Dementia of the Alzheimer's Type
Conditions
Keywords
memantine, Alzheimer's disease, moderate to severe Alzheimer's disease
Brief summary
The objective of this study is to evaluate the safety, tolerability, and efficacy of memantine compared to placebo in outpatients diagnosed with moderate-to-severe dementia of the Alzheimer's type on a concurrent acetylcholinesterase inhibitor (AChEI).
Detailed description
Memantine is a therapeutic agent that represents a unique class of Alzheimer's disease (AD) treatment options. A once daily (QD) dosing regimen in an AD population would simplify administration for the caregiver. The purpose of this study is to evaluate the safety and efficacy of modified release memantine taken once daily in outpatients with moderate-to-severe AD on a concurrent AChEI.
Interventions
DRUGmemantine ER
28mg(7mg capsules) once daily and oral administration for 24 weeks.
DRUGPlacebo
Matching placebo oral administration once daily.
Sponsors
Forest Laboratories
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Ambulatory patients aged \>/= 50 years * Diagnostic evidence of probable Alzheimer's disease consistent with criteria from the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) * Confirmatory magnetic resonance imaging (MRI) or computed tomographic (CT) scan within the prior 12 months. * Mini-Mental State Examination (MMSE) scores \>/= 3 and \</= 14 at Screening (Visit 1) and Baseline (Visit 2) * Ongoing daily acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for at least 3 months prior to Screening (Visit 1). It is preferred that patients continue to receive the same AChEI therapy for the duration of the study.
Exclusion criteria
* Patients with a modified Hachinski Ischemia Score greater than 4 at Screening. * Patients who have taken memantine within one month of Screening (Visit 1) * Patients who have a known hypersensitivity to memantine, neramexane, rimantadine, or amantadine. * Patients whose AChEI therapy is likely to be interrupted or discontinued during the course of the study. * Patients who are receiving therapy with more than one AChEI. * Patients with computed tomography (CT) or magnetic resonance imaging (MRI) evidence of hydrocephalus, stroke, a space-occupying lesion, cerebral infection, or any clinically significant central nervous system disease other than Alzheimer's disease. * Patients with a DSM-IV Axis I disorder other than Alzheimer's disease, including amnestic disorders, schizophrenia or schizoaffective disorder, bipolar disorder, current major depressive episode, psychosis, panic, or post-traumatic stress disorder. * Patients who, in the clinician's judgement, are likely to be placed in a nursing home within the next 6 months. * Patients who had evidence of other neurological disorders that included, but were not limited to, stroke, Parkinson's disease, seizure disorder, or head injury with loss of consciousness within the prior 5 years * Patients who had dementia that was complicated by other organic disease * Patients who had dementia complicated by the presence of predominant delusions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF) | Baseline to week 24 | The SIB was developed for the evaluation of cognitive function in patients with more advanced dementia, and evaluates the areas of memory, language, praxis, orientation, and attention. The SIB test items consist of simple, one-step commands presented with gestural cues that are repeated if necessary. The test contains 51 items, and the range of possible scores is 0 to 100 (with 0 being the worst result). The SIB has been shown to be a valid and reliable instrument sensitive to longitudinal change. |
| Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF) | Week 24 | The CIBIC-Plus is a measure of an overall clinical effect and is based on a comprehensive evaluation at Baseline and later visits of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. A skilled clinician interviews the patient, and includes information supplied by a knowledgeable caregiver. The CIBIC-Plus is a rating of the patient's global status relative to Baseline, ranging from a score of 1, indicating marked improvement to a score of 4, indicating no change to a score of 7, indicating marked worsening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the 19-Item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF) | Baseline to week 24 | The ADCS-ADL19 modified inventory consists of 19 items used to measure the functional capabilities of patients with moderate to severe dementia. Each activity-of-daily-living (ADL) item comprises a series of hierarchical subquestions ranging from the highest level of independent performance to complete loss of ability to perform the ADL Inventory. The inventory is performed 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. Response range is 0 (total disability) to 54 (total independence). |
Countries
Argentina, Chile, Mexico, United States
Participant flow
Recruitment details
The recruitment period was from May 20, 2005 to April 18th, 2007 at 83 study centers in four countries (23 in Argentina, 11 in Chile, 11 in Mexico, and 38 in the US)
Pre-assignment details
Study consisted of 1-2 weeks single-blind placebo treatment followed by 24 weeks double-blind treatment. At the end of single-blind placebo treatment, patients meeting entry criteria were randomized (1:1) to 1 of 2 double-blind treatment groups receiving memantine or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo oral administration once daily for 24 weeks. | 335 |
| Memantine ER 28mg once daily oral administration for 24 weeks. | 341 |
| Total | 676 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 21 | 34 |
| Overall Study | Lack of Efficacy | 8 | 3 |
| Overall Study | Lost to Follow-up | 5 | 4 |
| Overall Study | Protocol Violation | 6 | 14 |
| Overall Study | Withdrawal by Subject | 18 | 10 |
| Overall Study | Withdrawn for other reasons | 5 | 4 |
Baseline characteristics
| Characteristic | Total | Memantine ER | Placebo |
|---|---|---|---|
| Age Continuous | 76.5 years STANDARD_DEVIATION 8.07 | 76.2 years STANDARD_DEVIATION 8.35 | 76.8 years STANDARD_DEVIATION 7.76 |
| Age, Customized <= 64 years | 60 participants | 34 participants | 26 participants |
| Age, Customized 65-74 years | 164 participants | 85 participants | 79 participants |
| Age, Customized 75-84 years | 355 participants | 176 participants | 179 participants |
| Age, Customized >= 85 years | 97 participants | 46 participants | 51 participants |
| Region of Enrollment Argentina | 311 participants | 153 participants | 158 participants |
| Region of Enrollment Chile | 90 participants | 46 participants | 44 participants |
| Region of Enrollment Mexico | 97 participants | 49 participants | 48 participants |
| Region of Enrollment United States | 178 participants | 93 participants | 85 participants |
| Sex: Female, Male Female | 487 Participants | 244 Participants | 243 Participants |
| Sex: Female, Male Male | 189 Participants | 97 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 70 / 335 | 67 / 341 |
| serious Total, serious adverse events | 21 / 335 | 28 / 341 |
Outcome results
Primary
Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF)
The SIB was developed for the evaluation of cognitive function in patients with more advanced dementia, and evaluates the areas of memory, language, praxis, orientation, and attention. The SIB test items consist of simple, one-step commands presented with gestural cues that are repeated if necessary. The test contains 51 items, and the range of possible scores is 0 to 100 (with 0 being the worst result). The SIB has been shown to be a valid and reliable instrument sensitive to longitudinal change.
Time frame: Baseline to week 24
Population: Primary efficacy analysis was based on the Intent-to-Treat (ITT) Population. The ITT Population was consisted of all patients in the Safety Population who completed at least one post-Baseline efficacy assessment in SIB or CIBIC-Plus. The last-observation-carried-forward approach was used to impute missing post-Baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF) | -0.4 Units on a scale | Standard Error 0.65 |
| Memantine ER | Change From Baseline in Severe Impairment Battery (SIB) at Week 24 (LOCF) | 2.2 Units on a scale | Standard Error 0.65 |
Comparison: The co-primary efficacy parameter was change from Baseline to Week 24 in SIB total score. Missing SIB total scores at Week 24 were imputed using the last-observation-carried-forward (LOCF) approach.p-value: 0.00195% CI: [1, 4.2]ANCOVA
Primary
Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF)
The CIBIC-Plus is a measure of an overall clinical effect and is based on a comprehensive evaluation at Baseline and later visits of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. A skilled clinician interviews the patient, and includes information supplied by a knowledgeable caregiver. The CIBIC-Plus is a rating of the patient's global status relative to Baseline, ranging from a score of 1, indicating marked improvement to a score of 4, indicating no change to a score of 7, indicating marked worsening.
Time frame: Week 24
Population: Primary efficacy analysis was based on the Intent-to-Treat (ITT) Population. The ITT Population was consisted of all patients in the Safety Population who completed at least one post-Baseline efficacy assessment in SIB or CIBIC-Plus. The last-observation-carried-forward approach was used to impute missing post-Baseline values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF) | 4.1 Units on a scale | Standard Error 0.07 |
| Memantine ER | Clinician's Interview-Based Impression of Change With Caregiver Input (CIBIC-plus) at Week 24 (LOCF) | 3.8 Units on a scale | Standard Error 0.07 |
Comparison: The co-primary efficacy parameter was CIBIC-Plus total score at week 24. Missing CIBIC-Plus total scores at Week 24 were imputed using the last-observation-carried-forward (LOCF) approach.p-value: 0.008Cochran-Mantel-Haenszel
Secondary
Change From Baseline in the 19-Item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF)
The ADCS-ADL19 modified inventory consists of 19 items used to measure the functional capabilities of patients with moderate to severe dementia. Each activity-of-daily-living (ADL) item comprises a series of hierarchical subquestions ranging from the highest level of independent performance to complete loss of ability to perform the ADL Inventory. The inventory is performed 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. Response range is 0 (total disability) to 54 (total independence).
Time frame: Baseline to week 24
Population: The secondary efficacy analysis was based on the ITT Population. The last-observation-carried-forward approach was used to impute missing post-Baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the 19-Item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF) | -1.7 Units on a scale | Standard Error 0.44 |
| Memantine ER | Change From Baseline in the 19-Item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19) Scale at Week 24 (LOCF) | -1.0 Units on a scale | Standard Error 0.44 |
Comparison: The secondary efficacy parameter was change from Baseline at Week 24 in the total score of the 19-Item Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL19). Missing scores at week 24 were imputed using the last-observation-carried-forward (LOCF) approach.p-value: 0.17795% CI: [-0.3, 1.8]ANCOVA