Cognition
Conditions
Keywords
Anti-muscarinics, Anti-cholinergics, Cognition, Solifenacin
Brief summary
The purpose is to compare solifenacin and oxybutynin with an inactive tablet and assess any potential effects on mental ability.
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.
Interventions
DRUGSolifenacin
tablet
DRUGOxybutynin
capsule
DRUGPlacebo
tablet
Sponsors
Astellas Pharma Inc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
75 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Solifenacin / Oxybutynin / Placebo 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. | 3 |
| Solifenacin / Placebo / Oxybutynin 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. | 4 |
| Oxybutynin / Placebo / Solifenacin 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. | 5 |
| Oxybutynin / Solifenacin / Placebo 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. | 6 |
| Placebo / Solifenacin / Oxybutynin 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. | 4 |
| Placebo / Oxybutynin / Solifenacin 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. | 4 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 3 | 1 | 0 |
Baseline characteristics
| Characteristic | Solifenacin / Oxybutynin / Placebo | Solifenacin / Placebo / Oxybutynin | Oxybutynin / Placebo / Solifenacin | Oxybutynin / Solifenacin / Placebo | Placebo / Solifenacin / Oxybutynin | Placebo / Oxybutynin / Solifenacin | Total |
|---|---|---|---|---|---|---|---|
| Age Continuous | 79.7 years STANDARD_DEVIATION 3.8 | 78.8 years STANDARD_DEVIATION 2.5 | 80.2 years STANDARD_DEVIATION 4.4 | 76.7 years STANDARD_DEVIATION 2 | 79.3 years STANDARD_DEVIATION 2.9 | 79.0 years STANDARD_DEVIATION 4.1 | 78.8 years STANDARD_DEVIATION 3.2 |
| Race/Ethnicity, Customized White | 3 participants | 4 participants | 5 participants | 6 participants | 4 participants | 4 participants | 26 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 12 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 14 Participants |
| Stockholm criteria for mild cognitive impairment No | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Stockholm criteria for mild cognitive impairment Yes | 3 participants | 4 participants | 5 participants | 6 participants | 4 participants | 4 participants | 26 participants |
| Total Geriatric Depression Scale (GDS) Score | 1.0 scores on a scale STANDARD_DEVIATION 1.73 | 1.0 scores on a scale STANDARD_DEVIATION 0.82 | 1.4 scores on a scale STANDARD_DEVIATION 1.67 | 1.0 scores on a scale STANDARD_DEVIATION 0.63 | 1.3 scores on a scale STANDARD_DEVIATION 0.96 | 1.8 scores on a scale STANDARD_DEVIATION 1.26 | 1.2 scores on a scale STANDARD_DEVIATION 1.11 |
| Total Mini-Mental State Examination (MMSE) Score | 27.7 scores on a scale STANDARD_DEVIATION 0.58 | 28.3 scores on a scale STANDARD_DEVIATION 1.26 | 28.0 scores on a scale STANDARD_DEVIATION 1 | 27.3 scores on a scale STANDARD_DEVIATION 1.75 | 26.5 scores on a scale STANDARD_DEVIATION 1 | 27.3 scores on a scale STANDARD_DEVIATION 2.06 | 27.5 scores on a scale STANDARD_DEVIATION 1.39 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 23 | 14 / 25 | 6 / 22 |
| serious Total, serious adverse events | 1 / 23 | 1 / 25 | 0 / 22 |
Outcome results
Primary
Change From Baseline in Cognitive Function Composite Score - Continuity of Attention
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Baseline at 2 hours [Oxybutynin Tmax] | 91.591 Scores on a scale | Standard Deviation 3.2462 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Change from Baseline at 2 hours | 0.545 Scores on a scale | Standard Deviation 2.0637 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Baseline at 6 hours [Solifenacin Tmax] | 91.228 Scores on a scale | Standard Deviation 2.0454 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Change from Baseline at 6 hours | -0.318 Scores on a scale | Standard Deviation 2.7143 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Change from Baseline at 6 hours | 0.100 Scores on a scale | Standard Deviation 2.7121 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Baseline at 2 hours [Oxybutynin Tmax] | 91.300 Scores on a scale | Standard Deviation 2.5775 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Baseline at 6 hours [Solifenacin Tmax] | 91.901 Scores on a scale | Standard Deviation 2.404 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Change from Baseline at 2 hours | 0.150 Scores on a scale | Standard Deviation 3.2653 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Change from Baseline at 6 hours | -0.045 Scores on a scale | Standard Deviation 3.4566 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Change from Baseline at 2 hours | 0.909 Scores on a scale | Standard Deviation 2.6168 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Baseline at 6 hours [Solifenacin Tmax] | 91.728 Scores on a scale | Standard Deviation 3.6929 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Continuity of Attention | Baseline at 2 hours [Oxybutynin Tmax] | 91.364 Scores on a scale | Standard Deviation 2.3409 |
Comparison: 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.p-value: 0.568495% CI: [-2.293, 1.279]ANCOVA
Comparison: 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.p-value: 0.234895% CI: [-2.122, 0.538]ANCOVA
Primary
Change From Baseline in Cognitive Function Composite Score - Power of Attention
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Baseline at 2 hours [Oxybutynin Tmax] | 1413.67 msec | Standard Deviation 180.242 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Change from Baseline at 2 hours | -5.86 msec | Standard Deviation 71.371 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Baseline at 6 hours [Solifenacin Tmax] | 1421.80 msec | Standard Deviation 191.303 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Change from Baseline at 6 hours | -14.80 msec | Standard Deviation 87.918 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Change from Baseline at 6 hours | -0.74 msec | Standard Deviation 62.65 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Baseline at 2 hours [Oxybutynin Tmax] | 1423.38 msec | Standard Deviation 186.163 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Baseline at 6 hours [Solifenacin Tmax] | 1405.41 msec | Standard Deviation 182.929 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Change from Baseline at 2 hours | 17.81 msec | Standard Deviation 92.34 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Change from Baseline at 6 hours | 11.77 msec | Standard Deviation 93.655 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Change from Baseline at 2 hours | 1.99 msec | Standard Deviation 54.145 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Baseline at 6 hours [Solifenacin Tmax] | 1393.98 msec | Standard Deviation 189.128 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Power of Attention | Baseline at 2 hours [Oxybutynin Tmax] | 1401.21 msec | Standard Deviation 177.194 |
Comparison: 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.p-value: 0.377195% CI: [-68.58, 26.607]ANCOVA
Comparison: 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.p-value: 0.448795% CI: [-28.854, 63.87]ANCOVA
Primary
Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Baseline at 2 hours [Oxybutynin Tmax] | 111.893636 Scores on a scale | Standard Deviation 48.52511 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Change from Baseline at 2 hours | -3.788636 Scores on a scale | Standard Deviation 35.609118 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Baseline at 6 hours [Solifenacin Tmax] | 101.363485 Scores on a scale | Standard Deviation 44.919411 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Change from Baseline at 6 hours | 7.728182 Scores on a scale | Standard Deviation 30.836915 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Change from Baseline at 6 hours | -3.502000 Scores on a scale | Standard Deviation 48.822365 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Baseline at 2 hours [Oxybutynin Tmax] | 107.666333 Scores on a scale | Standard Deviation 55.168759 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Baseline at 6 hours [Solifenacin Tmax] | 104.917167 Scores on a scale | Standard Deviation 50.380503 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Change from Baseline at 2 hours | -0.917833 Scores on a scale | Standard Deviation 28.198821 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Change from Baseline at 6 hours | 1.589394 Scores on a scale | Standard Deviation 35.687431 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Change from Baseline at 2 hours | 0.531515 Scores on a scale | Standard Deviation 42.576179 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Baseline at 6 hours [Solifenacin Tmax] | 106.515000 Scores on a scale | Standard Deviation 45.147568 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Episodic Secondary Memory | Baseline at 2 hours [Oxybutynin Tmax] | 110.000152 Scores on a scale | Standard Deviation 51.736947 |
Comparison: 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.p-value: 0.631595% CI: [-14.858, 24.167]ANCOVA
Comparison: 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.p-value: 0.86795% CI: [-18.976, 16.062]ANCOVA
Primary
Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Baseline at 2 hours [Oxybutynin Tmax] | 1.7921 Scores on a scale | Standard Deviation 0.24313 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Change from Baseline at 2 hours | -0.0867 Scores on a scale | Standard Deviation 0.39254 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Baseline at 6 hours [Solifenacin Tmax] | 1.6666 Scores on a scale | Standard Deviation 0.35805 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Change from Baseline at 6 hours | 0.0580 Scores on a scale | Standard Deviation 0.46462 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Change from Baseline at 6 hours | 0.0633 Scores on a scale | Standard Deviation 0.46684 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Baseline at 2 hours [Oxybutynin Tmax] | 1.7251 Scores on a scale | Standard Deviation 0.31582 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Baseline at 6 hours [Solifenacin Tmax] | 1.6441 Scores on a scale | Standard Deviation 0.34113 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Change from Baseline at 2 hours | -0.0043 Scores on a scale | Standard Deviation 0.35428 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Change from Baseline at 6 hours | 0.0047 Scores on a scale | Standard Deviation 0.41656 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Change from Baseline at 2 hours | 0.0492 Scores on a scale | Standard Deviation 0.37776 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Baseline at 6 hours [Solifenacin Tmax] | 1.7548 Scores on a scale | Standard Deviation 0.35808 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Quality of Working Memory | Baseline at 2 hours [Oxybutynin Tmax] | 1.7087 Scores on a scale | Standard Deviation 0.24215 |
Comparison: 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.p-value: 0.627595% CI: [-0.208, 0.127]ANCOVA
Comparison: 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.p-value: 0.536195% CI: [-0.194, 0.103]ANCOVA
Primary
Change From Baseline in Cognitive Function Composite Score - Speed of Memory
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Baseline at 2 hours [Oxybutynin Tmax] | 4505.96 msec | Standard Deviation 957.434 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Change from Baseline at 2 hours | 24.09 msec | Standard Deviation 762.881 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Baseline at 6 hours [Solifenacin Tmax] | 4496.65 msec | Standard Deviation 653.186 |
| Solifenacin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Change from Baseline at 6 hours | -149.79 msec | Standard Deviation 494.835 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Change from Baseline at 6 hours | -118.14 msec | Standard Deviation 471.318 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Baseline at 2 hours [Oxybutynin Tmax] | 4545.75 msec | Standard Deviation 789.173 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Baseline at 6 hours [Solifenacin Tmax] | 4606.51 msec | Standard Deviation 846.669 |
| Oxybutynin | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Change from Baseline at 2 hours | -11.56 msec | Standard Deviation 571.131 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Change from Baseline at 6 hours | -126.04 msec | Standard Deviation 728.87 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Change from Baseline at 2 hours | -240.62 msec | Standard Deviation 471.516 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Baseline at 6 hours [Solifenacin Tmax] | 4655.29 msec | Standard Deviation 923.39 |
| Placebo | Change From Baseline in Cognitive Function Composite Score - Speed of Memory | Baseline at 2 hours [Oxybutynin Tmax] | 4741.30 msec | Standard Deviation 820.101 |
Comparison: 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.p-value: 0.595395% CI: [-372.814, 216.976]ANCOVA
Comparison: 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.p-value: 0.352695% CI: [-182.015, 497.581]ANCOVA
Secondary
Change From Baseline in Postural Stability Test
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.
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Solifenacin | Change From Baseline in Postural Stability Test | Baseline at 2 hours [Oxybutynin Tmax] | 37.7 1/3 degree of angle of sway | Standard Deviation 23.35 |
| Solifenacin | Change From Baseline in Postural Stability Test | Change from Baseline at 2 hours | 5.2 1/3 degree of angle of sway | Standard Deviation 9.65 |
| Solifenacin | Change From Baseline in Postural Stability Test | Baseline at 6 hours [Solifenacin Tmax] | 37.7 1/3 degree of angle of sway | Standard Deviation 19.42 |
| Solifenacin | Change From Baseline in Postural Stability Test | Change from Baseline at 6 hours | 9.9 1/3 degree of angle of sway | Standard Deviation 16.14 |
| Oxybutynin | Change From Baseline in Postural Stability Test | Change from Baseline at 6 hours | 0.7 1/3 degree of angle of sway | Standard Deviation 17.6 |
| Oxybutynin | Change From Baseline in Postural Stability Test | Baseline at 2 hours [Oxybutynin Tmax] | 36.2 1/3 degree of angle of sway | Standard Deviation 20.05 |
| Oxybutynin | Change From Baseline in Postural Stability Test | Baseline at 6 hours [Solifenacin Tmax] | 38.9 1/3 degree of angle of sway | Standard Deviation 23.59 |
| Oxybutynin | Change From Baseline in Postural Stability Test | Change from Baseline at 2 hours | 2.7 1/3 degree of angle of sway | Standard Deviation 17.04 |
| Placebo | Change From Baseline in Postural Stability Test | Change from Baseline at 6 hours | -0.1 1/3 degree of angle of sway | Standard Deviation 10.64 |
| Placebo | Change From Baseline in Postural Stability Test | Change from Baseline at 2 hours | 0.4 1/3 degree of angle of sway | Standard Deviation 16.81 |
| Placebo | Change From Baseline in Postural Stability Test | Baseline at 6 hours [Solifenacin Tmax] | 40.0 1/3 degree of angle of sway | Standard Deviation 26.19 |
| Placebo | Change From Baseline in Postural Stability Test | Baseline at 2 hours [Oxybutynin Tmax] | 37.5 1/3 degree of angle of sway | Standard Deviation 20.04 |
Comparison: 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.p-value: 0.050595% CI: [-0.023, 18.326]ANCOVA
Comparison: 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.p-value: 0.675395% CI: [-7.02, 10.713]ANCOVA