Alzheimer's Disease
Conditions
Keywords
Memantine, Neuroimaging, MRI, Brain atrophy
Brief summary
Pre-clinical studies have demonstrated that memantine can decrease the neuronal toxicity associated with excessive glutamate release and calcium overload in neurons. Previous studies have shown that memantine helps to treat the symptoms of Alzheimer's Disease (AD). In AD, the rate of brain tissue loss, or atrophy, is faster than in normal aging and this seems to go hand in hand with some of the symptoms of the disease. This suggests that memantine treatment in AD could provide both symptomatic improvement and neuro-protective effects. The purpose of this study was to show whether memantine, in addition to providing symptomatic benefits, can slow the rate of brain atrophy as assessed using magnetic resonance imaging (MRI) technology.
Detailed description
The primary objective of this study was to evaluate the effects of memantine on the rate of brain atrophy compared to placebo in patients with AD (moderate severity) over a 1-year period. This was a multinational, randomised, double-blind, parallel-group, placebo-controlled, fixed-dose study (20 mg memantine). The study also included secondary imaging, cognitive and behavioural measures.
Interventions
DRUGMemantine
10 mg tablets twice daily
DRUGPlacebo
Tablets twice 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 at least 50 years of age with a current diagnosis of probable AD of moderate severity (MMSE score between 12 and 20, inclusive) consistent with NINCDS-ADRDA criteria and MRI scans * Patients must have had a knowledgeable and reliable caregiver to accompany them to all clinic visits during the study * Patients were either on or off existing acetylcholinesterase inhibitor (AChEI) treatment provided that the treatment had been initiated \>6 months prior to screening, had stabilised with respect to dose for \>3 months, and remained fixed during the entire study. AChEI treatment could not be initiated or modified during the study
Exclusion criteria
* The patient had evidence of clinically significant active disease (including recent myocardial infarction and uncompensated congestive heart failure \[NYHA II-IV\]) * The patient had evidence of any clinically significant neurodegenerative disease or neurological disorder other than AD * The patient was contraindicated for MRI Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Brain Atrophy Rate Estimated Using Brain Boundary Shift Integral (BBSI) | Baseline to 1 year | Measures direct changes in total brain volume per visit interval (screening to Week 4, 42, or 52 or from Week 4 to Week 42 or 52) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Total Hippocampal Volume (HCV) | Baseline to 1 year | Estimated mean changes in total HCV |
| Cognitive and Behavioural Outcomes: Controlled Oral Word Association Test (COWAT) Total Score | Baseline to 1 year | Adjusted mean change from baseline on cognitive and behavioural scores. COWAT: Verbal fluency test. The patient was asked to, during 1 minute, generate as many words as possible beginning with three pre-specified letters. The total score was calculated as the sum of acceptable words generated, with higher scores indicating lower cognitive impairment |
| Cognitive and Behavioural Outcomes: Mini Mental State Examination (MMSE) Total Score | Baseline to 1 year | Adjusted mean change from baseline on cognitive and behavioural scores. MMSE: Brief, structured examination of mental status that assesses orientation, memory, attention, naming, comprehension, and praxis. The range is 0 to 30, with a lower score indicating a worse mental state |
Participant flow
Recruitment details
The patients were recruited from each investigator's outpatient clinic.
Pre-assignment details
After a 3-week run-in period during which MRI scans were performed, the patients were randomised to either placebo or memantine and stratified according to AChEI treatment. Memantine-treated patients started with 5 mg/day and were uptitrated by 5 mg/day every week for 4 weeks. The target dose of 20 mg/day was administered from the start of Week 4.
Participants by arm
| Arm | Count |
|---|---|
| Memantine 10 mg Tablets Twice Daily | 133 |
| Placebo Tablets Twice Daily | 144 |
| Total | 277 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative or other reason(s) | 4 | 3 |
| Overall Study | Adverse Event | 15 | 12 |
| Overall Study | Lack of Efficacy | 1 | 3 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Non-compliance | 4 | 0 |
| Overall Study | Protocol Violation | 2 | 5 |
| Overall Study | Withdrawal by Subject | 4 | 6 |
Baseline characteristics
| Characteristic | Memantine 10 mg Tablets Twice Daily | Total | Placebo Tablets Twice Daily |
|---|---|---|---|
| ADAS-cog-Orientation Test (ADAS-cog-OT): Baseline Efficacy Scores | 4.2 Points STANDARD_DEVIATION 1.6 | 4.1 Points STANDARD_DEVIATION 1.7 | 4.0 Points STANDARD_DEVIATION 1.7 |
| Age Continuous | 73.7 years STANDARD_DEVIATION 8.8 | 74.1 years STANDARD_DEVIATION 8.3 | 74.4 years STANDARD_DEVIATION 7.7 |
| Category Fluency Test (CFT): Baseline Efficacy Scores | 13.5 Number of words STANDARD_DEVIATION 5.8 | 13.4 Number of words STANDARD_DEVIATION 5.9 | 13.3 Number of words STANDARD_DEVIATION 5.9 |
| Controlled Oral Word Association Test (COWAT): Baseline Efficacy Scores | 19.7 Number of words STANDARD_DEVIATION 10.3 | 19.4 Number of words STANDARD_DEVIATION 9.6 | 19.2 Number of words STANDARD_DEVIATION 8.8 |
| Magnetic Resonance Imaging (MRI) Descriptives Hippocampal Volume (HCV) | 5063.0 mL; mm^3 STANDARD_DEVIATION 1014.3 | 5086.1 mL; mm^3 STANDARD_DEVIATION 924.9 | 5107.6 mL; mm^3 STANDARD_DEVIATION 836.7 |
| Magnetic Resonance Imaging (MRI) Descriptives Total Brain Volume (TBV) | 957.9 mL; mm^3 STANDARD_DEVIATION 103.3 | 963.6 mL; mm^3 STANDARD_DEVIATION 105.8 | 968.9 mL; mm^3 STANDARD_DEVIATION 108.3 |
| Mini Mental State Examination (MMSE): Baseline Efficacy Scores | 16.9 Points STANDARD_DEVIATION 2.4 | 16.9 Points STANDARD_DEVIATION 2.4 | 17.0 Points STANDARD_DEVIATION 2.4 |
| Neuropsychiatric Inventory (NPI): Baseline Efficacy Scores | 13.1 Points STANDARD_DEVIATION 12.8 | 13.0 Points STANDARD_DEVIATION 12.6 | 12.8 Points STANDARD_DEVIATION 12.4 |
| Sex: Female, Male Female | 83 Participants | 158 Participants | 75 Participants |
| Sex: Female, Male Male | 50 Participants | 119 Participants | 69 Participants |
| Stroop Interference Test - Congruent (SIT-C): Baseline Efficacy Scores | 70.5 Seconds STANDARD_DEVIATION 49.1 | 69.6 Seconds STANDARD_DEVIATION 45.4 | 68.8 Seconds STANDARD_DEVIATION 41.7 |
| Stroop Interference Test - Incongruent (SIT-I): Baseline Efficacy Scores | 170.3 Seconds STANDARD_DEVIATION 60.4 | 173.4 Seconds STANDARD_DEVIATION 58.5 | 176.4 Seconds STANDARD_DEVIATION 56.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 133 | 36 / 144 |
| serious Total, serious adverse events | 17 / 133 | 20 / 144 |
Outcome results
Primary
Total Brain Atrophy Rate Estimated Using Brain Boundary Shift Integral (BBSI)
Measures direct changes in total brain volume per visit interval (screening to Week 4, 42, or 52 or from Week 4 to Week 42 or 52)
Time frame: Baseline to 1 year
Population: FAS-MRI: Full-analysis set for all patients in the all-patients-treated set (APTS) who had at least one valid MRI scan \>=6 months after initiation of investigational medicinal product (IMP). The FAS (full analysis set, efficacy set) replaces the intention-to-treat (ITT) concept used in older terminology.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine 10 mg Tablets Twice Daily | Total Brain Atrophy Rate Estimated Using Brain Boundary Shift Integral (BBSI) | 15.24 mL/year | Standard Error 0.97 |
| Placebo Tablets Twice Daily | Total Brain Atrophy Rate Estimated Using Brain Boundary Shift Integral (BBSI) | 15.32 mL/year | Standard Error 0.91 |
Comparison: Linear mixed model relating direct change in brain volume (BBSI) to time and its interaction with treatment group. This model additionally includes a time-by-AChEI group interaction as a fixed effect.p-value: 0.975495% CI: [-2.6, 2.52]Mixed Models Analysis
Secondary
Changes in Total Hippocampal Volume (HCV)
Estimated mean changes in total HCV
Time frame: Baseline to 1 year
Population: FAS-MRI
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine 10 mg Tablets Twice Daily | Changes in Total Hippocampal Volume (HCV) | -218 mm^3/year | Standard Deviation 182 |
| Placebo Tablets Twice Daily | Changes in Total Hippocampal Volume (HCV) | -220 mm^3/year | Standard Deviation 171 |
Comparison: Mixed model repeated measurements (MMRM) with unstructured covariance including time, time-by-treatment, visit, pre-treatment HCV, and AChEI group.p-value: 0.84295% CI: [-38.04, 31.04]MMRM
Secondary
Cognitive and Behavioural Outcomes: Controlled Oral Word Association Test (COWAT) Total Score
Adjusted mean change from baseline on cognitive and behavioural scores. COWAT: Verbal fluency test. The patient was asked to, during 1 minute, generate as many words as possible beginning with three pre-specified letters. The total score was calculated as the sum of acceptable words generated, with higher scores indicating lower cognitive impairment
Time frame: Baseline to 1 year
Population: FAS, observed cases (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Memantine 10 mg Tablets Twice Daily | Cognitive and Behavioural Outcomes: Controlled Oral Word Association Test (COWAT) Total Score | 0.78 Scale scores | Standard Error 0.71 |
| Placebo Tablets Twice Daily | Cognitive and Behavioural Outcomes: Controlled Oral Word Association Test (COWAT) Total Score | -0.90 Scale scores | Standard Error 0.69 |
p-value: 0.03495% CI: [0.13, 3.23]MMRM
Secondary
Cognitive and Behavioural Outcomes: Mini Mental State Examination (MMSE) Total Score
Adjusted mean change from baseline on cognitive and behavioural scores. MMSE: Brief, structured examination of mental status that assesses orientation, memory, attention, naming, comprehension, and praxis. The range is 0 to 30, with a lower score indicating a worse mental state
Time frame: Baseline to 1 year
Population: FAS, OC
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Memantine 10 mg Tablets Twice Daily | Cognitive and Behavioural Outcomes: Mini Mental State Examination (MMSE) Total Score | -0.50 Scale scores | Standard Error 0.45 |
| Placebo Tablets Twice Daily | Cognitive and Behavioural Outcomes: Mini Mental State Examination (MMSE) Total Score | -0.74 Scale scores | Standard Error 0.44 |
p-value: 0.60295% CI: [-0.67, 1.15]MMRM