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

Phase 4

Completed

• Conditions: Cognition
• Interventions: Drug: Solifenacin; Drug: Placebo; Drug: Oxybutynin

• Registration Number: NCT01126424
• Lead Sponsor: Astellas Pharma Inc

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.

Study Timeline

• Study Start: 2010-04
• Study First Submitted: 2010-04-29
• Study First Submitted QC: 2010-05-18
• Study First Posted: 2010-05-19
• Primary Completion: 2010-12
• Study Completion: 2010-12
• Disposition First Submitted: 2011-12-12
• Disposition First Submitted QC: 2011-12-12
• Disposition First Posted: 2011-12-22
• Results First Submitted: 2012-07-05
• Status Verified: 2012-09
• Results First Submitted QC: 2012-09-13
• Last Update Submitted: 2012-09-13
• Results First Posted: 2012-10-15
• Last Update Posted: 2012-10-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 26

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Solifenacin	Solifenacin	Participants received 21 days of treatment with 5 mg solifenacin, in tablet form once a day.
Placebo	Placebo	Participants received 21 days of treatment with placebo.
Oxybutynin	Oxybutynin	Participants received 21 days of treatment with 10 mg oxybutynin (1 x 5 mg twice daily) in capsule form.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.