Study Comparing 3 Dosage Levels Of SAM-531 In Outpatients With Mild To Moderate Alzheimer Disease

Study Overview
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Brief Summary
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The study will evaluate the efficacy and safety of an investigational drug called SAM-531 at three dosage levels. Subjects will receive either one of the 3 dosage levels of SAM-531, donepezil or placebo for the first 24 weeks of the study (period I). Subjects who receive placebo for period I will be assigned to receive the highest dose of SAM-531 SAM-531 for the remaining 28 weeks of the study, while subjects who received one of the three SAM-531 dosage levels or donepezil in period I will continue with the same study drug (period II).

Detailed Description
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The study was stopped (date of termination was 13April2011) due to a 6 month interim analysis: all of the 3 SAM-531 dosage levels were declared futile. There were no safety concerns.

Official Title
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A 52-Week, Two-Period, Multicenter, Randomized, Double-Blind, Donepezil-Referenced, Placebo-Controlled, Efficacy And Safety Study Of 3 Dosage Levels Of SAM-531 In Outpatients With Mild To Moderate Alzheimer Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: SAM-531 1.5 mg
* Drug: SAM-531 3.0 mg
* Drug: SAM-531 5.0 mg
* Drug: Donepezil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of probable Alzheimer Disease according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Diseases and Related Disorders Association (NINCDS-ADRDA) criteria. Mini-Mental State Examination (MMSE) score of 12 to 24 at screening Rosen Modified Hachinski Ischemic score < or equal to 4 at screening. Exclusion Criteria: Relevant neurologic disease other than Alzheimer Disease that may affect cognition or ability to complete the study. Current major depressive disorder or other current major psychiatric disorder. History of clinically evident stroke or clinically important carotid or vertebrobasilar stenosis or plaque. Use of prescription or nonprescription medications for cognitive enhancement (including memantine, ginkgo biloba, huperzine A, and cholinesterase inhibitors) within 3 months before the baseline visit.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br>Placebo | Drug: Placebo<br>* Capsules SAM-531 placebo and 5 mg tablet encapsulated Donepezil placebo capsules, once a day during 24 weeks.<br>|
| Experimental: 2<br>SAM-531 1.5 mg | Drug: SAM-531 1.5 mg<br>* Capsules SAM-531 1.5 mg, once a day during 52 weeks.<br>|
| Experimental: 3<br>SAM-531 3.0 mg | Drug: SAM-531 3.0 mg<br>* Capsules SAM-531 3.0 mg, once a day during 52 weeks.<br>|
| Experimental: 4<br>SAM-531 5.0 mg | Drug: SAM-531 5.0 mg<br>* Capsules SAM-531 5.0 mg, once a day during 24 weeks or 52 weeks.<br>|
| Active Comparator: 5<br>Donepezil | Drug: Donepezil<br>* Encapsulated Donepezil 5 mg tablets, once a day during 52 weeks. After Day 42, the dose can up titrated up to 10 mg of Donepezil.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) Total Score at Week 24 | 14-item scale to assess severity of cognitive impairment in Alzheimer's Disease. Items: word recall, naming objects and fingers, following commands, constructional praxis, ideational praxis, orientation, word recognition, recall of test instructions, spoken language ability, word-finding difficulty, comprehension of spoken language, concentration/distractibility, number cancellation and executive maze. Rating scale ranged from 0 (not present) to 5 (severe). Total score was sum of individual scores (items 1-11) and ranged from 0 to 70 with higher scores indicating greater cognitive impairment. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disability Assessment for Dementia (DAD) Total Score at Week 24 | Caregiver interview-based instrument assessing 10 areas of activities of daily living (ADL) to measure participant's actual performance over the previous 2 weeks. Items included hygiene, dressing, continence, eating, meal preparation, telephoning, outings, finance/correspondence, medications and leisure/housework. Responses scored as 1 (yes) or 0 (no), response of Not Applicable was not scored. Total DAD score was sum of scores for 40 items, expressed as a percentage of the number of items answered yes or no. Total score ranged from 0 to 100, higher scores represented less disability in ADL. | Baseline, Week 24 | 
| Change From Baseline in Neuropsychiatry Inventory (NPI) at Week 24 | Caregiver interview-based rating scale assessed 10 behavioral, 2 neurovegetative disturbances occurring in dementia: delusions, hallucination, agitation/aggression, depression, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability, aberrant motor behavior, appetite/eating disorders and sleep/nightime behavior disorders. Each symptom score derived by symptom frequency (1 [occasionally] to 4 [very frequently] * symptom severity (1 [mild] to 3 [severe]) and ranged 0-12. Total score = sum of symptom scores; range 0-144, higher score indicating greater behavioral disturbances | Baseline, Week 24 | 
| Number of Participants With Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC) Scores at Week 24 | Caregiver and participant interview-based tool to rate the overall impression of participant's clinical change of the disease over time. Areas covered in the interview include: relevant history, observation/evaluation, mental/cognitive state, behavior and functioning. Change categorized into 1 of 7 categories: marked improvement, moderate improvement, minimal improvement, no change, minimal worsening, moderate worsening, marked worsening. | Baseline, Week 24 | 
| Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associate Learning (PAL)Total Errors (N, Shapes, Adjusted) at Week 24 | CANTAB PAL-assessed visual memory/new learning using one or more patterns randomly displayed in boxes on a screen. Participants were to touch the box where patterns first appeared. Stage 1 (practice) and difficulty increased Stage 2 (2 patterns) to Stage 6 (6 patterns). When all locations correctly identified moved to next Stage. Test terminated when a stage could not be completed in 6 attempts. Total Errors=total number of incorrect boxes chosen plus adjustment for estimated possible errors on problems, attempts, and recalls not reached. Total score 0 to 106, lower scores=better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB PAL - Number of Patterns Reached at Week 24 | CANTAB PAL-assessed visual memory/new learning using one or more patterns randomly displayed in boxes on a screen. Participants were to touch the box where patterns first appeared. Stage 1 (practice) and difficulty increased Stage 2 (2 patterns) to Stage 6 (6 patterns). When all locations correctly identified moved to next Stage. Test terminated when a stage could not be completed in 6 attempts. Total score was the number of patterns presented at last stage successfully completed and ranged from 2 to 6, higher scores indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB PAL - First Trial Memory Score, Patterns at Week 24 | CANTAB PAL-assessed visual memory/new learning using one or more patterns randomly displayed in boxes on a screen. Participants were to touch the box where patterns first appeared. Stage 1 (practice) and difficulty increased Stage 2 (2 patterns) to Stage 6 (6 patterns). When all locations correctly identified moved to next Stage. Test terminated when a stage could not be completed in 6 attempts. Total score was the number of correct choices made on the first attempt at each Stage. Total score ranged from 0 to 20, higher scores indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB Spatial Working Memory (SWM) - Between Errors (4 Boxes) at Week 24 | CANTAB-SWM assessed participant's retention of spatial information, ability to manipulate remembered items and strategize. Participant asked to find tokens in on-screen boxes, move them. Difficulty ranged 4-8 boxes to assess, 2 trials per assessment. Between errors: number of times participant revisited a box where a token previously found. In 4 box assessments the maximum number of errors per trial was 20. Test ended with 20 errors in a trial. Less than 20 errors in both trials the participant went to the next level of difficulty. Scores ranged from 0 to 39. Lower scores: better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB-SWM - Between Errors (6 Boxes) at Week 24 | CANTAB-SWM assessed participant's retention of spatial information, ability to manipulate remembered items and strategize. Participant asked to find tokens in on-screen boxes, move them. Difficulty ranged 4-8 boxes to assess, 2 trials per assessment. Between errors: number of times participant revisited a box where a token previously found. In 6 box assessments the maximum number of errors per trial was 30. Test ended with 30 errors in a trial. Less than 30 errors in both trials the participant went to the next level of difficulty. Scores ranged from 0 to 59. Lower scores: better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB SWM - Between Errors (8 Boxes) at Week 24 | CANTAB-SWM assessed participant's retention of spatial information, ability to manipulate remembered items and strategize. Participant asked to find tokens in on-screen boxes, move them. Difficulty ranged 4-8 boxes to assess, 2 trials per assessment. Between errors: number of times participant revisited a box where a token previously found. In 8 box assessments the maximum number of errors per trial was 40. Test ended with 40 errors in a trial. Less than 40 errors in both trials the participant went to the next level of difficulty. Scores ranged from 0 to 79. Lower scores: better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB SWM - Between Errors (N Boxes) at Week 24 | CANTAB-SWM assessed participant's retention of spatial information, ability to manipulate remembered items and strategize. Participant was asked to find tokens in on-screen boxes and move them. Difficulty ranged from 4 to 8 box assessments, 2 trials for each assessment. Possible errors for each successful assessment: 4 box 0-38; 6 box 0-58; 8 box 0-78. Between Errors for N Boxes was the cumulative number of errors per each successful trial. Total scores ranged from 0 to 175. Lower scores indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB SWM Strategy at Week 24 | CANTAB-SWM assessed participant's ability to strategize. Participant was asked to find tokens in on-screen boxes and move them. Difficulty ranged from 4 to 8 box assessments, 2 trials per assessment. Strategy score was the number of unique boxes the participant searched in the two 6 and 8 box trials. 6 box trial scores ranged from 1 (1 box searched for all 6 tokens) to 6 (6 boxes searched for 6 tokens). 8 box trial score ranged from 1 (1 box searched) to 8 (8 boxes searched for 8 tokens). Total of the 4 trial scores ranged from 4 to 28. Lower score indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB Pattern Recognition Memory (PRM)-Mean Correct Latency at Week 24 | CANTAB-PRM assessed participant's visual pattern recognition memory in a 2-choice forced discrimination paradigm. Participants presented with a series of 12 visual patterns singly. In recognition phase, participants were required to choose between a pattern previously seen and a novel pattern. Patterns in the recognition phase appeared sequentially in reverse order on the screen. Assessment was repeated with 12 new patterns. Latency in correct responses ranged from 0 to infinity millisecond (msec), lower scores indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB PRM-Percentage Correct at Week 24 | CANTAB-PRM assessed participant's visual pattern recognition memory in a 2-choice forced discrimination paradigm. Participants presented with a series of 12 visual patterns singly. In recognition phase, participants were required to choose between a pattern previously seen and a novel pattern. Patterns in the recognition phase appeared sequentially in reverse order on the screen. Assessment was repeated with 12 new patterns. Correct response total expressed as a percentage, ranged from 0 to 100, higher scores indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB Reaction Time (RTI) Five-Choice Accuracy at Week 24 | CANTAB-RTI assessed participant's reaction, movement time and vigilance during a 5-choice reaction time trial and to measure anticipatory/premature and perseverative responses. In the trial, a yellow spot appeared on a computer screen in 1 of 5 locations, the participant responded by letting go of a press pad and touching the screen where the spot appeared. 5-Choice Accuracy was the total number of trials where participant responded correctly. Total ranged from 0 to 30, higher score indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB RTI Five-Choice Movement Time at Week 24 | CANTAB-RTI assessed participant's reaction, movement time and vigilance during 5-choice reaction time trial and also measured anticipatory/premature responses. In the test, a yellow spot appeared on a computer screen in 1 of 5 locations, the participant responded by letting go of a press pad and touching the screen where the spot appeared. 5-Choice Movement Time was the time from release of press pad to screen touch where the spot had been in trials the participant responded correctly. Possible score ranged from 100 to 5100 msec, lower score indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB RTI Five-Choice Reaction Time at Week 24 | CANTAB-RTI assessed participant's reaction, movement time and vigilance during 5-choice reaction time trial and also measured anticipatory/premature responses. In the test, a yellow spot appeared on a computer screen in 1 of 5 locations, the participant responded by letting go of a press pad and touching the screen where the spot appeared. 5-Choice Reaction Time was the time from appearance of yellow spot on computer screen to time to release press pad in trials the participant responded correctly. Total ranged from 100 to 5100 (maximum allowed) msec, lower score indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB RTI Simple Movement Time at Week 24 | CANTAB-RTI assessed participant's reaction, movement time and vigilance during simple (1 choice) reaction time trial and also measured anticipatory/premature responses. In the test, 1 yellow spot appeared on a computer screen in 1 location, the participant responded by letting go of a press pad and touching the screen where the spot appeared. Simple Movement Time was the time from release of press pad to touch the screen where the spot had been in trials the participant responded correctly. Total ranged from 100 to 5100 (maximum allowed) msec, lower score indicated better performance. | Baseline, Week 24 | 
| Change From Baseline in CANTAB RTI Simple Reaction Time at Week 24 | CANTAB-RTI assessed participant's reaction, movement time and vigilance during simple (1 choice) reaction time trial and also measured anticipatory/premature responses. In the test, 1 yellow spot appeared on a computer screen in 1 location, the participant responded by letting go of a press pad and touching the screen where the spot appeared. Simple Reaction Time was the time from appearance of yellow spot on computer screen to time to release press pad in trials the participant responded correctly. Total ranged from 100 to 5100 (maximum allowed) msec, lower score indicated better performance. | Baseline, Week 24 | 
| Percentage of Participants Who Were Responders at Week 24 | Responder defined as a participant who demonstrated an improvement of at least 3 points from baseline in the ADAS-Cog total score and no worsening in the DAD total score and in ADCS-CGIC. Participants were considered a responder at Week 24 if all 3 criteria were met. | Week 24 |