Alzheimer Disease
Conditions
Keywords
Alzheimer's, Patch, Cognitive, Decline
Brief summary
The purpose of this study was to support the optimal use of rivastigmine patch in long-term treatment of Alzheimer's Disease in patients demonstrating functional and cognitive decline at the target maintenance dose of rivastigmine patch 10 cm\^2.
Interventions
DRUGRivastigmine 5 cm^2
5 cm\^2 transdermal patch
DRUGRivastigmine 10 cm^2
10 cm\^2 transdermal patch.
DRUGRivastigmine 15 cm^2
15 cm\^2 transdermal patch.
DRUGPlacebo to 15 cm^2 patch
Placebo of rivastigmine transdermal patch 15 cm\^2.
DRUGPlacebo to 10 cm^2 patch
Placebo of rivastigmine transdermal patch 10 cm\^2.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male or female patients between 50 and 85 years of age with a diagnosis of probable Alzheimers Disease, * Baseline Mini-Mental State Examination (MMSE) score 10-24 inclusive, * A primary caregiver willing to accept responsibility for supervising treatment, assessing the patient's condition throughout the study, and for providing input into efficacy assessments. * For double blind only: Meet the decline criteria of functional (as assessed by the investigator) and cognitive (assessed by a 1 point reduction in Mini-Mental State Examination) score between visits or a 3 point reduction from baseline) decline at weeks 23, 36 or 48.
Exclusion criteria
* Presence of an advanced, severe, progressive, or unstable disease of any type that could interfere with efficacy and safety assessments or put the patient at particular risk, * Any medical or neurological condition other than Alzheimers Disease that could explain the patient's dementia, * A diagnosis of probable or possible vascular dementia, * A current diagnosis of unsuccessfully-treated depression, or any other mental disorder that may interfere with the evaluation of the patient's response to study medication, * A history or current diagnosis of cerebrovascular disease (e.g. stroke), * A current diagnosis of severe or unstable cardiovascular disease (e.g. unstable coronary artery disease). Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period | Baseline and week 48 of double blind period | The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) subscale comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. |
| Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period | Baseline and week 48 of double blind period | The Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) is a 16 item subscale of the caregiver-based ADCS-IADL scale, developed for the use in dementia studies. The ADCS-IADL total score ranges from 0 to 56, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period | Baseline and week 48 of double blind period | Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part B. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. TMT has two parts: Part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-Part B except the person must alternate between numbers and letters. Total values for TMT part B range between 0 and 420 seconds. A negative change from baseline indicates an improvement in condition. |
| Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period | 390 days was the maximum | Functional decline was defined by either an at least 1 point decrease in the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) subscale score in a visit and confirmed by the following visit/assessment or at least 2 points decrease from the double blind randomization baseline. |
| Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | 30 days after a maximum of 96 weeks treatment | — |
| Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period | Baseline and week 48 of double blind period | Change from baseline to week 48 as assessed by the Neuropsychiatric Inventory (NPI)-10 total score. The scale consists of 10 domains that are rated for both frequency (range 1-4) and severity (range 1-3). A composite score for each domain is calculated (frequency x severity) which ranges from 1 to 12. There is a leading question for each item. If the symptom is not present then the frequency, severity and distress scores are not completed. In this case the score is 0 for the item. The sum of the composite scores yields the NPI-10 total score (range 0-120). A negative change in score indicates an improvement from baseline (symptom reduction). |
| Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period | Baseline and week 48 of double blind period | Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part A. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. The score represents the amount of time required to complete the task. Total values for TMT part A range between 0 and 300 seconds. A negative change indicates an improvement from baseline. |
Countries
Canada, France, Germany, Italy, Spain, Switzerland, United States
Participant flow
Pre-assignment details
1,584 participants were enrolled, 1582 received study drug during the initial open label period; of these, 567 were qualified to enter a double blind randomized period.
Participants by arm
| Arm | Count |
|---|---|
| Total Patients Total number of patients enrolled in the initial open label period that may have been randomized in the double blind period or may have continued in the extended open label period. | 1,584 |
| Total | 1,584 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double Blind (Maximum 48 Weeks ) | Administrative problems | 0 | 3 | 2 | 0 |
| Double Blind (Maximum 48 Weeks ) | Adverse Event | 0 | 33 | 28 | 0 |
| Double Blind (Maximum 48 Weeks ) | Condition no longer requires study drug | 0 | 0 | 1 | 0 |
| Double Blind (Maximum 48 Weeks ) | Death | 0 | 5 | 3 | 0 |
| Double Blind (Maximum 48 Weeks ) | Lost to Follow-up | 0 | 4 | 6 | 0 |
| Double Blind (Maximum 48 Weeks ) | Protocol Violation | 0 | 5 | 3 | 0 |
| Double Blind (Maximum 48 Weeks ) | Unsatisfactory therapeutic effect | 0 | 13 | 13 | 0 |
| Double Blind (Maximum 48 Weeks ) | Withdrawal by Subject | 0 | 20 | 17 | 0 |
| Extended Open Label (Maximum 48 Weeks) | Administrative problems | 0 | 0 | 0 | 4 |
| Extended Open Label (Maximum 48 Weeks) | Adverse Event | 0 | 0 | 0 | 18 |
| Extended Open Label (Maximum 48 Weeks) | Death | 0 | 0 | 0 | 7 |
| Extended Open Label (Maximum 48 Weeks) | Lost to Follow-up | 0 | 0 | 0 | 8 |
| Extended Open Label (Maximum 48 Weeks) | Protocol Violation | 0 | 0 | 0 | 5 |
| Extended Open Label (Maximum 48 Weeks) | Unsatisfactory therapeutic effect | 0 | 0 | 0 | 6 |
| Extended Open Label (Maximum 48 Weeks) | Withdrawal by Subject | 0 | 0 | 0 | 14 |
| Initial Open Label (Maximum 48 Weeks) | Abnormal laboratory value | 1 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Abnormal test procedure results | 1 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Administrative problem | 7 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Adverse Event | 272 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Death | 22 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Lost to Follow-up | 22 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Protocol Violation | 28 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Unsatisfactory therapeutic effect | 58 | 0 | 0 | 0 |
| Initial Open Label (Maximum 48 Weeks) | Withdrawal by Subject | 88 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total Patients |
|---|---|
| Age Continuous | 74.93 years STANDARD_DEVIATION 7.131 |
| Sex: Female, Male Female | 992 Participants |
| Sex: Female, Male Male | 592 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 732 / 1,582 | 110 / 283 | 151 / 280 | 112 / 457 |
| serious Total, serious adverse events | 227 / 1,582 | 44 / 283 | 44 / 280 | 59 / 457 |
Outcome results
Primary
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period
The Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) subscale comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline.
Time frame: Baseline and week 48 of double blind period
Population: Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double Blind: Rivastigmine (10 cm^2) | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period | 4.9 units on a scale | Standard Deviation 7.49 |
| Double Blind: Rivastigmine (15 cm^2) | Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) Subscale at Week 48 of Double Blind Period | 4.1 units on a scale | Standard Deviation 8 |
Primary
Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period
The Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) is a 16 item subscale of the caregiver-based ADCS-IADL scale, developed for the use in dementia studies. The ADCS-IADL total score ranges from 0 to 56, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline.
Time frame: Baseline and week 48 of double blind period
Population: Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double Blind: Rivastigmine (10 cm^2) | Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period | -6.2 units on a scale | Standard Deviation 8.78 |
| Double Blind: Rivastigmine (15 cm^2) | Change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale Score From Baseline to Week 48 of Double Blind Period | -4.4 units on a scale | Standard Deviation 8.21 |
Secondary
Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period
Change from baseline to week 48 as assessed by the Neuropsychiatric Inventory (NPI)-10 total score. The scale consists of 10 domains that are rated for both frequency (range 1-4) and severity (range 1-3). A composite score for each domain is calculated (frequency x severity) which ranges from 1 to 12. There is a leading question for each item. If the symptom is not present then the frequency, severity and distress scores are not completed. In this case the score is 0 for the item. The sum of the composite scores yields the NPI-10 total score (range 0-120). A negative change in score indicates an improvement from baseline (symptom reduction).
Time frame: Baseline and week 48 of double blind period
Population: Intent to treat population double blind (ITT-DB): included all randomized patients with an assessment at baseline and week 48, who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog, ADCS-IADL).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double Blind: Rivastigmine (10 cm^2) | Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period | 0.9 units on a scale | Standard Deviation 10.98 |
| Double Blind: Rivastigmine (15 cm^2) | Change From Baseline in Neuropsychiatric Inventory (NPI)-10 Score at Week 48 of Double Blind Period | 1.4 units on a scale | Standard Deviation 11.51 |
Secondary
Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period
Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part A. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. The TMT part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. The score represents the amount of time required to complete the task. Total values for TMT part A range between 0 and 300 seconds. A negative change indicates an improvement from baseline.
Time frame: Baseline and week 48 of double blind period
Population: Intent to treat population (ITT-DB): included all randomized patients with an assessment at baseline and week 48 who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog and ADCS-IADL).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double Blind: Rivastigmine (10 cm^2) | Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period | 18.2 Time in seconds | Standard Deviation 62.57 |
| Double Blind: Rivastigmine (15 cm^2) | Change in Attention and Executive Function as Assessed by the Trail Making Test (Part A) at Week 48 of the Double Blind Period | 16.3 Time in seconds | Standard Deviation 66.09 |
Secondary
Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period
Change from baseline to week 48 in total time to perform Trail Making Test (TMT) part B. This test provides information on visual search, scanning, speed of processing, mental flexibility, and executive functions. TMT has two parts: Part A requires an individual to draw lines sequentially connecting 25 encircled numbers distributed on a sheet of paper. Task requirements are similar for TMT-Part B except the person must alternate between numbers and letters. Total values for TMT part B range between 0 and 420 seconds. A negative change from baseline indicates an improvement in condition.
Time frame: Baseline and week 48 of double blind period
Population: Intent to treat population (ITT-DB): included all randomized patients with an assessment at baseline and week 48 who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables (ADAS-cog, ADCS-IADL).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double Blind: Rivastigmine (10 cm^2) | Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period | 9.3 Time in seconds | Standard Deviation 68.8 |
| Double Blind: Rivastigmine (15 cm^2) | Change in Attention and Executive Function as Assessed by the Trail Making Test (Part B) at Week 48 of Double Blind Period | 5.8 Time in seconds | Standard Deviation 65.38 |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events
Time frame: 30 days after a maximum of 96 weeks treatment
Population: The safety set included all patients who received at least one dose of study medication and who had at least one post-baseline safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double Blind: Rivastigmine (10 cm^2) | Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | 1135 Participants |
| Double Blind: Rivastigmine (15 cm^2) | Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | 193 Participants |
| Double Blind: Rivastigmine (15 cm^2) | Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | 210 Participants |
| Extended Open Label (10 cm^2) | Number of Patients With Adverse Events, Serious Adverse Events and Discontinuations Due to Adverse Events | 263 Participants |
Secondary
Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period
Functional decline was defined by either an at least 1 point decrease in the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) subscale score in a visit and confirmed by the following visit/assessment or at least 2 points decrease from the double blind randomization baseline.
Time frame: 390 days was the maximum
Population: Intent to treat population double blind (ITT-DB): included all randomized patients who received at least 1 dose of double blind study drug, and had at least 1 post-randomization assessment for both co-primary efficacy variables: Alzheimer's Disease Assessment Scale-Cognitive and Disease Cooperative Study-Instrumental Activities of Daily Living.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double Blind: Rivastigmine (10 cm^2) | Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period | 90 Time in days |
| Double Blind: Rivastigmine (15 cm^2) | Time to Functional Decline as Measured by Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-IADL) Subscale During the Double Blind Period | 91 Time in days |