Evaluation of the Efficacy of Varenicline on Cognition, Safety, Tolerability and Pharmacokinetics in Subjects With Mild-to-Moderate Alzheimer's Disease

12-item scale to assess severity of cognitive impairment in AD. Items include word recall, naming objects and fingers, following commands, constructional praxis, ideational praxis, orientation, word recognition, spoken language ability, comprehension of spoken language, word finding difficulty in spontaneous speech, remembering test instructions, and concentration/distractibility. Total score range from 0-75 with 75 indicating worse cognition.

Time frame: Week 6

Population: Full analysis set (FAS): all participants who were randomized and took at least 1 dose of randomized study medication. N = number of participants with ADAS-Cog 75 results at Week 6.

11-item scale designed to assess the severity of cognitive impairments in AD subjects. Items include word recall, naming objects and fingers, following commands, constructional praxis, ideational praxis, orientation, word recognition, spoken language ability, comprehension of spoken language, word finding difficulty in spontaneous speech, and remembering test instructions. Total score range from 0-70 with 70 indicating worse cognition.

Time frame: Week 3

Population: FAS. N = number of participants with ADAS-Cog 70 results at Week 3.

11-item scale designed to assess the severity of cognitive impairments in AD subjects. Items include word recall, naming objects and fingers, following commands, constructional praxis, ideational praxis, orientation, word recognition, spoken language ability, comprehension of spoken language, word finding difficulty in spontaneous speech, and remembering test instructions. Total score range from 0-70 with 70 indicating worse cognition.

Time frame: Week 6

Population: FAS. N = number of participants with ADAS-Cog 70 results at Week 6.

12-item scale to assess severity of cognitive impairment in AD. Items include word recall, naming objects and fingers, following commands, constructional praxis, ideational praxis, orientation, word recognition, spoken language ability, comprehension of spoken language, word finding difficulty in spontaneous speech, remembering test instructions, and concentration/distractibility. Total score range from 0-75 with 75 indicating worse cognition.

Time frame: Week 3

Population: FAS; N = number of participants with ADAS-Cog 75 results at Week 3.

Assessment of the cognitive domain visual episodic memory (associate learning) through responses within 7 minutes to 4 targets x 4 rounds (mild AD) or 3 targets x 4 rounds (moderate AD); score range: 35 to 100. Performance variable: number of errors made in correctly placing each of the 4 patterns in their location four times.

Time frame: Week 1

Population: FAS; N = number of participants with a CogState score for Continuous Paired Associate Learning at Week 1.

Assessment of the cognitive domain visual episodic memory (associate learning) through responses within 7 minutes to 4 targets x 4 rounds (mild AD) or 3 targets x 4 rounds (moderate AD); score range: 35 to 100. Performance variable: number of errors made in correctly placing each of the 4 patterns in their location four times.

Time frame: Week 3

Population: FAS; N = number of participants with a CogState score for Continuous Paired Associate Learning at Week 3.

Assessment of the cognitive domain visual episodic memory (associate learning) through responses within 7 minutes to 4 targets x 4 rounds (mild AD) or 3 targets x 4 rounds (moderate AD); score range: 35 to 100. Performance variable: number of errors made in correctly placing each of the 4 patterns in their location four times.

Time frame: Week 6

Population: FAS; N = number of participants with a CogState score for Continuous Paired Associate Learning at Week 6.

Assessment of the cognitive domain psychomotor function through yes or no responses within 5 minutes to 30 trials; score range: 0 to 3.69. Performance variable: speed of performance; average of the log10 t transformed reaction time for correct responses. Reaction times longer than 5 seconds (log10 \[5000\]) were excluded as reflecting responses that were abnormally slow.

Time frame: Week 1

Population: FAS; N = number of participants with a CogState score for Detection at Week 1.

Assessment of the cognitive domain psychomotor function through yes or no responses within 5 minutes to 30 trials; score range: 0 to 3.69. Performance variable: speed of performance; average of the log10 t transformed reaction time for correct responses. Reaction times longer than 5 seconds (log10 \[5000\]) were excluded as reflecting responses that were abnormally slow.

Time frame: Week 3

Population: FAS; N = number of participants with a CogState score for Detection at Week 3.

Assessment of the cognitive domain psychomotor function through yes or no responses within 5 minutes to 30 trials; score range: 0 to 3.69. Performance variable: speed of performance; average of the log10 t transformed reaction time for correct responses. Reaction times longer than 5 seconds (log10 \[5000\]) were excluded as reflecting responses that were abnormally slow.

Time frame: Week 6

Population: FAS; N = number of participants with a CogState score for Detection at Week 6.

Assessment of the cognitive domain visual attention through a yes or no response to 30 trials within 5 minutes; score range: 0 to 3.69. Performance variable: speed of performance; average log10 transformed reaction time for correct responses. Reaction times longer than 5 seconds ( log10 \[5000\]) were excluded as reflecting responses that were abnormally slow.

Time frame: Week 1

Population: FAS; N = number of participants with a CogState score for Identification at Week 1.

Assessment of the cognitive domain visual attention through a yes or no response to 30 trials within 5 minutes; score range: 0 to 3.69. Performance variable: speed of performance; average log10 transformed reaction time for correct responses. Reaction times longer than 5 seconds ( log10 \[5000\]) were excluded as reflecting responses that were abnormally slow.

Time frame: Week 3

Population: FAS; N = number of participants with a CogState score for Identification at Week 3.

Assessment of the cognitive domain visual attention through a yes or no response to 30 trials within 5 minutes; score range: 0 to 3.69. Performance variable: speed of performance; average log10 transformed reaction time for correct responses. Reaction times longer than 5 seconds ( log10 \[5000\]) were excluded as reflecting responses that were abnormally slow.

Time frame: Week 6

Population: FAS; N = number of participants with a CogState score for Identification at Week 6.

Assessment of the cognitive domain working memory through yes or no responses to 30 trials within 5 minutes; score range: 0 to 1.57. Performance variable: accuracy of performance; arcsine transformation of proportion correct responses.

Time frame: Week 1

Population: FAS; N = number of participants with a CogState score for One Back Working Memory at Week 1.

Assessment of the cognitive domain working memory through yes or no responses to 30 trials within 5 minutes; score range: 0 to 1.57. Performance variable: accuracy of performance; arcsine transformation of proportion correct responses.

Time frame: Week 3

Population: FAS; N = number of participants with a CogState score for One Back Working Memory at Week 3.

Assessment of the cognitive domain working memory through yes or no responses to 30 trials within 5 minutes; score range: 0 to 1.57. Performance variable: accuracy of performance; arcsine transformation of proportion correct responses.

Time frame: Week 6

Population: FAS; N = number of participants with a CogState score for One Back Working Memory at Week 6.

Assessment of the cognitive domain episodic memory through yes or no responses within 5 minutes to 4 targets repeated among 6 distractors on 4 rounds (mild Alzheimer's disease \[AD\], or 3 targets repeated among 4 distractors on 4 rounds (moderate AD) ; score range: 0 to 1.57. Performance variable: accuracy of performance; arcsine transformation of proportion correct responses.

Time frame: Week 1

Population: FAS; N = number of participants with a CogState score for Visual Learning at Week 1.

Assessment of the cognitive domain episodic memory through yes or no responses within 5 minutes to 4 targets repeated among 6 distractors on 4 rounds (mild Alzheimer's disease \[AD\], or 3 targets repeated among 4 distractors on 4 rounds (moderate AD) ; score range: 0 to 1.57. Performance variable: accuracy of performance; arcsine transformation of proportion correct responses.

Time frame: Week 3

Population: FAS; N = number of participants with a CogState score for Visual Learning at Week 3.

Assessment of the cognitive domain episodic memory through yes or no responses within 5 minutes to 4 targets repeated among 6 distractors on 4 rounds (mild Alzheimer's disease \[AD\], or 3 targets repeated among 4 distractors on 4 rounds (moderate AD) ; score range: 0 to 1.57. Performance variable: accuracy of performance; arcsine transformation of proportion correct responses.

Time frame: Week 6

Population: FAS; N = number of participants with a CogState score for Visual Learning at Week 6.

CGI-I: 7-point clinician rated scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved), 2 (much improved), or 3 (minimally improved) on the scale. Higher score = more affected.

Time frame: Week 6

Population: FAS; N = number of participants with a CGI-I score at Week 6.

Caregiver interview-based rating scale assessing 12 behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, appetite/eating, and sleep. Each symptom score derived by frequency of symptoms \* severity of symptoms (range 0-12). Total score = sum of symptom scores; range: 0-144 with higher score indicating greater behavioral disturbances.

Time frame: Week 3

Population: FAS. N = number of participants with a NPI total score at Week 3.

Caregiver interview-based rating scale assessing 12 behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, appetite/eating, and sleep. Each symptom score derived by frequency of symptoms \* severity of symptoms (range 0-12). Total score = sum of symptom scores; range: 0-144 with higher score indicating greater behavioral disturbances.

Time frame: Week 6

Population: FAS. N = number of participants with a NPI total score at Week 6.