The effectiveness of the Rivastigmine Transdermal System in dementia of the Alzheimer's type and dementia associated with Parkinson's disease was based on the results of 3 controlled trials of Rivastigmine Transdermal System in patients with Alzheimer's disease (Studies 1, 2, and 3) (see below); 3 controlled trials of oral rivastigmine in patients with dementia of the Alzheimer's type; and 1 controlled trial of oral rivastigmine in patients with dementia associated with Parkinson's disease. See the prescribing information for oral rivastigmine for details of the four studies of oral rivastigmine.

Mild-to-Moderate Alzheimer's Disease

International 24-Week Study of Rivastigmine Transdermal System in Dementia of the Alzheimer's Type (Study 1)

This study was a randomized double-blind, double dummy clinical investigation in patients with Alzheimer's disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score greater than or equal to 10 and less than or equal to 20] (Study 1). The mean age of patients participating in this trial was 74 years with a range of 50 to 90 years. Approximately 67% of patients were women, and 33% were men. The racial distribution was Caucasian 75%, Black 1%, Asian 9%, and other races 15%.

The effectiveness of the Rivastigmine Transdermal System was evaluated in Study 1 using a dual outcome assessment strategy, evaluating for changes in both cognitive performance and overall clinical effect.

The ability of the Rivastigmine Transdermal System to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer's disease patients. The ADAS-Cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language, and praxis. The ADAS-Cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.

The ability of the Rivastigmine Transdermal System to produce an overall clinical effect was assessed using the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more standardized form of the Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus) and is also scored as a 7-point categorical rating; scores range from 1, indicating "markedly improved," to 4, indicating "no change," to 7, indicating "marked worsening."

In Study 1, 1195 patients were randomized to 1 of the following 4 treatments: Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine Transdermal System 17.4 mg/24 hours, Rivastigmine Capsules in a dose of 6 mg twice daily, or placebo. This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase. In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability.

Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study. At 24 weeks, the mean differences in the ADAS-Cog change scores for the rivastigmine-treated patients compared to the patients on placebo, were 1.8, 2.9, and 1.8 units for the Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine Transdermal System 17.4 mg/24 hours, and Rivastigmine Capsule 6 mg twice daily groups, respectively. The difference between each of these groups and placebo was statistically significant. Although a slight improvement was observed with the 17.4 mg/24 hours patch compared to the 9.5 mg/24 hours patch on this outcome measure, no meaningful difference between the two was seen on the global evaluation (see Figure 4).

Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 1

Figure 4 presents the distribution of patients' scores on the ADCS-CGIC for all 4 treatment groups. At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the rivastigmine-treated groups with the patients on placebo was 0.2 units. The difference between each of these groups and placebo was statistically significant.

International 48-Week Study of Rivastigmine Transdermal System in Dementia of the Alzheimer's Type (Study 2)

This study was a randomized double-blind clinical investigation in patients with Alzheimer's disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 10 and less than or equal to 24] (Study 2). The mean age of patients participating in this trial was 76 years with a range of 50 to 85 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 97%, Black 2%, Asian 0.5%, and other races 1%. Approximately 27% of the patients were taking memantine throughout the entire duration of the study.

Alzheimer's disease patients who received 24 to 48 weeks open-label treatment with Rivastigmine Transdermal System 9.5 mg/24 hours and who demonstrated functional and cognitive decline were randomized into treatment with either Rivastigmine Transdermal System 9.5 mg/24 hours or Rivastigmine Transdermal System 13.3 mg/24 hours in a 48-week, double-blind treatment phase. Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of greater than or equal to 2 points from the previous visit or a decrease of greater than or equal to 3 points from baseline.

Study 2 was designed to compare the efficacy of Rivastigmine Transdermal System 13.3 mg/ 24 hours versus that of Rivastigmine Transdermal System 9.5 mg/24 hours during the 48-week, double-blind treatment phase.

The ability of the Rivastigmine Transdermal System 13.3 mg/24 hours to improve cognitive performance over that provided by the Rivastigmine Transdermal System 9.5 mg/24 hours was assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) [see Clinical Studies (14)].

The ability of the Rivastigmine Transdermal System 13.3 mg/24 hours to improve overall function versus that provided by Rivastigmine Transdermal System 9.5 mg/24 hours was assessed by the instrumental subscale of the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-IADL).

The ADCS-IADL subscale is composed of items 7 to 23 of the caregiver-based ADCS-ADL scale. The ADCS-IADL assesses activities such as those necessary for communicating and interacting with other people, maintaining a household, and conducting hobbies and interests. A sum score is calculated by adding the scores of the individual items and can range from 0 to 56, with higher scores indicating less impairment.

Out of a total of 1584 patients enrolled in the initial open-label phase of the study, 567 patients were classified as decliners and were randomized into the 48-week double-blind treatment phase of the study. Two hundred eighty-seven (287) patients entered the 9.5 mg/24 hours Rivastigmine Transdermal System treatment group and 280 patients entered the 13.3 mg/24 hours Rivastigmine Transdermal System treatment group.

Figure 5 illustrates the time course for the mean change from double-blind baseline in ADCS-IADL scores for each treatment group over the course of the 48-week treatment phase of the study. Decline in the mean ADCS-IADL score from the double-blind baseline for the Intent to Treat–Last Observation Carried Forward (ITT-LOCF) analysis was less at each time point in the 13.3 mg/24 hour Rivastigmine Transdermal System treatment group than in the 9.5 mg/24 hours Rivastigmine Transdermal System treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 9.5mg/24 hours dose at weeks 16, 24, 32, and 48 (primary endpoint).

Figure 6 illustrates the time course for the mean change from double-blind baseline in ADAS-Cog scores for both treatment groups over the 48-week treatment phase. The between-treatment group difference for Rivastigmine Transdermal System 13.3 mg/24 hours versus Rivastigmine Transdermal System 9.5 mg/24 hours was nominally statistically significant at week 24 (p=0.027), but not at week 48 (p=0.227), which was the primary endpoint.

Severe Alzheimer's Disease

24-Week United States Study with Rivastigmine Transdermal System in Severe Alzheimer's Disease (Study 3)

This was a 24-week randomized double-blind, clinical investigation in patients with severe Alzheimer's disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 3 and less than or equal to 12]. The mean age of patients participating in this trial was 78 years with a range of 51 to 96 years with 62% aged greater than 75 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 87%, Black 7%, Asian 1%, and other races 5%. Patients on a stable dose of memantine were permitted to enter the study.

Approximately 61% of the patients in each treatment group were taking memantine throughout the entire duration of the study.

The study was designed to compare the efficacy of Rivastigmine Transdermal System 13.3 mg/ 24 hours versus that of Rivastigmine Transdermal System 4.6 mg/24 hours during the 24-week double-blind treatment phase.

The ability of the 13.3 mg/24 hours Rivastigmine Transdermal System to improve cognitive performance versus that provided by the 4.6 mg/24 hours Rivastigmine Transdermal System was assessed with the Severe Impairment Battery (SIB) which uses a validated 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced AD patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuospatial ability, construction, and orienting to name. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability.

The ability of the 13.3 mg/ 24 hours Rivastigmine Transdermal System to improve overall function versus that provided by the 4.6 mg/24 hours Rivastigmine Transdermal System was assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living–Severe Impairment Version (ADCS-ADL-SIV) which is a caregiver-based ADL scale composed of 19 items developed for use in clinical studies of dementia. It is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. A sum score is calculated by adding the scores of the individual items and can range from 0 to 54, with higher scores indicating less functional impairment.

In this study, 716 patients were randomized into one of the following treatments: Rivastigmine Transdermal System 13.3 mg/24 hours or Rivastigmine Transdermal System 4.6 mg/24 hours in a 1:1 ratio. This 24-week study was divided into an 8-week titration phase followed by a 16-week maintenance phase. In the active treatment arms of this study, temporary dose adjustments below the target dose were permitted during the titration and maintenance phase in the event of poor tolerability.

Figure 7 illustrates the time course for the mean change from baseline SIB scores for each treatment group over the course of the 24-week treatment phase of the study. Decline in the mean SIB score from the baseline for the Modified Full Analysis Set (MFAS)-Last Observation Carried Forward (LOCF) analysis was less at each timepoint in the 13.3 mg/24 hour Rivastigmine Transdermal System treatment group than in the 4.6 mg/24 hours Rivastigmine Transdermal System treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).

Figure 8 illustrates the time course for the mean change from baseline in ADCS-ADL-SIV scores for each treatment group over the course of the 24-week treatment phase of the study. Decline in the mean ADCS-ADL-SIV score from baseline for the MFAS-LOCF analysis was less at each time point in the 13.3 mg/24 hours Rivastigmine Transdermal System treatment group than in the 4.6 mg/24 hours Rivastigmine Transdermal System treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).