Alzheimer's Disease
Conditions
Keywords
Alzheimer's Disease
Brief summary
The primary objective of this study is to examine the efficacy of memantine on cognition and behavioural symptoms in outpatients with moderate to severe dementia of the Alzheimer's type.
Detailed description
Memantine is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Pre-clinical studies have demonstrated that memantine can decrease the neuronal toxicity associated with excessive glutamate release and calcium overload in neurons. Results from clinical trials in patients with moderate to severe Alzheimer's Disease (AD) have demonstrated memantine's efficacy and safety by showing positive treatment effects on cognitive, global and functional decline. This 24-week randomised, double-blind, placebo-controlled, multicentre study examines the effect of memantine 20 mg, administered once daily, on cognitive and behavioural symptoms in outpatients diagnosed with moderate to severe AD and significant psychopathology.
Interventions
DRUGMemantine
20 mg Oral Tablets Once Daily
DRUGPlacebo
Oral Tablets Once Daily
Sponsors
H. Lundbeck A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Outpatients who: * had a primary diagnosis of probable Alzheimer's Disease (AD) according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINDS-ADRDA) criteria, and with Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revised (DSM IV TR) criteria for dementia of the Alzheimer's type * had moderate to severe dementia, defined as a Mini Mental State Examination (MMSE) total score \>=5 and \<=15 at screening. Before substantial protocol amendment SA04 (dated 7 October 2004) was implemented, the MMSE total score range at screening was \>=8 and \<=18. Substantial protocol amendment SA07 (dated 4 September 2009) allowed patients who had previously had an MMSE score of 16 or 17 to be re-screened \>6 months after their initial screening and, if there was documented evidence of cognitive decline, to be enrolled in the study * had a Neuropsychiatric Inventory (NPI) total score \>=13 and an NPI agitation/aggression subitem score \>=1 at screening and baseline * did not have vascular dementia or a modified Hachinski Ischaemia Scale score \>4 at screening
Exclusion criteria
* Evidence of clinically significant active disease, evidence of other neurological disorders, and previous treatment with memantine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Memantine on Behavioural Symptoms in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the NPI - 12 Items Version Total Score. | Baseline to Week 24 | Change from Baseline in Neuropsychiatric Inventory (NPI) total score. NPI is a validated scale that assesses behavioural disturbances in patients with dementia. The 12 item version consists of 10 behavioural and 2 neurovegetative areas. It provides both a total score as well as scores for a number of sub-scales. The frequency, severity and caregiver distress for each domain are measured. The NPI is based upon responses obtained from the caregiver. The total score is from 0 to 144. A higher score reflects more frequency and severity of the disturbances. |
| Efficacy of Memantine on Cognition in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the SIB Total Score. | Baseline to Week 24 | Change from Baseline in Severe Impairment Battery (SIB) total score. SIB is a validated scale used to assess cognitive function in patients with moderate to severe dementia. Items are single words or one-step commands combined with gestures. Nine domains are assessed, and the total score is between 0 and 100. A lower total score reflects the loss of cognitive function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Memantine on Global Condition Using CIBIC-plus. | Baseline to Week 24 | Clinician's Interview-Based Impression of Change-Plus Version (CIBIC-plus). Improvement evaluated with reference to Baseline. CIBIC-plus is a global rating that is derived through an independent, comprehensive interview with the patient and caregiver by a rater who is barred from knowledge of all other psychometric test scores conducted as part of this protocol as well as from reported safety data. The rating is made on a 7-point scale ranging from 1 = marked improvement to 7 = marked worsening. A score of 4 indicates no change. |
| Efficacy of Memantine on Functioning Using ADCS-ADL - 19 Items Total Score. | Baseline to Week 24 | Change from Baseline on the Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) 19-item version total score. ADCS-ADL- 19 items version for moderate to severe AD will measure patient's functioning. This battery of ADL questions is used here to measure the functional capabilities of patients with dementia. The inventory is done by interviewing a person in close contact with the patient and covers the most usual and consistent performance of the patient over the preceding 4 weeks. Total score is from 0 to 54. The higher score, the lower impairment. |
| Efficacy of Memantine on Functioning Using CMAI - Long Form Total Score. | Baseline to Week 24 | Change from Baseline on the Cohen-Mansfield Agitation Inventory (CMAI) - Long Form total score. CMAI - Long Form looks specifically at agitated behaviour in patients with cognitive impairment. It is a seven-point rating scale assessing the frequency of up to 29 agitated behaviours, ranging from 1 = Never to 7 = Several times an hour. Rating is based on responses obtained from interviews with the caregiver. The total score ranges from 29 to 203, with a higher score reflecting more frequent behavioural disturbances. |
Countries
Canada
Participant flow
Recruitment details
The patients were recruited from the investigators' outpatient clinics.
Pre-assignment details
At the Baseline Visit, the patients were randomised (1:1) to 24 weeks of treatment with placebo or memantine. Patients randomised to memantine were up-titrated in weekly increments of 5 mg over a 4-week dose-escalation period. The target dose of 20 mg/day was administered at the start of the fourth week and maintained for the rest of the study.
Participants by arm
| Arm | Count |
|---|---|
| Memantine 20 mg Oral Tablets Once Daily | 182 |
| Placebo Oral Tablets Once Daily | 187 |
| Total | 369 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 10 |
| Overall Study | Non-compliance | 1 | 1 |
| Overall Study | Nursing Home Placement | 2 | 9 |
| Overall Study | Other Reasons | 1 | 3 |
| Overall Study | Protocol Violation | 2 | 2 |
| Overall Study | Withdrawal of Consent | 10 | 7 |
Baseline characteristics
| Characteristic | Memantine | Total | Placebo |
|---|---|---|---|
| ADCS-ADL - 19 items: Baseline Total Score | 35.3 Scores on a scale STANDARD_DEVIATION 9.9 | 35.8 Scores on a scale STANDARD_DEVIATION 9.3 | 36.4 Scores on a scale STANDARD_DEVIATION 8.6 |
| Age Continuous | 74.7 years STANDARD_DEVIATION 7.9 | 74.9 years STANDARD_DEVIATION 7.4 | 75.1 years STANDARD_DEVIATION 6.9 |
| CIBIC-plus: Baseline Severity Score | 4.4 Scores on a scale STANDARD_DEVIATION 0.9 | 4.4 Scores on a scale STANDARD_DEVIATION 0.9 | 4.4 Scores on a scale STANDARD_DEVIATION 0.9 |
| CMAI - Long Form: Baseline Total Score | 46.8 Scores on a scale STANDARD_DEVIATION 10.9 | 46.9 Scores on a scale STANDARD_DEVIATION 10.9 | 47.0 Scores on a scale STANDARD_DEVIATION 10.9 |
| NPI: Baseline Total Score | 30.9 Scores on a scale STANDARD_DEVIATION 14.8 | 30.1 Scores on a scale STANDARD_DEVIATION 14 | 29.2 Scores on a scale STANDARD_DEVIATION 13.3 |
| Sex: Female, Male Female | 105 Participants | 215 Participants | 110 Participants |
| Sex: Female, Male Male | 77 Participants | 154 Participants | 77 Participants |
| SIB: Baseline Total Score | 82.3 Scores on a scale STANDARD_DEVIATION 14.6 | 82.1 Scores on a scale STANDARD_DEVIATION 13.7 | 82.0 Scores on a scale STANDARD_DEVIATION 12.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 51 / 182 | 35 / 187 |
| serious Total, serious adverse events | 18 / 182 | 11 / 187 |
Outcome results
Primary
Efficacy of Memantine on Behavioural Symptoms in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the NPI - 12 Items Version Total Score.
Change from Baseline in Neuropsychiatric Inventory (NPI) total score. NPI is a validated scale that assesses behavioural disturbances in patients with dementia. The 12 item version consists of 10 behavioural and 2 neurovegetative areas. It provides both a total score as well as scores for a number of sub-scales. The frequency, severity and caregiver distress for each domain are measured. The NPI is based upon responses obtained from the caregiver. The total score is from 0 to 144. A higher score reflects more frequency and severity of the disturbances.
Time frame: Baseline to Week 24
Population: Full-analysis Set (FAS) - all randomised patients on current treatment with an acetylcholinesterase inhibitor (AChEI) who took at least one dose of investigational medicinal product (IMP) and had at least one post-baseline assessment on both co-primary efficacy variables.~Last Observation Carried Forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Efficacy of Memantine on Behavioural Symptoms in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the NPI - 12 Items Version Total Score. | -3.90 Scores on a scale | Standard Error 1.24 |
| Placebo | Efficacy of Memantine on Behavioural Symptoms in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the NPI - 12 Items Version Total Score. | -5.13 Scores on a scale | Standard Error 1.23 |
p-value: 0.41895% CI: [-1.75, 4.21]ANCOVA
Primary
Efficacy of Memantine on Cognition in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the SIB Total Score.
Change from Baseline in Severe Impairment Battery (SIB) total score. SIB is a validated scale used to assess cognitive function in patients with moderate to severe dementia. Items are single words or one-step commands combined with gestures. Nine domains are assessed, and the total score is between 0 and 100. A lower total score reflects the loss of cognitive function.
Time frame: Baseline to Week 24
Population: FAS; LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Efficacy of Memantine on Cognition in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the SIB Total Score. | -2.34 Scores on a scale | Standard Error 0.76 |
| Placebo | Efficacy of Memantine on Cognition in Outpatients With Moderate to Severe Dementia of the Alzheimer's Type Using the SIB Total Score. | -1.86 Scores on a scale | Standard Error 0.75 |
p-value: 0.60395% CI: [-2.3, 1.34]ANCOVA
Secondary
Efficacy of Memantine on Functioning Using ADCS-ADL - 19 Items Total Score.
Change from Baseline on the Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) 19-item version total score. ADCS-ADL- 19 items version for moderate to severe AD will measure patient's functioning. This battery of ADL questions is used here to measure the functional capabilities of patients with dementia. The inventory is done by interviewing a person in close contact with the patient and covers the most usual and consistent performance of the patient over the preceding 4 weeks. Total score is from 0 to 54. The higher score, the lower impairment.
Time frame: Baseline to Week 24
Population: FAS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Efficacy of Memantine on Functioning Using ADCS-ADL - 19 Items Total Score. | -4.36 Scores on a scale | Standard Error 0.67 |
| Placebo | Efficacy of Memantine on Functioning Using ADCS-ADL - 19 Items Total Score. | -2.56 Scores on a scale | Standard Error 0.65 |
p-value: 0.01795% CI: [-3.29, -0.32]ANCOVA
Secondary
Efficacy of Memantine on Functioning Using CMAI - Long Form Total Score.
Change from Baseline on the Cohen-Mansfield Agitation Inventory (CMAI) - Long Form total score. CMAI - Long Form looks specifically at agitated behaviour in patients with cognitive impairment. It is a seven-point rating scale assessing the frequency of up to 29 agitated behaviours, ranging from 1 = Never to 7 = Several times an hour. Rating is based on responses obtained from interviews with the caregiver. The total score ranges from 29 to 203, with a higher score reflecting more frequent behavioural disturbances.
Time frame: Baseline to Week 24
Population: FAS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Efficacy of Memantine on Functioning Using CMAI - Long Form Total Score. | -0.26 Scores on a scale | Standard Error 0.79 |
| Placebo | Efficacy of Memantine on Functioning Using CMAI - Long Form Total Score. | -1.16 Scores on a scale | Standard Error 0.79 |
p-value: 0.3695% CI: [-1.03, 2.83]ANCOVA
Secondary
Efficacy of Memantine on Global Condition Using CIBIC-plus.
Clinician's Interview-Based Impression of Change-Plus Version (CIBIC-plus). Improvement evaluated with reference to Baseline. CIBIC-plus is a global rating that is derived through an independent, comprehensive interview with the patient and caregiver by a rater who is barred from knowledge of all other psychometric test scores conducted as part of this protocol as well as from reported safety data. The rating is made on a 7-point scale ranging from 1 = marked improvement to 7 = marked worsening. A score of 4 indicates no change.
Time frame: Baseline to Week 24
Population: FAS; Observed Cases (OC).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Efficacy of Memantine on Global Condition Using CIBIC-plus. | 4.68 Scores on a scale | Standard Error 0.11 |
| Placebo | Efficacy of Memantine on Global Condition Using CIBIC-plus. | 4.63 Scores on a scale | Standard Error 0.11 |
p-value: 0.73495% CI: [-0.22, 0.31]ANCOVA