Mild to Moderate Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease
Brief summary
To evaluate the efficacy of rivastigmine patch with 1-step titration on cognitive function measured as change from baseline to week 24 in the total score of Mini-Mental State Examination (MMSE) in mild to moderate Alzheimer's disease (AD) patients who failed to benefit from other cholinesterase inhibitors (ChEIs).
Interventions
Alzheimer's disease patient who is applicable to 1 step titration method (initial loading dose is a rivastigmine patch 9.0 mg/day and will be up-titrated after 4 weeks to reach the maintenance dose of 18 mg/day). Rivastigmine patch is a marketed drug, therefore the dose, dose regimen and titration scheme are in accordance with product label.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Outpatient status at baseline. 2. Males, and females not of child-bearing potential (surgically sterile, or one year or more from last menses). 3. A diagnosis of dementia of the Alzheimer's type according to the DSM-IV criteria. 4. A clinical diagnosis of probable AD according to National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. 5. Brain scan (magnetic resonance imaging \[MRI\], or computed tomography \[CT\]) were met diagnosis criteria conducted within 3 years prior to baseline. 6. Positron emission tomography (PET) or single photon emission computed tomography (SPECT) was met diagnosis criteria conducted within 3 years prior to baseline visit, as long as in the past a brain scan (MRI or CT) also was met. 7. MMSE score of ≥ 10 and ≤ 23 at screening and baseline. 8. Patients are currently on the oral monotherapy (donepezil, 5 mg), or galantamine (16-24 mg) for 4 weeks prior to baseline visit. 9. Patients who failed to receive enough treatment benefit from the previous treatment can be defined if the patients meet at least one of following conditions at screening and baseline (multiple choices allowed) 10. Patients who declined ≥ 2 points of MMSE despite of treatment of other oral Cholinesterase (ChE) inhibitors within initial 3-month and continued to show insufficient treatment effect until at baseline. 11. During 6 months prior to screening visit, patients who declined ≥2 points of MMSE with other oral ChE inhibitors and continued to show insufficient treatment effect until at baseline. 12. Patients who show marked worsening of BPSD, or ADL (can be defined by 1 state progression of FAST) judged by a physician despite of treatment of other oral ChE inhibitors in initial 3-month or last 6-month with other oral ChE inhibitors 13. Patients having difficulties being treated orally with ChEIs (donepezil or galantamine) by physician's judgement. 14. Poor compliance or adverse event except GI symptoms 15. Patients with swallowing difficulties.
Exclusion criteria
1. Any medical or neurological condition other than AD that could explain the patient's dementia (e.g., abnormal thyroid function tests, vitamin B12 or folate deficiency, posttraumatic conditions, syphilis, head injury, Huntington's disease, Parkinson's disease, subdural hematoma, normal pressure hydrocephalus, brain tumor) at baseline 2. Any other DSM-IV Axis 1 diagnosis that may interfere with the evaluation of the patient's response to study medication, including other primary neurodegenerative dementia, schizophrenia, or bipolar disorder 3. 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 4. Current diagnosis of an active skin lesion/disorder 5. Patients with a history of hypersensitivity to any ingredients of rivastigmine or carbamate derivatives 6. Each patient will be required to have 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. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MMSE Total Score: Change From Baseline to Week 8 and Week 24 (Full Analysis Set) | baseline, weeks 8 and 24 | Evaluation of the efficacy of rivastigmine patch with 1-step titration on cognitive function measured as change from baseline to week 24 in the total score of MMSE in mild to moderate Alzheimer's disease (AD) patients who failed to benefit from other cholinesterase inhibitors (ChEIs) The MMSE is a 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 from baseline. Abbreviated Scale title: Mini Mental State Evaluation Minimum Score: 0 Maximum score: 30 Higher score indicated better cognitive function |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE) Total Score | baseline and week 8 | Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as the MMSE score at week 8 for patients who had 1-step titration MMSE total score: change from baseline to Week 8 and Week 24 for patients who had 1-step titration Unabbreviated Scale : MMSE - Mini Mental State Evaluation: Minimum values - 0 Maximum value - 30 Higher Value means a better outcome Positive change score from baseline indicates better outcome |
| Change in Neuropsychiatric Inventory - 10 Item (NPI-10) Score From Baseline to Week 8 and Week 24 | baseline, week 8, week 24 | Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as the Neuropsychiatric Inventory - 10 Item (NPI-10) score at week 8 and week 24. Per protocol, Neuropsychiatric The NPI-10 total score is a sum of the 10 items, where the score for a domain is defined as the product of frequency (range: 1-4) and severity (range: 1-3). Each domain has a maximum score of 12 and all domains are equally weighted for the total score (thus the range for the total score is 0 to 120). A higher score indicates more severe impairment. Neuropsychiatry Inventory - 10 Minimum Score = 0 Maximum Score = 120 Higher Score indicates worse outcome |
| Change in QOL-AD Score From Baseline to Week 24 | baseline and week 24 | Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as QOL-AD score at week 24. Unabbreviated Scale Name: Quality of Life - Alzheimer's Disease Minimum Score = 13 Maximum Score = 52 Higher value indicates a better outcome QOL-AD is a 13-item questionnaire to assess the quality of life of Alzheimer's patients from the perspectives of patients and their caregivers. It covers several aspects, for example, the perception of health status, mood, functional capacity, personal relationships and leisure, financial situation, and life as a whole. Each item is quantified using a Likert scale with score one classified as poor, and score four as excellent where total scores range from 13 to 52. A lower score indicates more severe impairment. |
| MMSE Total Score: Change From Baseline to Week 8 and Week 24 | baseline, weeks 8 and 24 | Evaluation of the safety, tolerability of rivastigmine patch with 1-step titration for up to 24 weeks. Per Protocol, The MMSE is a brief, practical screening test for cognitive dysfunction. The MMSE consists of 2 parts: language (time orientation, registration and attention) and performance (recall, response to written/verbal commands, writing ability and reproduction of complex polygons), and the total possible score is 30. Lower score indicates more severe impairment. It is the most common and simple cognitive scale for Alzheimer's disease. Unabbreviated Scale : MMSE - Mini Mental State Evaluation: Minimum values - 0 Maximum value - 30 Higher Value means a better outcome Positive change score from baseline indicates improvement in cognitive function |
| Change in as Modified Crichton Scale Score From Baseline to Week 4, 8, 16 and 24 | baseline, weeks 4, 8, 16, 24 | Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as Modified Crichton Scale score week 4, week 8, week 16, and week 24. Modified Crichton Scale that assess basic activation of daily living, communication functions, and quality of life The following 7 items will be evaluated by caregiver. Total score is in the 0 to 56 range. Higher score means more severe impairment. Unabbreviated Scale Title: Modified Crichton scale Minimum score = 0 Maximum Score = 56 Higher score indicates worse outcome |
| Formulation Usability Questionnaire Form Score up to Week 24 | Up to week 24 | Evaluation of the formulation usability of rivastigmine patch for up to 24 weeks as measured by the formulation usability questionnaire answered by caregiver. The Formulation usability preference questionnaire had been used to compare the previous oral AD drugs versus the patch The caregiver selects one of the following answers (1. Very easy to use, 2. Easy to use, 3. No change, 4. Not easy to use, 5. Not easy to use at all, 6. Unknown). This questionnaire data is used to assess if the usability of rivastigmine patch was preferred by the majority (\> 50%) of AD patient caregivers or not. Unabbreviated Questionnaire title: Formulation Usability questionnaire Minimum Score = 1 Maximum Score = 6 A higher score indicates its not easy to use and worse outcome. |
| Change in J-CGIC Score From Baseline and at Week 24 | baseline and week 24 | Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as the The Japanese-Clinical Global Impression of Change (J-CGIC) score at baseline and week 24 J-CGIC is a 7-grade investigator's impression scale: 1. Markedly improved, 2. Improved, 3. Slightly improved, 4. No change, 5. Slightly aggravated, 6. Aggravated, 7. Markedly aggravated At week 24, 103 patients had available data Total score is in the 0 to 56 range. Higher score means more severe impairment. Unabbreviated scale title: Japanese -Cinical Global Impression of Change Minimum Score - 1 Maximum Score - 7 |
Countries
Japan
Participant flow
Recruitment details
The full analysis set (FAS) included all patients who received at least one dose of study treatment and had at least a baseline and any post-baseline assessment on treatment.
Pre-assignment details
In total, 147 patients were screened for the study. 129 completed screening and 18 discontinued from screening. 118 patients were enrolled and the remaining 11 patients discontinued at baseline. All 118 enrolled patients received study treatment. 102 completed the study and 16 discontinued
Participants by arm
| Arm | Count |
|---|---|
| Rivastigmine Patch Alzheimer's disease patient who is applicable to 1 step titration method (initial loading dose is a rivastigmine patch 9.0 mg/day and was up-titrated after 4 weeks to reach the maintenance dose of 18 mg/day). Rivastigmine patch is a marketed drug, therefore the dose, dose regimen and titration scheme are in accordance with product label. | 118 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 14 |
| Overall Study | Study stopped by sponsor | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Rivastigmine Patch |
|---|---|
| Age, Continuous | 76.4 years STANDARD_DEVIATION 6.43 |
| Race/Ethnicity, Customized Asian | 117 Participants |
| Race/Ethnicity, Customized Caucasian | 1 Participants |
| Sex: Female, Male Female | 71 Participants |
| Sex: Female, Male Male | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 118 |
| other Total, other adverse events | 57 / 118 |
| serious Total, serious adverse events | 5 / 118 |
Outcome results
Primary
MMSE Total Score: Change From Baseline to Week 8 and Week 24 (Full Analysis Set)
Evaluation of the efficacy of rivastigmine patch with 1-step titration on cognitive function measured as change from baseline to week 24 in the total score of MMSE in mild to moderate Alzheimer's disease (AD) patients who failed to benefit from other cholinesterase inhibitors (ChEIs) The MMSE is a 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 from baseline. Abbreviated Scale title: Mini Mental State Evaluation Minimum Score: 0 Maximum score: 30 Higher score indicated better cognitive function
Time frame: baseline, weeks 8 and 24
Population: The full analysis set (FAS) included all patients who received at least one dose of study treatment and had at least a baseline and any post-baseline assessment on treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rivastigmine Patch | MMSE Total Score: Change From Baseline to Week 8 and Week 24 (Full Analysis Set) | baseline | 17.33 scores on a scale | Standard Deviation 3.8 |
| Rivastigmine Patch | MMSE Total Score: Change From Baseline to Week 8 and Week 24 (Full Analysis Set) | change at week 8 | 0.29 scores on a scale | Standard Deviation 2.17 |
| Rivastigmine Patch | MMSE Total Score: Change From Baseline to Week 8 and Week 24 (Full Analysis Set) | change at week 24 | -0.36 scores on a scale | Standard Deviation 2.64 |
p-value: 0.17595% CI: [-0.87, 0.16]t-test, 2 sided
Secondary
Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE) Total Score
Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as the MMSE score at week 8 for patients who had 1-step titration MMSE total score: change from baseline to Week 8 and Week 24 for patients who had 1-step titration Unabbreviated Scale : MMSE - Mini Mental State Evaluation: Minimum values - 0 Maximum value - 30 Higher Value means a better outcome Positive change score from baseline indicates better outcome
Time frame: baseline and week 8
Population: FAS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rivastigmine Patch | Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE) Total Score | baseline | 17.25 scores on a scale | Standard Deviation 3.82 |
| Rivastigmine Patch | Change From Baseline to Week 8 in Mini-Mental State Examination (MMSE) Total Score | week 8 | 0.31 scores on a scale | Standard Deviation 2.18 |
Secondary
Change in as Modified Crichton Scale Score From Baseline to Week 4, 8, 16 and 24
Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as Modified Crichton Scale score week 4, week 8, week 16, and week 24. Modified Crichton Scale that assess basic activation of daily living, communication functions, and quality of life The following 7 items will be evaluated by caregiver. Total score is in the 0 to 56 range. Higher score means more severe impairment. Unabbreviated Scale Title: Modified Crichton scale Minimum score = 0 Maximum Score = 56 Higher score indicates worse outcome
Time frame: baseline, weeks 4, 8, 16, 24
Population: FAS~The number of participants analysed per row (modified crichton scale) differs from overall number of participants because this is based on available data and patient continuation/discontinuation during that respective study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rivastigmine Patch | Change in as Modified Crichton Scale Score From Baseline to Week 4, 8, 16 and 24 | baseline | 18.38 scores on a scale | Standard Deviation 9.41 |
| Rivastigmine Patch | Change in as Modified Crichton Scale Score From Baseline to Week 4, 8, 16 and 24 | week 4 | -0.41 scores on a scale | Standard Deviation 5.44 |
| Rivastigmine Patch | Change in as Modified Crichton Scale Score From Baseline to Week 4, 8, 16 and 24 | week 8 | -0.55 scores on a scale | Standard Deviation 6.58 |
| Rivastigmine Patch | Change in as Modified Crichton Scale Score From Baseline to Week 4, 8, 16 and 24 | week 16 | 1.04 scores on a scale | Standard Deviation 6.94 |
| Rivastigmine Patch | Change in as Modified Crichton Scale Score From Baseline to Week 4, 8, 16 and 24 | week 24 | 2.23 scores on a scale | Standard Deviation 6.69 |
Secondary
Change in J-CGIC Score From Baseline and at Week 24
Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as the The Japanese-Clinical Global Impression of Change (J-CGIC) score at baseline and week 24 J-CGIC is a 7-grade investigator's impression scale: 1. Markedly improved, 2. Improved, 3. Slightly improved, 4. No change, 5. Slightly aggravated, 6. Aggravated, 7. Markedly aggravated At week 24, 103 patients had available data Total score is in the 0 to 56 range. Higher score means more severe impairment. Unabbreviated scale title: Japanese -Cinical Global Impression of Change Minimum Score - 1 Maximum Score - 7
Time frame: baseline and week 24
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Markedly improved | 3 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Unassessable | 0 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Patients without worsening, total | 91 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Patients with improvement | 48 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Patients with worsening, total | 12 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Improved | 6 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Slightly improved | 39 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | No change | 43 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Slightly aggravated | 11 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Aggravated | 1 Participants |
| Rivastigmine Patch | Change in J-CGIC Score From Baseline and at Week 24 | Markedly aggravated | 0 Participants |
Secondary
Change in Neuropsychiatric Inventory - 10 Item (NPI-10) Score From Baseline to Week 8 and Week 24
Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as the Neuropsychiatric Inventory - 10 Item (NPI-10) score at week 8 and week 24. Per protocol, Neuropsychiatric The NPI-10 total score is a sum of the 10 items, where the score for a domain is defined as the product of frequency (range: 1-4) and severity (range: 1-3). Each domain has a maximum score of 12 and all domains are equally weighted for the total score (thus the range for the total score is 0 to 120). A higher score indicates more severe impairment. Neuropsychiatry Inventory - 10 Minimum Score = 0 Maximum Score = 120 Higher Score indicates worse outcome
Time frame: baseline, week 8, week 24
Population: FAS The number of participants analysed per row differs from overall number of participants because this is based on available data and patient continuation/discontinuation during that respective study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rivastigmine Patch | Change in Neuropsychiatric Inventory - 10 Item (NPI-10) Score From Baseline to Week 8 and Week 24 | baseline | 11.43 scores on a scale | Standard Deviation 11.15 |
| Rivastigmine Patch | Change in Neuropsychiatric Inventory - 10 Item (NPI-10) Score From Baseline to Week 8 and Week 24 | week 8 | -1.81 scores on a scale | Standard Deviation 8.81 |
| Rivastigmine Patch | Change in Neuropsychiatric Inventory - 10 Item (NPI-10) Score From Baseline to Week 8 and Week 24 | week 24 | -0.89 scores on a scale | Standard Deviation 11.1 |
Secondary
Change in QOL-AD Score From Baseline to Week 24
Evaluation of the efficacy of rivastigmine patch with 1-step titration measured as QOL-AD score at week 24. Unabbreviated Scale Name: Quality of Life - Alzheimer's Disease Minimum Score = 13 Maximum Score = 52 Higher value indicates a better outcome QOL-AD is a 13-item questionnaire to assess the quality of life of Alzheimer's patients from the perspectives of patients and their caregivers. It covers several aspects, for example, the perception of health status, mood, functional capacity, personal relationships and leisure, financial situation, and life as a whole. Each item is quantified using a Likert scale with score one classified as poor, and score four as excellent where total scores range from 13 to 52. A lower score indicates more severe impairment.
Time frame: baseline and week 24
Population: FAS~The number of participants analysed per row differs from overall number of participants because this is based on available data and patient continuation/discontinuation during that respective study period.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rivastigmine Patch | Change in QOL-AD Score From Baseline to Week 24 | baseline - Patient's assessment | 34.37 scores on a scale | Standard Deviation 5.78 |
| Rivastigmine Patch | Change in QOL-AD Score From Baseline to Week 24 | week 24 - Patient's assessment | -0.34 scores on a scale | Standard Deviation 5.32 |
| Rivastigmine Patch | Change in QOL-AD Score From Baseline to Week 24 | baseline - Caregiver's assessment | 28.75 scores on a scale | Standard Deviation 5.74 |
| Rivastigmine Patch | Change in QOL-AD Score From Baseline to Week 24 | week 24 - Caregiver's assessment | -0.16 scores on a scale | Standard Deviation 5.42 |
Secondary
Formulation Usability Questionnaire Form Score up to Week 24
Evaluation of the formulation usability of rivastigmine patch for up to 24 weeks as measured by the formulation usability questionnaire answered by caregiver. The Formulation usability preference questionnaire had been used to compare the previous oral AD drugs versus the patch The caregiver selects one of the following answers (1. Very easy to use, 2. Easy to use, 3. No change, 4. Not easy to use, 5. Not easy to use at all, 6. Unknown). This questionnaire data is used to assess if the usability of rivastigmine patch was preferred by the majority (\> 50%) of AD patient caregivers or not. Unabbreviated Questionnaire title: Formulation Usability questionnaire Minimum Score = 1 Maximum Score = 6 A higher score indicates its not easy to use and worse outcome.
Time frame: Up to week 24
Population: FAS
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rivastigmine Patch | Formulation Usability Questionnaire Form Score up to Week 24 | Very easy to use | 38 Participants |
| Rivastigmine Patch | Formulation Usability Questionnaire Form Score up to Week 24 | Easy to use | 26 Participants |
| Rivastigmine Patch | Formulation Usability Questionnaire Form Score up to Week 24 | No change | 12 Participants |
| Rivastigmine Patch | Formulation Usability Questionnaire Form Score up to Week 24 | Not easy to use | 36 Participants |
| Rivastigmine Patch | Formulation Usability Questionnaire Form Score up to Week 24 | Not easy to use at all | 5 Participants |
Secondary
MMSE Total Score: Change From Baseline to Week 8 and Week 24
Evaluation of the safety, tolerability of rivastigmine patch with 1-step titration for up to 24 weeks. Per Protocol, The MMSE is a brief, practical screening test for cognitive dysfunction. The MMSE consists of 2 parts: language (time orientation, registration and attention) and performance (recall, response to written/verbal commands, writing ability and reproduction of complex polygons), and the total possible score is 30. Lower score indicates more severe impairment. It is the most common and simple cognitive scale for Alzheimer's disease. Unabbreviated Scale : MMSE - Mini Mental State Evaluation: Minimum values - 0 Maximum value - 30 Higher Value means a better outcome Positive change score from baseline indicates improvement in cognitive function
Time frame: baseline, weeks 8 and 24
Population: Per Protocol Set (PPS): The per protocol set includes all patients in the FAS who had only 1 step titration without any major deviations from the protocol procedures
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rivastigmine Patch | MMSE Total Score: Change From Baseline to Week 8 and Week 24 | baseline | 17.24 scores on a scale | Standard Deviation 3.84 |
| Rivastigmine Patch | MMSE Total Score: Change From Baseline to Week 8 and Week 24 | week 8 | 0.33 scores on a scale | Standard Deviation 2.19 |
| Rivastigmine Patch | MMSE Total Score: Change From Baseline to Week 8 and Week 24 | week 24 | -0.32 scores on a scale | Standard Deviation 2.63 |