Alzheimer's Disease
Conditions
Keywords
Rivastigmine, Alzheimer's disease, Transdermal patch
Brief summary
To evaluate the tolerability, safety and efficacy of 3-step titration versus 1-step titration of Rivastigmine patch in the Japanese population.
Interventions
DRUGActive Comparator
1-step titration group begin treatment with a rivastigmine patch 9 mg/day for 4 weeks, followed by a dose increase to 18 mg/day.
DRUGENA713
-3-step titration group will begin treatment with a rivastigmine patch 4.5 mg/day for 4 weeks, followed by a further dose increase of 4.5 mg/day at 4-week intervals up to the maintenance dose of 18 mg/day.
Sponsors
Ono Pharmaceutical Co. Ltd
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* A diagnosis of dementia of the Alzheimer's type according to the DSM-IV criteria * A clinical diagnosis of probable AD according to NINCDS/ADRDA criteria * An MMSE score of ≥ 10 and ≤ 20 at baseline
Exclusion criteria
* Any medical or neurological conditions other than AD that could explain the patient's dementia * A current diagnosis of probable or possible vascular dementia * A score of \> 5 on the Modified Hachinski Ischemic Scale (MHIS) * A current DSM-IV Axis 1 diagnosis that may interfere with the evaluation of the patient's response to study medication. * Treated with donepezil or galantamine within last 4 weeks before the efficacy assessment at baseline. * an advanced severe progressive or unstable disease of any type that may interfere with efficacy and safety assessments or put the patient's at special risk * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Adverse Events Leading to Study Drug Discontinuation | Up to 24 weeks | The primary variable of this study is the percentage of patients having an AE leading to study drug discontinuation during the 24-week double-blind treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Baseline, 8,16, and 24 weeks | The Alzheimer's Disease Assessment Scale - Japan cognitive subscale (ADAS-J cog) was used to measure change in cognitive function. The ADAS-J cog score ranges from 0-70, with higher total scores indicating more impairment. A negative change score indicates improvement from baseline. |
| Change From Baseline in Mini-Mental State Examination (MMSE) | Baseline and 24 weeks | The MMSE was used to measure severity of Alzheimer's disease. The test consists of 2 parts: language (time orientation, registration and attention) and performance (recall, response to written/verbal commands, sriting ability and reproduction of complex polygons); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement from baseline. |
| Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | 4, 8, 12,16, 20 and 24 weeks | The J-CGIC is simple 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) and a patient is defined to have improvement if J-CGIC tool the values 1, 2, or 3. |
| The Percentage of Treatment Retention. | Up to 24 weeks | Treatment retention rate at effective dose is defined as the proportion of patients who met all the followings - 1) completed the study, 2) received rivastigmine patch 18 mg/day throughout the last 8 weeks 3) received 18 mg/day for ≥75% of the days during the last 8 weeks |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rivastigmine Patch 1 Step 1-step titration group begins treatment with a rivastigmine patch 9 mg/day for 4 weeks, followed by a dose increase to 18 mg/day | 107 |
| Rivastigmine Patch 3 Step 3-step titration group begins treatment with a rivastigmine patch 4.5 mg/day for 4 weeks, followed by a further dose increase of 4.5 mg/day at 4-week intervals up to the maintenance dose of 18 mg/day. | 109 |
| Total | 216 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 20 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Protocol deviation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Rivastigmine Patch 1 Step | Rivastigmine Patch 3 Step | Total |
|---|---|---|---|
| Age, Continuous | 77.5 Years STANDARD_DEVIATION 6.54 | 77.6 Years STANDARD_DEVIATION 5.89 | 77.5 Years STANDARD_DEVIATION 6.21 |
| Sex/Gender, Customized Female | 69 Participants | 76 Participants | 145 Participants |
| Sex/Gender, Customized Male | 38 Participants | 32 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 69 / 107 | 68 / 108 |
| serious Total, serious adverse events | 9 / 107 | 10 / 108 |
Outcome results
Primary
Percentage of Patients With Adverse Events Leading to Study Drug Discontinuation
The primary variable of this study is the percentage of patients having an AE leading to study drug discontinuation during the 24-week double-blind treatment period.
Time frame: Up to 24 weeks
Population: Safety population (SAF) This population consisted of all randomized patients who received at least one dose of study medication and had at least one safety assessment after baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivastigmine Patch 1 Step | Percentage of Patients With Adverse Events Leading to Study Drug Discontinuation | 15 Percentage of participants |
| Rivastigmine Patch 3 Step | Percentage of Patients With Adverse Events Leading to Study Drug Discontinuation | 18.5 Percentage of participants |
Secondary
Change From Baseline in Mini-Mental State Examination (MMSE)
The MMSE was used to measure severity of Alzheimer's disease. The test consists of 2 parts: language (time orientation, registration and attention) and performance (recall, response to written/verbal commands, sriting ability and reproduction of complex polygons); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement from baseline.
Time frame: Baseline and 24 weeks
Population: Full analysis set (FAS): The FAS includes all randomized patients who received at least one dose of study drug and had at least one pre- and post-baseline assessment for any of the efficacy variables. n is the number of patients with an assessment at baseline and the corresponding visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rivastigmine Patch 1 Step | Change From Baseline in Mini-Mental State Examination (MMSE) | 0.6 Units on a scale | Standard Deviation 2.91 |
| Rivastigmine Patch 3 Step | Change From Baseline in Mini-Mental State Examination (MMSE) | 0.5 Units on a scale | Standard Deviation 3.15 |
Secondary
Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog)
The Alzheimer's Disease Assessment Scale - Japan cognitive subscale (ADAS-J cog) was used to measure change in cognitive function. The ADAS-J cog score ranges from 0-70, with higher total scores indicating more impairment. A negative change score indicates improvement from baseline.
Time frame: Baseline, 8,16, and 24 weeks
Population: Full analysis set (FAS): includes all randomized patients who received at least one dose of study drug and had at least one pre- and post-baseline assessment for any of the efficacy variables. n is the number of patients with an assessment at baseline and the corresponding visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rivastigmine Patch 1 Step | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Week 8 (n=99, 100) | -1.3 Units on a scale | Standard Deviation 3.94 |
| Rivastigmine Patch 1 Step | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Week 16 (n=100, 100) | -1.6 Units on a scale | Standard Deviation 5.01 |
| Rivastigmine Patch 1 Step | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Week 24 (n=100, 100) | -1.6 Units on a scale | Standard Deviation 4.66 |
| Rivastigmine Patch 3 Step | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Week 8 (n=99, 100) | -0.9 Units on a scale | Standard Deviation 4.49 |
| Rivastigmine Patch 3 Step | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Week 16 (n=100, 100) | -1.2 Units on a scale | Standard Deviation 5.48 |
| Rivastigmine Patch 3 Step | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Week 24 (n=100, 100) | -1.8 Units on a scale | Standard Deviation 5.58 |
Secondary
Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly
The J-CGIC is simple 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) and a patient is defined to have improvement if J-CGIC tool the values 1, 2, or 3.
Time frame: 4, 8, 12,16, 20 and 24 weeks
Population: Full analysis set (FAS): The FAS includes all randomized patients who received at least one dose of study drug and had at least one pre- and post-baseline assessment for any of the efficacy variables. n is the number of patients with an assessment at baseline and the corresponding visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rivastigmine Patch 1 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 4 | 22 Participants |
| Rivastigmine Patch 1 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 8 | 35 Participants |
| Rivastigmine Patch 1 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 12 | 37 Participants |
| Rivastigmine Patch 1 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 16 | 35 Participants |
| Rivastigmine Patch 1 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 20 | 32 Participants |
| Rivastigmine Patch 1 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 24 | 39 Participants |
| Rivastigmine Patch 3 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 20 | 32 Participants |
| Rivastigmine Patch 3 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 4 | 23 Participants |
| Rivastigmine Patch 3 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 16 | 31 Participants |
| Rivastigmine Patch 3 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 8 | 26 Participants |
| Rivastigmine Patch 3 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 24 | 38 Participants |
| Rivastigmine Patch 3 Step | Number of Participants With Improvement in Japanese Clinical Global Impression of Change (J-CGIC). Patients With Improvement: a Total of 1. Markedly Improved, 2. Improved, and 3. Slightly | Week 12 | 33 Participants |
Secondary
The Percentage of Treatment Retention.
Treatment retention rate at effective dose is defined as the proportion of patients who met all the followings - 1) completed the study, 2) received rivastigmine patch 18 mg/day throughout the last 8 weeks 3) received 18 mg/day for ≥75% of the days during the last 8 weeks
Time frame: Up to 24 weeks
Population: Safety population (SAF) This population consisted of all randomized patients who received at least one dose of study medication and had at least one safety assessment after baseline. Patients were analyzed according to the treatment group they were assigned to at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rivastigmine Patch 1 Step | The Percentage of Treatment Retention. | 71 Percentage of Participants |
| Rivastigmine Patch 3 Step | The Percentage of Treatment Retention. | 69.4 Percentage of Participants |