A Double-blind, Randomized, Multi-center Study
Study Start Date :
Apr 1, 2010
Actual Primary Completion Date :
Dec 1, 2010
Actual Study Completion Date :
Dec 1, 2010

Arms and Interventions

Arm Intervention/Treatment
Experimental: Solifenacin

Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day.

Drug: Solifenacin
tablet
Other Names:
  • YM905

    		•
    Active Comparator: Oxybutynin

    Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form.

    Drug: Oxybutynin
    capsule
    Placebo Comparator: Placebo

    Participants received 21 days of treatment with placebo.

    Drug: Placebo
    tablet

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Cognitive Function Composite Score - Power of Attention [Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.]

      Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration (Tmax) for solifenacin (6 hours) and oxybutynin (2 hours). Power of attention is calculated from the sum of three cognitive function speed tests: Simple Reaction Time, Choice Reaction Time and the Speed of Detections in Digit Vigilance task. A low score reflects a fast reaction time and a high intensity of concentration. A positive change from baseline reflects impairment compared to the baseline assessment.

    2. Change From Baseline in Cognitive Function Composite Score - Continuity of Attention [Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.]

      Cognitive effects were assessed using a computerized assessment system at time points close to the predicted time of maximum plasma concentration for solifenacin and oxybutynin. For continuity of attention, the number of correct responses (out of 50) for choice reaction time was added to the total number of targets correctly identified (out of 45) digit vigilance minus the number of false alarms (total score of -45 to 95). A high score reflects someone able to keep his/her mind on a single task for a prolonged period. A negative change from baseline reflects impairment compared to baseline.

    3. Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory [Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.]

      Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration (Tmax) for solifenacin (6 hours) and oxybutynin (2 hours). Quality of working memory is calculated from the sum of two cognitive function sensitivity tests: Numeric Working Memory Sensitivity and Spatial Working Memory Sensitivity, and ranges from -2 to 2. A higher score reflects a good working memory and a negative change from baseline reflects impairment compared to the baseline assessment.

    4. Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory [Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.]

      Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time of maximum plasma concentration for solifenacin and oxybutynin. Quality of episodic secondary memory is calculated from the sum of 4 tests: Immediate and delayed word recall, and word and picture recognition, and ranges from -200 to 400. A high score reflects a good ability to store, hold and retrieve information of an episodic nature (i.e. an event or a name) and a negative change from baseline reflects impairment compared to baseline.

    5. Change From Baseline in Cognitive Function Composite Score - Speed of Memory [Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.]

      Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration for solifenacin and oxybutynin. Speed of Memory was calculated from the sum of 4 cognitive function speed tests: numeric and spatial working memory and word and picture recognition. A low score reflects that a person is able to recall a name, a face or any other item fast from the episodic secondary memory; a positive change from baseline reflects impairment compared to baseline.

    Secondary Outcome Measures

    1. Change From Baseline in Postural Stability Test [Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.]

      The postural stability test measures the ability to stand upright without moving, and was assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration for solifenacin and oxybutynin. Using apparatus modeled on the Wright Ataxia-meter, a cord from the meter is attached to the patient who is required to stand as still as possible with feet apart and eyes closed for 1 minute. The amount of sway is expressed as the total angular movement, summed regardless of sign, in the antero-posterior plane and calibrated in units of one-third degree of angle of sway. Wright (1971) described a range of 20-30 units as a normal range for adults with eyes wide open, increasing by 50 to 100% with eyes shut.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    75 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes
    Inclusion Criteria:

    • The subject has mild cognitive impairment as determined by mini-mental state examination (MMSE) ≥ grade 24

    • The subject conforms to the Stockholm criteria for mild cognitive impairment as assessed by the investigator

    • The subject has a body mass index (BMI) between 18.0 to 30.0 kg/m2 inclusive

    • The subject is available to complete the study

    Exclusion Criteria:

    • The subject has moderate or severe cognitive impairment as determined by MMSE criteria at screening, ≤ grade 23

    • The subject has depression as determined by Geriatric Depression Scale (GDS) short form ≥ 5 at screening

    • The subject has a history of urinary retention, severe gastrointestinal obstruction (including paralytic ileus or intestinal atony or toxic megacolon or severe ulcerative colitis), myasthenia gravis, uncontrolled narrow angle glaucoma or shallow anterior chamber or deemed to be at risk for these conditions

    • The subject is undergoing hemodialysis or has severe renal impairment or moderate hepatic impairment and who are on treatment with a potent CYP3A4 inhibitor, e.g. Ketoconazole

    • The subject has uncontrolled diabetes mellitus

    • The subject has a positive pre-study hepatitis B surface antigen, hepatitis C antibody or HIV result at time of screening

    • The subject has a history of drug and / or alcohol abuse at time of screening

    • The subject has an average weekly alcohol intake of greater than 21 units (male) or 14 units (female) within ≤ 3 months prior to screening (1 unit is 270cc of beer, 40cc of spirits or 125cc of wine)

    • The subject has a history of smoking more than 10 cigarettes (or the equivalent amount of tobacco) per day within ≤ 3 months prior to screening

    • The subject has a history of known or suspected hypersensitivity to solifenacin succinate, oxybutynin hydrochloride, other anti-cholinergics or lactose, to any component of the dosage form

    • The subject has taken any unstable doses of prescribed medication within ≤ 1 month prior to screening or over-the-counter medicine (including vitamins and herbal remedies) within 48 hours prior to the first study day, which in the opinion of the Investigator, will interfere with the study procedures or compromise safety

    • The subject is currently dosing with medication(s) intended to treat overactive bladder symptoms or has history of non-drug treatment intended to treat overactive bladder symptoms within ≤ 3 months prior to screening

    • The subject has any clinically significant abnormality following Investigator review of the physical examination

    • The subject has any clinically significant abnormality following the Investigator's review of the ECG

    • The subject has mobility impairment that precludes the assessment of postural stability

    • The subject has any clinically significant abnormal heart rate or blood pressure measurements, at the screening visit (dBP > 90mmHg, sBP > 160mmHg or HR < 40bpm or > 100bpm)

    • The subject has any clinically significant abnormality following Investigator's review of the biochemistry & hematology results which, in the opinion of the Investigator, contraindicates their participation

    • The subject has donated blood or plasma within ≤ 3 months prior to screening or more than 500ml or 1 unit of blood or plasma within ≤ 6 months prior to screening

    • The subject, may find it difficult to adhere to the provisions of treatment and observation specified in the protocol

    • The subject has participated in any clinical study within ≤ 3 months prior to screening

    • The subject has any clinical condition, diagnosis, symptomatology or ongoing investigation, which, contraindicates their participation

    • The subject is an employee of Astellas Pharma, Cognitive Drug Research, and any other third party related to the study site

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Blackpool Lancashire United Kingdom FY2 0JH
    2 Manchester Lancashire United Kingdom M50 2GY
    3 Bradford Yorkshire United Kingdom BD3 0DQ

    Sponsors and Collaborators

    • Astellas Pharma Inc

    Investigators

    • Study Director: Use Central Contact, Astellas Pharma Europe Ltd.

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Astellas Pharma Inc
    ClinicalTrials.gov Identifier:
    NCT01126424
    Other Study ID Numbers:
    • 905-EC-008
    • 2008-005966-29
    First Posted:
    May 19, 2010
    Last Update Posted:
    Oct 15, 2012
    Last Verified:
    Sep 1, 2012
    Keywords provided by Astellas Pharma Inc
    Anti-muscarinics
    Anti-cholinergics
    Cognition
    Solifenacin
    Additional relevant MeSH terms:
    Solifenacin Succinate
    Oxybutynin

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Solifenacin / Oxybutynin / Placebo Solifenacin / Placebo / Oxybutynin Oxybutynin / Placebo / Solifenacin Oxybutynin / Solifenacin / Placebo Placebo / Solifenacin / Oxybutynin Placebo / Oxybutynin / Solifenacin
    Arm/Group Description Participants received 21 days of each treatment in the following order: 5 mg solifenacin, 10 mg oxybutynin, placebo. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: 5 mg solifenacin, placebo, 10 mg oxybutynin. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: 10 mg oxybutynin, placebo, 5 mg solifenacin. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: 10 mg oxybutynin, 5 mg solifenacin, placebo. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: placebo, 5 mg solifenacin, 10 mg oxybutynin. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: placebo, 10 mg oxybutynin, 5 mg solifenacin. There was a 21-day washout period between each treatment period.
    Period Title: Overall Study
    STARTED 3 4 5 6 4 4
    Safety Analysis Subset 1 (SAF 1) 3 4 4 4 4 4
    COMPLETED 3 4 4 3 2 4
    NOT COMPLETED 0 0 1 3 2 0

    Baseline Characteristics

    Arm/Group Title Solifenacin / Oxybutynin / Placebo Solifenacin / Placebo / Oxybutynin Oxybutynin / Placebo / Solifenacin Oxybutynin / Solifenacin / Placebo Placebo / Solifenacin / Oxybutynin Placebo / Oxybutynin / Solifenacin Total
    Arm/Group Description Participants received 21 days of each treatment in the following order: 5 mg solifenacin, 10 mg oxybutynin, placebo. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: 5 mg solifenacin, placebo, 10 mg oxybutynin. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: 10 mg oxybutynin, placebo, 5 mg solifenacin. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: 10 mg oxybutynin, 5 mg solifenacin, placebo. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: placebo, 5 mg solifenacin, 10 mg oxybutynin. There was a 21-day washout period between each treatment period. Participants received 21 days of each treatment in the following order: placebo, 10 mg oxybutynin, 5 mg solifenacin. There was a 21-day washout period between each treatment period. Total of all reporting groups
    Overall Participants 3 4 5 6 4 4 26
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    79.7
    (3.8)
    78.8
    (2.5)
    80.2
    (4.4)
    76.7
    (2.0)
    79.3
    (2.9)
    79.0
    (4.1)
    78.8
    (3.2)
    Sex: Female, Male (Count of Participants)
    Female
    1
    33.3%
    1
    25%
    3
    60%
    3
    50%
    2
    50%
    2
    50%
    12
    46.2%
    Male
    2
    66.7%
    3
    75%
    2
    40%
    3
    50%
    2
    50%
    2
    50%
    14
    53.8%
    Race/Ethnicity, Customized (participants) [Number]
    White
    3
    100%
    4
    100%
    5
    100%
    6
    100%
    4
    100%
    4
    100%
    26
    100%
    Stockholm criteria for mild cognitive impairment (participants) [Number]
    Yes
    3
    100%
    4
    100%
    5
    100%
    6
    100%
    4
    100%
    4
    100%
    26
    100%
    No
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Total Mini-Mental State Examination (MMSE) Score (scores on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [scores on a scale]
    27.7
    (0.58)
    28.3
    (1.26)
    28.0
    (1.00)
    27.3
    (1.75)
    26.5
    (1.00)
    27.3
    (2.06)
    27.5
    (1.39)
    Total Geriatric Depression Scale (GDS) Score (scores on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [scores on a scale]
    1.0
    (1.73)
    1.0
    (0.82)
    1.4
    (1.67)
    1.0
    (0.63)
    1.3
    (0.96)
    1.8
    (1.26)
    1.2
    (1.11)

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Cognitive Function Composite Score - Power of Attention
    Description Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration (Tmax) for solifenacin (6 hours) and oxybutynin (2 hours). Power of attention is calculated from the sum of three cognitive function speed tests: Simple Reaction Time, Choice Reaction Time and the Speed of Detections in Digit Vigilance task. A low score reflects a fast reaction time and a high intensity of concentration. A positive change from baseline reflects impairment compared to the baseline assessment.
    Time Frame Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    The number of participants analyzed represents the Safety Analysis Subset 1 (SAF1), consisting of all randomized patients who took at least one dose of the study medication and who completed the cognitive function tests for at least two treatment periods. The number of participants per arm is consistent for all categories / rows of the data table.
    Arm/Group Title Solifenacin Oxybutynin Placebo
    Arm/Group Description Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day. Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form. Participants received 21 days of treatment with placebo.
    Measure Participants 22 20 22
    Baseline at 2 hours [Oxybutynin Tmax]
    1413.67
    (180.242)
    1423.38
    (186.163)
    1401.21
    (177.194)
    Change from Baseline at 2 hours
    -5.86
    (71.371)
    17.81
    (92.340)
    1.99
    (54.145)
    Baseline at 6 hours [Solifenacin Tmax]
    1421.80
    (191.303)
    1405.41
    (182.929)
    1393.98
    (189.128)
    Change from Baseline at 6 hours
    -14.80
    (87.918)
    -0.74
    (62.650)
    11.77
    (93.655)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Solifenacin, Placebo
    Comments Comparison of solifenacin versus placebo change from Baseline at 6 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3771
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -20.986
    Confidence Interval (2-Sided) 95%
    -68.580 to 26.607
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Oxybutynin, Placebo
    Comments Comparison of oxybutynin versus placebo change from Baseline at 2 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4487
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value 17.508
    Confidence Interval (2-Sided) 95%
    -28.854 to 63.870
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in Postural Stability Test
    Description The postural stability test measures the ability to stand upright without moving, and was assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration for solifenacin and oxybutynin. Using apparatus modeled on the Wright Ataxia-meter, a cord from the meter is attached to the patient who is required to stand as still as possible with feet apart and eyes closed for 1 minute. The amount of sway is expressed as the total angular movement, summed regardless of sign, in the antero-posterior plane and calibrated in units of one-third degree of angle of sway. Wright (1971) described a range of 20-30 units as a normal range for adults with eyes wide open, increasing by 50 to 100% with eyes shut.
    Time Frame Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    The number of participants analyzed represents the Safety Analysis Subset 1 (SAF1), consisting of all randomized patients who took at least one dose of the study medication and who completed the cognitive function tests for at least two treatment periods. The number of participants per arm is consistent for all categories / rows of the data table.
    Arm/Group Title Solifenacin Oxybutynin Placebo
    Arm/Group Description Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day. Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form. Participants received 21 days of treatment with placebo.
    Measure Participants 22 20 22
    Baseline at 2 hours [Oxybutynin Tmax]
    37.7
    (23.35)
    36.2
    (20.05)
    37.5
    (20.04)
    Change from Baseline at 2 hours
    5.2
    (9.65)
    2.7
    (17.04)
    0.4
    (16.81)
    Baseline at 6 hours [Solifenacin Tmax]
    37.7
    (19.42)
    38.9
    (23.59)
    40.0
    (26.19)
    Change from Baseline at 6 hours
    9.9
    (16.14)
    0.7
    (17.60)
    -0.1
    (10.64)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Solifenacin, Placebo
    Comments Comparison of solifenacin versus placebo change from Baseline at 6 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0505
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value 9.152
    Confidence Interval (2-Sided) 95%
    -0.023 to 18.326
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Oxybutynin, Placebo
    Comments Comparison of oxybutynin versus placebo change from Baseline at 2 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6753
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value 1.846
    Confidence Interval (2-Sided) 95%
    -7.020 to 10.713
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Primary Outcome
    Title Change From Baseline in Cognitive Function Composite Score - Continuity of Attention
    Description Cognitive effects were assessed using a computerized assessment system at time points close to the predicted time of maximum plasma concentration for solifenacin and oxybutynin. For continuity of attention, the number of correct responses (out of 50) for choice reaction time was added to the total number of targets correctly identified (out of 45) digit vigilance minus the number of false alarms (total score of -45 to 95). A high score reflects someone able to keep his/her mind on a single task for a prolonged period. A negative change from baseline reflects impairment compared to baseline.
    Time Frame Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    The number of participants analyzed represents the Safety Analysis Subset 1 (SAF1), consisting of all randomized patients who took at least one dose of the study medication and who completed the cognitive function tests for at least two treatment periods. The number of participants per arm is consistent for all categories / rows of the data table.
    Arm/Group Title Solifenacin Oxybutynin Placebo
    Arm/Group Description Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day. Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form. Participants received 21 days of treatment with placebo.
    Measure Participants 22 20 22
    Baseline at 2 hours [Oxybutynin Tmax]
    91.591
    (3.2462)
    91.300
    (2.5775)
    91.364
    (2.3409)
    Change from Baseline at 2 hours
    0.545
    (2.0637)
    0.150
    (3.2653)
    0.909
    (2.6168)
    Baseline at 6 hours [Solifenacin Tmax]
    91.228
    (2.0454)
    91.901
    (2.4040)
    91.728
    (3.6929)
    Change from Baseline at 6 hours
    -0.318
    (2.7143)
    0.100
    (2.7121)
    -0.045
    (3.4566)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Solifenacin, Placebo
    Comments Comparison of solifenacin versus placebo change from Baseline at 6 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5684
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -0.507
    Confidence Interval (2-Sided) 95%
    -2.293 to 1.279
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Oxybutynin, Placebo
    Comments Comparison of oxybutynin versus placebo change from Baseline at 2 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2348
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -0.792
    Confidence Interval (2-Sided) 95%
    -2.122 to 0.538
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Primary Outcome
    Title Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory
    Description Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration (Tmax) for solifenacin (6 hours) and oxybutynin (2 hours). Quality of working memory is calculated from the sum of two cognitive function sensitivity tests: Numeric Working Memory Sensitivity and Spatial Working Memory Sensitivity, and ranges from -2 to 2. A higher score reflects a good working memory and a negative change from baseline reflects impairment compared to the baseline assessment.
    Time Frame Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    The number of participants analyzed represents the Safety Analysis Subset 1 (SAF1), consisting of all randomized patients who took at least one dose of the study medication and who completed the cognitive function tests for at least two treatment periods. The number of participants per arm is consistent for all categories / rows of the data table.
    Arm/Group Title Solifenacin Oxybutynin Placebo
    Arm/Group Description Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day. Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form. Participants received 21 days of treatment with placebo.
    Measure Participants 22 20 22
    Baseline at 2 hours [Oxybutynin Tmax]
    1.7921
    (0.24313)
    1.7251
    (0.31582)
    1.7087
    (0.24215)
    Change from Baseline at 2 hours
    -0.0867
    (0.39254)
    -0.0043
    (0.35428)
    0.0492
    (0.37776)
    Baseline at 6 hours [Solifenacin Tmax]
    1.6666
    (0.35805)
    1.6441
    (0.34113)
    1.7548
    (0.35808)
    Change from Baseline at 6 hours
    0.0580
    (0.46462)
    0.0633
    (0.46684)
    0.0047
    (0.41656)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Solifenacin, Placebo
    Comments Comparison of solifenacin versus placebo change from Baseline at 6 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6275
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -0.040
    Confidence Interval (2-Sided) 95%
    -0.208 to 0.127
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Oxybutynin, Placebo
    Comments Comparison of oxybutynin versus placebo change from Baseline at 2 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5361
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -0.046
    Confidence Interval (2-Sided) 95%
    -0.194 to 0.103
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Primary Outcome
    Title Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory
    Description Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time of maximum plasma concentration for solifenacin and oxybutynin. Quality of episodic secondary memory is calculated from the sum of 4 tests: Immediate and delayed word recall, and word and picture recognition, and ranges from -200 to 400. A high score reflects a good ability to store, hold and retrieve information of an episodic nature (i.e. an event or a name) and a negative change from baseline reflects impairment compared to baseline.
    Time Frame Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    The number of participants analyzed represents the Safety Analysis Subset 1 (SAF1), consisting of all randomized patients who took at least one dose of the study medication and who completed the cognitive function tests for at least two treatment periods. The number of participants per arm is consistent for all categories / rows of the data table.
    Arm/Group Title Solifenacin Oxybutynin Placebo
    Arm/Group Description Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day. Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form. Participants received 21 days of treatment with placebo.
    Measure Participants 22 20 22
    Baseline at 2 hours [Oxybutynin Tmax]
    111.893636
    (48.525110)
    107.666333
    (55.168759)
    110.000152
    (51.736947)
    Change from Baseline at 2 hours
    -3.788636
    (35.609118)
    -0.917833
    (28.198821)
    0.531515
    (42.576179)
    Baseline at 6 hours [Solifenacin Tmax]
    101.363485
    (44.919411)
    104.917167
    (50.380503)
    106.515000
    (45.147568)
    Change from Baseline at 6 hours
    7.728182
    (30.836915)
    -3.502000
    (48.822365)
    1.589394
    (35.687431)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Solifenacin, Placebo
    Comments Comparison of solifenacin versus placebo change from Baseline at 6 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6315
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value 4.655
    Confidence Interval (2-Sided) 95%
    -14.858 to 24.167
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Oxybutynin, Placebo
    Comments Comparison of oxybutynin versus placebo change from Baseline at 2 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.8670
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -1.457
    Confidence Interval (2-Sided) 95%
    -18.976 to 16.062
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Primary Outcome
    Title Change From Baseline in Cognitive Function Composite Score - Speed of Memory
    Description Cognitive effects were assessed at the end of each treatment period using a computerized assessment system at time points close to the predicted time to attain maximum plasma concentration for solifenacin and oxybutynin. Speed of Memory was calculated from the sum of 4 cognitive function speed tests: numeric and spatial working memory and word and picture recognition. A low score reflects that a person is able to recall a name, a face or any other item fast from the episodic secondary memory; a positive change from baseline reflects impairment compared to baseline.
    Time Frame Assessed at each treatment period baseline visit (the day prior to the first dose of each treatment; Days -1, 42, 84) and at the end of each treatment period (Days 21, 63 and 105). At each visit, tests were performed at 2 and 6 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    The number of participants analyzed represents the Safety Analysis Subset 1 (SAF1), consisting of all randomized patients who took at least one dose of the study medication and who completed the cognitive function tests for at least two treatment periods. The number of participants per arm is consistent for all categories / rows of the data table.
    Arm/Group Title Solifenacin Oxybutynin Placebo
    Arm/Group Description Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day. Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form. Participants received 21 days of treatment with placebo.
    Measure Participants 22 20 22
    Baseline at 2 hours [Oxybutynin Tmax]
    4505.96
    (957.434)
    4545.75
    (789.173)
    4741.30
    (820.101)
    Change from Baseline at 2 hours
    24.09
    (762.881)
    -11.56
    (571.131)
    -240.62
    (471.516)
    Baseline at 6 hours [Solifenacin Tmax]
    4496.65
    (653.186)
    4606.51
    (846.669)
    4655.29
    (923.390)
    Change from Baseline at 6 hours
    -149.79
    (494.835)
    -118.14
    (471.318)
    -126.04
    (728.870)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Solifenacin, Placebo
    Comments Comparison of solifenacin versus placebo change from Baseline at 6 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5953
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value -77.919
    Confidence Interval (2-Sided) 95%
    -372.814 to 216.976
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Oxybutynin, Placebo
    Comments Comparison of oxybutynin versus placebo change from Baseline at 2 hours The null hypothesis was that the mean change from baseline was the same in both treatments.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3526
    Comments
    Method ANCOVA
    Comments The analysis was performed using an ANCOVA model with fixed effect for treatment, period, subjects as a random effect and baseline as a covariate.
    Method of Estimation Estimation Parameter Least Square Mean Difference
    Estimated Value 157.783
    Confidence Interval (2-Sided) 95%
    -182.015 to 497.581
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Treatment emergent adverse events were collected by treatment period from first administration of the study/comparative drug until within 7 days of taking the last dose.
    Adverse Event Reporting Description A treatment period consists of about 21 treatment days with a follow-up of either about 21 washout days prior to start of next treatment period or a follow-up of 7 days for the last treatment period.
    Arm/Group Title Solifenacin Oxybutynin Placebo
    Arm/Group Description Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day. Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form. Participants received 21 days of treatment with placebo.
    All Cause Mortality
    Solifenacin Oxybutynin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Solifenacin Oxybutynin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/23 (4.3%) 1/25 (4%) 0/22 (0%)
    Eye disorders
    Vitreous detachment 1/23 (4.3%) 0/25 (0%) 0/22 (0%)
    Gastrointestinal disorders
    Gastrointestinal disorders 0/23 (0%) 1/25 (4%) 0/22 (0%)
    Other (Not Including Serious) Adverse Events
    Solifenacin Oxybutynin Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/23 (21.7%) 14/25 (56%) 6/22 (27.3%)
    Gastrointestinal disorders
    Dry mouth 4/23 (17.4%) 13/25 (52%) 2/22 (9.1%)
    Dyspepsia 0/23 (0%) 3/25 (12%) 0/22 (0%)
    Musculoskeletal and connective tissue disorders
    Pain in extremity 0/23 (0%) 2/25 (8%) 0/22 (0%)
    Nervous system disorders
    Balance disorder 2/23 (8.7%) 0/25 (0%) 0/22 (0%)
    Renal and urinary disorders
    Micturition disorder 0/23 (0%) 0/25 (0%) 2/22 (9.1%)
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain 0/23 (0%) 1/25 (4%) 2/22 (9.1%)
    Skin and subcutaneous tissue disorders
    Pruritus 1/23 (4.3%) 0/25 (0%) 2/22 (9.1%)

    Limitations/Caveats

    Company makes no warranties or representations of any kind as to the posting, expressed or implied, including warranties of merchantability and fitness for a particular purpose, and shall not be liable for any damages.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Institute and/or Principal Investigator may not publish trial data generated at their specific study site without prior written approval of the Sponsor.

    Results Point of Contact

    Name/Title Associate Medical Director Urology
    Organization Astellas Pharma Europe Ltd.
    Phone
    Email clinicaltrials@us.astellas.com
    Responsible Party:
    Astellas Pharma Inc
    ClinicalTrials.gov Identifier:
    NCT01126424
    Other Study ID Numbers:
    • 905-EC-008
    • 2008-005966-29
    First Posted:
    May 19, 2010
    Last Update Posted:
    Oct 15, 2012
    Last Verified:
    Sep 1, 2012