Alzheimer's Disease
Conditions
Keywords
Alzheimer's Disease
Brief summary
The primary objective of the study was to examine the safety and tolerability of memantine in outpatients with moderate to severe Alzheimer's Disease.
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. The purpose of this 24-week open-label extension study was to collect additional long-term safety and tolerability data on memantine in patients who completed the lead-in double-blind placebo-controlled Study 10158. In agreement with Health Canada the study was prematurely terminated due to recruitment difficulties in the lead-in Study 10158. Patients ongoing in the study when the decision to terminate was taken were allowed to complete it.
Interventions
DRUGMemantine
20 mg oral tablets once daily
Sponsors
H. Lundbeck A/S
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ambulatory outpatients with moderate to severe dementia of the Alzheimer's type who have completed the 24-week Study 10158 and who have a knowledgeable and reliable caregiver who will accompany the patient to all clinic visits during the course of the study.
Exclusion criteria
* Diseases/medication which judged by the investigator could interfere with the assessments of safety, tolerability or efficacy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events (AEs) | Baseline to Week 24 | Overview of AEs |
| Percentage of Patients Who Withdrew Due to Intolerance to Treatment | Baseline to Week 24 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Long-term Efficacy of Memantine on Behavioural Symptoms Using the Neuropsychiatric Inventory (NPI) - 12 Items Version Total Score. | Baseline and Week 24 | Change from Baseline in the NPI total score. Analysed by descriptive methods only. 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. |
| Long-term Efficacy of Memantine on Cognition Using the Severe Impairment Battery (SIB) Total Score. | Baseline and Week 24 | Change from Baseline in the SIB total score. Analysed by descriptive methods only. 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. |
| Long-term Efficacy of Memantine on Global Condition Using the Clinician's Interview-Based Impression of Change-Plus Version (CIBIC-plus). | Week 24 | CIBIC-plus. Improvement evaluated with reference to Baseline. Analysed by descriptive methods only. 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. |
| Long-term Efficacy of Memantine on Functioning Using the Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) 19-item Version Total Score | Baseline and Week 24 | Change from Baseline on the ADCS-ADL 19-item version total score. Analysed by descriptive methods only. 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. |
Countries
Canada
Participant flow
Recruitment details
This was an interventional, multi-centre, open-label, fixed-dose extension study to Study 10158. The Baseline visit in Study 10252 was scheduled to occur at the same time as the Week 24 Visit in Study 10158.
Pre-assignment details
Placebo patients from Study 10158 were uptitrated in weekly increments of 5 mg over a 4-week, double-blind period. Target dose of 20 mg/day was reached at the start of the 4th week and maintained for the rest of the study. Memantine patients in Study 10158 continued on 20 mg/day. From the end of Week 4, the study was open-label.
Participants by arm
| Arm | Count |
|---|---|
| Memantine 20 mg Oral Tablets Once Daily | 297 |
| Total | 297 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 24 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 4 |
| Overall Study | Non-compliance | 1 |
| Overall Study | Nursing Home Placement | 14 |
| Overall Study | Other Reasons | 2 |
| Overall Study | Withdrawal of Consent | 9 |
Baseline characteristics
| Characteristic | Memantine |
|---|---|
| ADCS-ADL - 19 items: Baseline Total Score | 33.43 Scores on a scale STANDARD_DEVIATION 10.06 |
| Age Continuous | 75 years STANDARD_DEVIATION 7.3 |
| CIBIC-plus: Baseline Severity Score | 4.52 Scores on a scale STANDARD_DEVIATION 0.85 |
| NPI: Baseline Total Score | 22.32 Scores on a scale STANDARD_DEVIATION 15.41 |
| Sex: Female, Male Female | 172 Participants |
| Sex: Female, Male Male | 125 Participants |
| SIB: Baseline Total Score | 79.99 Scores on a Scale STANDARD_DEVIATION 16.36 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 85 / 297 |
| serious Total, serious adverse events | 27 / 297 |
Outcome results
Primary
Number of Patients With Adverse Events (AEs)
Overview of AEs
Time frame: Baseline to Week 24
Population: Completers from lead-in study 10158 were eligible for this open-label extension study. We analysed the All-patients-treated Set (APTS) - all patients who took at least one dose of investigational medicinal product (IMP)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Memantine | Number of Patients With Adverse Events (AEs) | Patients with Baseline Events | 1 participants |
| Memantine | Number of Patients With Adverse Events (AEs) | Patients with AEs | 191 participants |
| Memantine | Number of Patients With Adverse Events (AEs) | Patients with serious AEs (SAEs) | 27 participants |
| Memantine | Number of Patients With Adverse Events (AEs) | Patients with AEs Leading to Withdrawal | 24 participants |
Primary
Percentage of Patients Who Withdrew Due to Intolerance to Treatment
Time frame: Baseline to Week 24
Population: APTS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Memantine | Percentage of Patients Who Withdrew Due to Intolerance to Treatment | 8.1 percentage of participants |
Secondary
Long-term Efficacy of Memantine on Behavioural Symptoms Using the Neuropsychiatric Inventory (NPI) - 12 Items Version Total Score.
Change from Baseline in the NPI total score. Analysed by descriptive methods only. 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 and Week 24
Population: APTS; Observed cases (OC)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Long-term Efficacy of Memantine on Behavioural Symptoms Using the Neuropsychiatric Inventory (NPI) - 12 Items Version Total Score. | 2.11 Scores on a scale | Standard Deviation 16.12 |
Secondary
Long-term Efficacy of Memantine on Cognition Using the Severe Impairment Battery (SIB) Total Score.
Change from Baseline in the SIB total score. Analysed by descriptive methods only. 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 and Week 24
Population: APTS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Long-term Efficacy of Memantine on Cognition Using the Severe Impairment Battery (SIB) Total Score. | -5.60 Scores on a scale | Standard Deviation 9.81 |
Secondary
Long-term Efficacy of Memantine on Functioning Using the Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) 19-item Version Total Score
Change from Baseline on the ADCS-ADL 19-item version total score. Analysed by descriptive methods only. 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 and Week 24
Population: APTS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Long-term Efficacy of Memantine on Functioning Using the Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) 19-item Version Total Score | -4.16 Scores on a scale | Standard Deviation 6.45 |
Secondary
Long-term Efficacy of Memantine on Global Condition Using the Clinician's Interview-Based Impression of Change-Plus Version (CIBIC-plus).
CIBIC-plus. Improvement evaluated with reference to Baseline. Analysed by descriptive methods only. 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: Week 24
Population: APTS; OC
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine | Long-term Efficacy of Memantine on Global Condition Using the Clinician's Interview-Based Impression of Change-Plus Version (CIBIC-plus). | 4.75 Scores on a scale | Standard Deviation 1.14 |