Alzheimer's Disease
Conditions
Keywords
Alzheimer's Disease, Cognitive dysfunction, Dementia, Galantamine, R113675
Brief summary
The purpose of this study is to evaluate the efficacy and safety of two fixed doses (16mg/day and 24mg/day) of galantamine (a drug for treating dementia) versus placebo for the treatment of patients with Alzheimer's disease.
Detailed description
This is a randomized (study drug assigned by chance), double-blind (neither the physician nor the patient know the name of the study medication), placebo-controlled, parallel-group study to evaluate the efficacy and safety of two fixed doses of galantamine (16 and 24 milligrams per day \[mg/day\]) in patients with Alzheimer's disease. The study consists of a 4-week screening period during which all patients will receive placebo, and a 24-week double-blind treatment period during which patients will receive placebo, galantamine 16 mg/day, or galantamine 24 mg/day. For patients receiving galantamine treatment, the starting dose is 8 mg/day and increases at 4-week intervals in increments of 8 mg/day. The primary measures of effectiveness are the change from baseline to the end of the study (week 24) in the Alzheimer's Disease Assessment Scale - Japan cognitive subscale (ADAS-J cog) and the Clinician's Interview-Based Impression of Change plus - Japan (CIBIC plus-J). Safety assessments include the incidence of adverse events, clinical laboratory tests, vital signs, electrocardiograms (ECGs), and physical examination findings. The study hypothesis is that galantamine will be effective in the treatment of Alzheimer's disease. Study drug taken orally twice a day.
Interventions
DRUGPlacebo
Form= tablet, route= oral use. Corresponding placebo tablets confirmed to be indistinguishable from the galantamine tablets will be administered for 24 weeks.
DRUGGalantamine 16 mg/day
Type= exact number, number= 8, 16, unit= mg/day, form= tablet, route= oral use. Patients will receive 8 mg galantamine daily for the first 4 weeks, and 16 mg galantamine daily for the remaining 20 weeks.
DRUGGalantamine 24 mg/day
Type= exact number, number= 8, 16, 24, unit= mg/day, form= tablet, route= oral use. Patients will receive 8 mg galantamine daily for the first 4 weeks, then 16 mg galantamine daily for the following 4 weeks, and 24 mg galantamine daily for the remaining 16 weeks.
Sponsors
Janssen Pharmaceutical K.K.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Outpatients with a diagnosis of Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria * Having a Mini-Mental Status Examination (MMSE) score of 10 - 22 inclusive * Having an Alzheimer's Disease Assessment Scale - Japan cognitive subscale (ADAS-J cog) score of at least 18 * Exhibiting an onset and progression of cognitive dysfunction during at least 6 months prior to the screening period
Exclusion criteria
* Patients with neurodegenerative diseases other than Alzheimer's disease, such as Lewy bodies disease, (dementia due to tiny round structures made of proteins that develop within nerve cells in the brain), Parkinsonism, etc * Patients with cognitive dysfunction due to cerebral damage resulting from a lack of oxygen, a brain injury, etc * Patients with multi-infarct dementia (brought on by a series of strokes) or active cerebrovascular disease * Patients with clinically significant cardiovascular disease * Patients currently taking drugs such as a cholinesterase inhibitors, which improve cerebral circulation/metabolism
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | Baseline and 24 weeks | ADAS-J cog is the Japanese version of the cognitive function subscale of the Alzheimer's disease assessment scale (ADAS). This scale is used to detect changes in cognitive function in individuals with Alzheimer disease on the basis of three domains: memory, language and behavior. The minimum score is zero (0) and means well cognitive function. The maximum total score is 70 points, and the larger the score, the more severe the degree of impairment. |
| Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | 24 weeks | CIBIC plus-J is the Japanese version of the Clinician's Interview-based Impression of Change plus the caregiver's input (CIBIC plus). It is a seven-point categorical assessment scale for evaluating the efficacy of antidementia drugs, ranging from markedly improved to markedly worse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Disability Assessment for Dementia (DAD) | Baseline and 24 weeks | Each of the 40 item of the DAD is scored as 1 point= Yes, 0 point= No, or non applicable= N/A. A total score (minimum=0; maximum=40) is the sum of points for each questions converted out 100. Items rated as Not Applicable (N/A) are not considered for the total score. The final score is a percentage that gives an appreciation of global function in activity of daily life (ADL). Higher scores represent less disability in ADL while lower scores indicate more dysfunction. |
| Change From Baseline in the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) | Baseline and 24 weeks | Behave-AD is a CIBIC plus-J subscale that rates the patient's severity of psychotic symptoms. This four-point scale varies from 0 (=none) to 3 (= serious). |
| Change From Baseline in the Mental Function Impairment Scale (MENFIS) | Baseline and 24 weeks | MENFIS is a Clinician's Interview-Based Impression of Change (CIBIC) plus-Japan subscale that rates the patient's severity for mental function impairment. This seven-point scale varies from 0 (= absolutely no impairment) to 6 (=complete impairment). |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Group | 191 |
| Galantamine Group 1 Galantamine 16 mg/day | 191 |
| Galantamine Group 2 Galantamine 24 mg/day | 192 |
| Total | 574 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 15 | 16 | 19 |
| Overall Study | Change of patients for CIBIC plus-J | 1 | 1 | 0 |
| Overall Study | Inappropriate as a subject | 1 | 1 | 1 |
| Overall Study | Missing or change of caregiver | 6 | 2 | 4 |
| Overall Study | Non-compliance | 0 | 1 | 1 |
| Overall Study | Other | 2 | 6 | 4 |
| Overall Study | Withdrawal by Subject | 9 | 11 | 14 |
Baseline characteristics
| Characteristic | Placebo Group | Galantamine Group 1 | Galantamine Group 2 | Total |
|---|---|---|---|---|
| Age, Continuous | 75.5 years STANDARD_DEVIATION 7.6 | 75.6 years STANDARD_DEVIATION 8.4 | 74.6 years STANDARD_DEVIATION 8.8 | 75.2 years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 132 Participants | 125 Participants | 145 Participants | 402 Participants |
| Sex: Female, Male Male | 59 Participants | 66 Participants | 47 Participants | 172 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 146 / 194 | 154 / 192 | 163 / 194 |
| serious Total, serious adverse events | 13 / 194 | 7 / 192 | 8 / 194 |
Outcome results
Primary
Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog)
ADAS-J cog is the Japanese version of the cognitive function subscale of the Alzheimer's disease assessment scale (ADAS). This scale is used to detect changes in cognitive function in individuals with Alzheimer disease on the basis of three domains: memory, language and behavior. The minimum score is zero (0) and means well cognitive function. The maximum total score is 70 points, and the larger the score, the more severe the degree of impairment.
Time frame: Baseline and 24 weeks
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) end point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Group | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | 0.90 Scores on a scale | Standard Deviation 5.89 |
| Galantamine Group 1 | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | -0.58 Scores on a scale | Standard Deviation 5.87 |
| Galantamine Group 2 | Change From Baseline in the Alzheimer's Disease Assessment Scale - Japan Cognitive Subscale (ADAS-J Cog) | -1.66 Scores on a scale | Standard Deviation 5.37 |
p-value: 0.011395% CI: [-2.64, -0.34]Least Square Means
p-value: <0.000195% CI: [-3.74, -1.44]Least Square Means
Primary
Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J)
CIBIC plus-J is the Japanese version of the Clinician's Interview-based Impression of Change plus the caregiver's input (CIBIC plus). It is a seven-point categorical assessment scale for evaluating the efficacy of antidementia drugs, ranging from markedly improved to markedly worse.
Time frame: 24 weeks
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) end point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Group | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Minimally worse | 62 patients |
| Placebo Group | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Moderately worse | 22 patients |
| Placebo Group | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Markedly worse | 0 patients |
| Placebo Group | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Minimally improved | 36 patients |
| Placebo Group | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Markedly improved | 0 patients |
| Placebo Group | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | No change | 64 patients |
| Placebo Group | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Moderately improved | 7 patients |
| Galantamine Group 1 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Markedly improved | 0 patients |
| Galantamine Group 1 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Minimally worse | 64 patients |
| Galantamine Group 1 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Moderately improved | 12 patients |
| Galantamine Group 1 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | No change | 60 patients |
| Galantamine Group 1 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Minimally improved | 39 patients |
| Galantamine Group 1 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Markedly worse | 0 patients |
| Galantamine Group 1 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Moderately worse | 16 patients |
| Galantamine Group 2 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Markedly worse | 1 patients |
| Galantamine Group 2 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Moderately worse | 20 patients |
| Galantamine Group 2 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Markedly improved | 1 patients |
| Galantamine Group 2 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Moderately improved | 4 patients |
| Galantamine Group 2 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Minimally improved | 32 patients |
| Galantamine Group 2 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | No change | 73 patients |
| Galantamine Group 2 | Distribution of Clinician's Interview-Based Impression of Change Plus - Japan (CIBIC Plus-J) | Minimally worse | 61 patients |
Secondary
Change From Baseline in the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD)
Behave-AD is a CIBIC plus-J subscale that rates the patient's severity of psychotic symptoms. This four-point scale varies from 0 (=none) to 3 (= serious).
Time frame: Baseline and 24 weeks
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) end point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Group | Change From Baseline in the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) | 0.0 Scores on a scale | Standard Deviation 3.1 |
| Galantamine Group 1 | Change From Baseline in the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) | -0.2 Scores on a scale | Standard Deviation 4.2 |
| Galantamine Group 2 | Change From Baseline in the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) | -0.3 Scores on a scale | Standard Deviation 3.1 |
p-value: 0.794295% CI: [-0.8, 0.6]Least Square Means
p-value: 0.841995% CI: [-0.6, 0.8]Least Square Means
Secondary
Change From Baseline in the Disability Assessment for Dementia (DAD)
Each of the 40 item of the DAD is scored as 1 point= Yes, 0 point= No, or non applicable= N/A. A total score (minimum=0; maximum=40) is the sum of points for each questions converted out 100. Items rated as Not Applicable (N/A) are not considered for the total score. The final score is a percentage that gives an appreciation of global function in activity of daily life (ADL). Higher scores represent less disability in ADL while lower scores indicate more dysfunction.
Time frame: Baseline and 24 weeks
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) end point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Group | Change From Baseline in the Disability Assessment for Dementia (DAD) | -2.8 Scores on a scale | Standard Deviation 10.3 |
| Galantamine Group 1 | Change From Baseline in the Disability Assessment for Dementia (DAD) | -1.0 Scores on a scale | Standard Deviation 9.4 |
| Galantamine Group 2 | Change From Baseline in the Disability Assessment for Dementia (DAD) | -2.2 Scores on a scale | Standard Deviation 9.3 |
p-value: 0.077495% CI: [-0.2, 3.7]Least Square Means
p-value: 0.620795% CI: [-1.5, 2.4]Least Square Means
Secondary
Change From Baseline in the Mental Function Impairment Scale (MENFIS)
MENFIS is a Clinician's Interview-Based Impression of Change (CIBIC) plus-Japan subscale that rates the patient's severity for mental function impairment. This seven-point scale varies from 0 (= absolutely no impairment) to 6 (=complete impairment).
Time frame: Baseline and 24 weeks
Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) end point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Group | Change From Baseline in the Mental Function Impairment Scale (MENFIS) | 2.2 Scores on a scale | Standard Deviation 5.2 |
| Galantamine Group 1 | Change From Baseline in the Mental Function Impairment Scale (MENFIS) | 1.6 Scores on a scale | Standard Deviation 5.2 |
| Galantamine Group 2 | Change From Baseline in the Mental Function Impairment Scale (MENFIS) | 1.9 Scores on a scale | Standard Deviation 5.2 |
p-value: 0.314195% CI: [-1.6, 0.5]Least Square Means
p-value: 0.608995% CI: [-1.3, 0.8]Least Square Means