Alzheimer's Disease
Conditions
Keywords
Dementia, Alzheimer's, Rivastigmine, donepezil
Brief summary
This study was designed to evaluate the safety and tolerability of switching from donepezil to an initial dose of 5cm\^2 rivastigmine patch formulation in patients with probable Alzheimer's Disease (MMSE 10-24). The study included a 5-week, open-label, randomized period followed by a 20-week open-label extension period. Patients were randomized to either an immediate switch from donepezil to rivastigmine patch formulation or to a switch to rivastigmine patch formulation following a 7-day withdrawal period.
Interventions
DRUGRivastigmine 5 cm^2 transdermal patch
Rivastigmine 5 cm\^2 patch size, loaded with 9 mg and providing 4.6 mg rivastigmine per 24 hours.
DRUGRivastigmine 10 cm^2 transdermal patch
Rivastigmine 10 cm\^2 patch size loaded with 18 mg and providing 9.5 mg rivastigmine per 24 hours.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Be at least 50 years of age; * Have a diagnosis of probable Alzheimer's Disease; * Have an MMSE score of \> or = 10 and \< or = 24; * Must have a caregiver who is able to attend all study visits; * Have received continuous treatment with donepezil for at least 6 months prior to screening, and received a stable dose of 5 mg/day or 10 mg/day for at least the last 3 of these 6 months.
Exclusion criteria
* Have an advanced, severe, progressive, or unstable disease of any type that may interfere with efficacy and safety assessments or put the patient at special risk; * Have a history of malignancy of any organ system, treated or untreated, within the past 5 years; * Have a history within the past year or current diagnosis of cerebrovascular disease; * Have a current diagnosis of severe or unstable cardiovascular disease; Have a history of myocardial infarction (MI) in the last six months; * Severe or unstable respiratory conditions (e.g., severe asthma , severe pulmonary (lung) disease); * Digestive problems related to peptic ulcer; * Urinary obstruction or current severe urinary tract infection; * Abnormal thyroid function tests; * Low folate or Vitamin B12; * Have a disability that may prevent the patient from completing all study requirements; * Have a current diagnosis of an active skin lesion/disorder that would prevent adhesion of a patch; Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued From the Study Due to Any Reason During the Core Phase of the Study | Baseline through the end of the core phase of the study (Week 5) | The primary objective of the study was to evaluate the safety and tolerability of 2 paradigms for switching from donepezil to rivastigmine patch in patients with Alzheimer's disease (AD). The primary variable to assess tolerability of switching was the number of participants who discontinued from the study due to any reason during the core phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Discontinued From Study Due to Any Reason During Extension Phase | From week 5 through the end of extension phase (25 weeks) | A secondary assessment of the safety and tolerability of 2 paradigms for switching from donepezil to rivastigmine patch in patients with Alzheimer's disease (AD) was the number of participants who discontinued from the study due to any reason during extension phases of the study. |
| Mean Change From Baseline in the Clinical Global Impression of Change (CGIC) Score at Week 5 and Week 25 | Baseline, Week 5 (end of the core phase) and Week 25 (end of the extension phase) | The CGIC is an assessment tool used by a skilled clinician to make a judgment of the severity or a change of a patient's condition. The clinician relies solely on information obtained from the patient at the Baseline visit as well as clinical information obtained throughout the study period. The clinician does not have access to any post-baseline cognitive testing data. The CGIC is rated on a seven-point scale, ranging from (1) very much improved to (4) no change to (7) very much worse. |
| Number of Participants Who Discontinued From the Study Due to Any Adverse Event (AE) During the Combined Core and Extension Phases of the Study | Baseline through the end of study (25 weeks) | A secondary assessment of the safety and tolerability of 2 paradigms for switching from donepezil to rivastigmine patch in patients with Alzheimer's disease (AD) was the number of participants who discontinued from the study due to an AE during the combined core and extension phases of the study. |
| Mean Change From Baseline in Neuropsychiatric Inventory - 10 Item (NPI-10) Score at Week 25 and at the End of Study. | Baseline, Week 25 (end of the extension phase) and at End of Study | The NPI-10 assesses a wide range of behavior problems encountered in dementia patients. The 10 behavioral domains comprising the NPI-10 are evaluated through an interview of the caregiver by a mental health professional. The scale includes both frequency and severity ratings of each domain as well as a composite domain score (frequency x severity). The sum of the composite scores for the 10 domains yields the NPI total score, which ranges from 0 to 120, the lower the score the less severe the symptoms. A negative change score from baseline indicates improvement. |
| Mean Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 25 and at the End of Study | Baseline, Week 25 (end of the extension phase) and at the end of Study | The ADCS-ADL scale is composed of 23 items to assess the 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, making judgments and decisions. Responses for each item are obtained through a caregiver interview. The total score is the sum of all items and sub-questions. The range for the total ADCS-ADL score is 0 to 78; a higher score indicates a more self-sufficient individual. A positive change from baseline indicates improvement. |
| Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 25 and at the End of Study | Baseline and Week 25 (end of the extension phase) and at the end of study | The MMSE is a brief, practical screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Immediate Switch Patients randomized to the immediate switch group continued treatment with donepezil through the evening prior to Day 8 of the study. On Day 8, all patients began open-label treatment with 5 cm\^2 rivastigmine patch formulation. A new patch was applied daily for 4 weeks. Patients who completed the core phase had the option of entering the extension phase, in which they received open-label treatment with rivastigmine patch formulation for an additional 20 weeks. In the absence of any dose-limiting adverse events (AEs), the dose was increased to 10 cm\^2 patch, and it remained the same through Week 25. Patients who experienced dose-limiting AEs had their dose reduced to 5 cm\^2 patch and continued on their best tolerated dose for the remainder of the study. | 131 |
| Delayed Switch Patients randomized to the delayed switch group were switched to 5 cm\^2 rivastigmine patch formulation on Day 8, following a 7-day withdrawal period from donepezil. A new patch was applied daily for 4 weeks. Patients who completed the core phase had the option of entering the extension phase, in which they received open-label treatment with rivastigmine patch formulation for an additional 20 weeks. In the absence of any dose-limiting adverse events (AEs), the dose was increased to 10 cm\^2 patch, and it remained the same through Week 25. Patients who experienced dose-limiting AEs had their dose reduced to 5 cm\^2 patch and continued on their best tolerated dose for the remainder of the study. | 130 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Phase | Abnormal test procedure result(s) | 0 | 1 |
| Core Phase | Adverse Event | 6 | 4 |
| Core Phase | Lack of Efficacy | 2 | 0 |
| Core Phase | Protocol deviation | 0 | 2 |
| Core Phase | Withdrawal by Subject | 3 | 4 |
| Extension Phase | Administrative problems | 1 | 1 |
| Extension Phase | Adverse Event | 17 | 11 |
| Extension Phase | Death | 1 | 0 |
| Extension Phase | Lack of Efficacy | 4 | 3 |
| Extension Phase | Lost to Follow-up | 0 | 3 |
| Extension Phase | Protocol Violation | 3 | 2 |
| Extension Phase | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Immediate Switch | Delayed Switch | Total |
|---|---|---|---|
| Age, Continuous | 77.8 years STANDARD_DEVIATION 7.66 | 76.7 years STANDARD_DEVIATION 8.41 | 77.3 years STANDARD_DEVIATION 8.04 |
| Sex: Female, Male Female | 79 Participants | 72 Participants | 151 Participants |
| Sex: Female, Male Male | 52 Participants | 58 Participants | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 131 | 51 / 130 |
| serious Total, serious adverse events | 14 / 131 | 9 / 130 |
Outcome results
Primary
Number of Participants Who Discontinued From the Study Due to Any Reason During the Core Phase of the Study
The primary objective of the study was to evaluate the safety and tolerability of 2 paradigms for switching from donepezil to rivastigmine patch in patients with Alzheimer's disease (AD). The primary variable to assess tolerability of switching was the number of participants who discontinued from the study due to any reason during the core phase.
Time frame: Baseline through the end of the core phase of the study (Week 5)
Population: The Safety population consisted of all randomized patients who had at least 1 post-baseline safety assessment. Patients were analyzed according to the treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Switch | Number of Participants Who Discontinued From the Study Due to Any Reason During the Core Phase of the Study | 11 Participants |
| Delayed Switch | Number of Participants Who Discontinued From the Study Due to Any Reason During the Core Phase of the Study | 10 Participants |
Secondary
Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 25 and at the End of Study
The MMSE is a brief, practical screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement.
Time frame: Baseline and Week 25 (end of the extension phase) and at the end of study
Population: The Intent-to-Treat (ITT) population included all randomized patients who entered the switch period for at least 1 day and had at least 1 post-baseline assessment of tolerability/safety. This outcome used observed cases without imputation (OC).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Immediate Switch | Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 25 and at the End of Study | At Week 25 (n= 96, 106) | -0.7 Scores on a scale | Standard Deviation 3.58 |
| Immediate Switch | Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 25 and at the End of Study | At the End of Study (n= 115, 118) | -0.5 Scores on a scale | Standard Deviation 3.62 |
| Delayed Switch | Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 25 and at the End of Study | At Week 25 (n= 96, 106) | -0.4 Scores on a scale | Standard Deviation 3.94 |
| Delayed Switch | Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 25 and at the End of Study | At the End of Study (n= 115, 118) | -0.3 Scores on a scale | Standard Deviation 4.11 |
Secondary
Mean Change From Baseline in Neuropsychiatric Inventory - 10 Item (NPI-10) Score at Week 25 and at the End of Study.
The NPI-10 assesses a wide range of behavior problems encountered in dementia patients. The 10 behavioral domains comprising the NPI-10 are evaluated through an interview of the caregiver by a mental health professional. The scale includes both frequency and severity ratings of each domain as well as a composite domain score (frequency x severity). The sum of the composite scores for the 10 domains yields the NPI total score, which ranges from 0 to 120, the lower the score the less severe the symptoms. A negative change score from baseline indicates improvement.
Time frame: Baseline, Week 25 (end of the extension phase) and at End of Study
Population: The Intent-to-Treat (ITT) population included all randomized patients who entered the switch period for at least 1 day and had at least 1 post-baseline assessment of tolerability/safety. This outcome used observed cases without imputation (OC).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Immediate Switch | Mean Change From Baseline in Neuropsychiatric Inventory - 10 Item (NPI-10) Score at Week 25 and at the End of Study. | At week 25 (n= 95, 107) | -0.1 Scores on a scale | Standard Deviation 9.53 |
| Immediate Switch | Mean Change From Baseline in Neuropsychiatric Inventory - 10 Item (NPI-10) Score at Week 25 and at the End of Study. | At the End of Study (n= 114, 118) | -0.8 Scores on a scale | Standard Deviation 11.22 |
| Delayed Switch | Mean Change From Baseline in Neuropsychiatric Inventory - 10 Item (NPI-10) Score at Week 25 and at the End of Study. | At week 25 (n= 95, 107) | 0.4 Scores on a scale | Standard Deviation 12.92 |
| Delayed Switch | Mean Change From Baseline in Neuropsychiatric Inventory - 10 Item (NPI-10) Score at Week 25 and at the End of Study. | At the End of Study (n= 114, 118) | 0.5 Scores on a scale | Standard Deviation 12.36 |
Secondary
Mean Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 25 and at the End of Study
The ADCS-ADL scale is composed of 23 items to assess the 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, making judgments and decisions. Responses for each item are obtained through a caregiver interview. The total score is the sum of all items and sub-questions. The range for the total ADCS-ADL score is 0 to 78; a higher score indicates a more self-sufficient individual. A positive change from baseline indicates improvement.
Time frame: Baseline, Week 25 (end of the extension phase) and at the end of Study
Population: The Intent-to-Treat (ITT) population included all randomized patients who entered the switch period for at least 1 day and had at least 1 post-baseline assessment of tolerability/safety. This outcome used observed cases without imputation (OC).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Immediate Switch | Mean Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 25 and at the End of Study | At Week 25 (n= 95, 107) | -3.9 Scores on a scale | Standard Deviation 8.72 |
| Immediate Switch | Mean Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 25 and at the End of Study | At the End of Study (n= 113, 117) | -3.1 Scores on a scale | Standard Deviation 9.44 |
| Delayed Switch | Mean Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 25 and at the End of Study | At Week 25 (n= 95, 107) | -4.2 Scores on a scale | Standard Deviation 9.91 |
| Delayed Switch | Mean Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score at Week 25 and at the End of Study | At the End of Study (n= 113, 117) | -4.2 Scores on a scale | Standard Deviation 9.65 |
Secondary
Mean Change From Baseline in the Clinical Global Impression of Change (CGIC) Score at Week 5 and Week 25
The CGIC is an assessment tool used by a skilled clinician to make a judgment of the severity or a change of a patient's condition. The clinician relies solely on information obtained from the patient at the Baseline visit as well as clinical information obtained throughout the study period. The clinician does not have access to any post-baseline cognitive testing data. The CGIC is rated on a seven-point scale, ranging from (1) very much improved to (4) no change to (7) very much worse.
Time frame: Baseline, Week 5 (end of the core phase) and Week 25 (end of the extension phase)
Population: The Intent-to-Treat (ITT) population included all randomized patients who entered the switch period for at least 1 day and had at least 1 post-baseline assessment of tolerability/safety. This outcome used observed cases without imputation (OC).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Immediate Switch | Mean Change From Baseline in the Clinical Global Impression of Change (CGIC) Score at Week 5 and Week 25 | At Week 5 (n= 116, 114) | 3.9 Scores on a scale | Standard Deviation 0.85 |
| Immediate Switch | Mean Change From Baseline in the Clinical Global Impression of Change (CGIC) Score at Week 5 and Week 25 | At Week 25 (n= 105, 109) | 4.1 Scores on a scale | Standard Deviation 1.16 |
| Delayed Switch | Mean Change From Baseline in the Clinical Global Impression of Change (CGIC) Score at Week 5 and Week 25 | At Week 5 (n= 116, 114) | 4.0 Scores on a scale | Standard Deviation 0.84 |
| Delayed Switch | Mean Change From Baseline in the Clinical Global Impression of Change (CGIC) Score at Week 5 and Week 25 | At Week 25 (n= 105, 109) | 4.3 Scores on a scale | Standard Deviation 0.96 |
Secondary
Number of Participants Who Discontinued From Study Due to Any Reason During Extension Phase
A secondary assessment of the safety and tolerability of 2 paradigms for switching from donepezil to rivastigmine patch in patients with Alzheimer's disease (AD) was the number of participants who discontinued from the study due to any reason during extension phases of the study.
Time frame: From week 5 through the end of extension phase (25 weeks)
Population: The Safety population consisted of all randomized patients who had at least 1 post-baseline safety assessment. Patients were analyzed according to the treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Switch | Number of Participants Who Discontinued From Study Due to Any Reason During Extension Phase | 32 Participants |
| Delayed Switch | Number of Participants Who Discontinued From Study Due to Any Reason During Extension Phase | 26 Participants |
Secondary
Number of Participants Who Discontinued From the Study Due to Any Adverse Event (AE) During the Combined Core and Extension Phases of the Study
A secondary assessment of the safety and tolerability of 2 paradigms for switching from donepezil to rivastigmine patch in patients with Alzheimer's disease (AD) was the number of participants who discontinued from the study due to an AE during the combined core and extension phases of the study.
Time frame: Baseline through the end of study (25 weeks)
Population: The Safety population consisted of all randomized patients who had at least 1 post-baseline safety assessment. Patients were analyzed according to the treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Switch | Number of Participants Who Discontinued From the Study Due to Any Adverse Event (AE) During the Combined Core and Extension Phases of the Study | 23 Participants |
| Delayed Switch | Number of Participants Who Discontinued From the Study Due to Any Adverse Event (AE) During the Combined Core and Extension Phases of the Study | 15 Participants |