Frontal Lobe Dementia, Frontotemporal Lobe Dementia, Semantic Dementia
Conditions
Keywords
Randomized, Double-Blind, Placebo-Controlled, memantine, Namenda, Frontotemporal Dementia, Semantic Dementia, FTD, SD, dementia, behavioral decline, cognitive decline
Brief summary
The primary objective of the study is to determine whether memantine is effective in slowing the rate of behavioral decline in frontotemporal dementia. The secondary objective of the study is to assess the safety and tolerability of long-term treatment with memantine in patients with frontotemporal dementia (FTD) or semantic dementia (SD). To determine whether memantine is effective in slowing the rate of cognitive decline in frontotemporal dementia. To evaluate whether memantine delays or decreases the emergence of parkinsonism in frontotemporal dementia. The tertiary objective of the study is to determine whether treatment with memantine affects changes in weight
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled trial of memantine 10 mg twice daily versus placebo, at a ratio of 1:1, to receive active drug or placebo. Screening and enrollment is planned to last approximately one year. A Data and Safety Monitoring Board, consisting of a clinical pharmacist and 3 neurologists will review all AE reports approximately every 3 months after study initiation. The DSMB will notify the principal investigator, the study sponsor and the CHR if significant concerns are raised by their review of the AE data. An interim analysis of efficacy data will be conducted after 50% of the targeted enrollment population has completed 26 weeks of drug treatment. Including screening and off-drug follow up, each subject will participate in the study for approximately 34 weeks. The entire study is anticipated to last 86 weeks if enrollment is completed within one year of study initiation. The targeted enrollment is 140.
Interventions
DRUGmemantine
memantine 10mg BID
DRUGPlacebo pill
Placebo pill BID
Sponsors
Forest Laboratories
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
A subject must meet ALL of the following criteria to be considered for enrollment in this study: 1. Signed and dated written informed consent obtained from the subject and the subject's caregiver in accordance with local IRB regulations. 2. Must meet criteria Neary et al. criteria for frontotemporal dementia (FTD) or semantic dementia (SD) 3. Age: 40-80 4. CT or MRI of brain within 12 months consistent with a diagnosis of FTD or SD. 5. MMSE ≥ 15 at screening visit. 6. Judged by investigator to be able to comply with neuropsychological evaluation at baseline. 7. Must have reliable caregiver accompany subject to all study visits. Caregiver must read, understand and speak English fluently in order to ensure comprehension of informed consent form and informant-based assessments of subject. Caregiver must also have frequent contact with subject (at least 3 times per week for one hour) and be willing to monitor study medication compliance and the subject's health and concomitant medications throughout the study. 8. In the opinion of the investigator, the patient and the caregiver will be compliant with the protocol and have a high probability of completing the study.
Exclusion criteria
Any one of the following will exclude a subject from being enrolled into the study: 1. Insufficient fluency in English to complete neuropsychological and functional assessments. 2. Concurrent Motor Neuron Disease judged by investigator to have bulbar or upper extremity impairments at baseline that would interfere with neuropsychological assessment, or that are expected to lead to such impairments within one month. 3.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neuropsychiatric Inventory (NPI) | Baseline, 26 weeks | NPI:12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, nighttime behavior. A screening question is asked about each sub-domain. If the responses to these questions indicate that the patient has problems with a particular sub-domain of behavior, the caregiver is only then asked all the questions about that domain, rating the frequency of the symptoms on a 4-point scale, their severity on a 3-point scale, and the distress the symptom causes them on a 5-point scale. Severity(1=Mild to 3=Severe),frequency(1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score(range 0-12). Total score=sum of each domain score(range 0-144);higher score=greater behavioral disturbances;negative change score from baseline=improvement. |
| Clinical Global Impression of Change (CGIC) | 26 Weeks | The scale is rated on a 7-point scale, using a range of responses from 1 (very much improved) through 7 (very much worse). The clinician compares the participant's current condition to the condition at admission to the project. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | Baseline and 26 Weeks | Clinical dementia rating sum of boxes CDR-SB (0-18) high scores indicate high impairment. Functional activities questionnaire FAQ (0-30) high scores indicate high impairment. Texas functional living scale TFLS (0 to 52) high scores suggest better instrumental activities of daily living functioning. Mini-Mental State Examination MMSE (0-30) low scores indicate low cognition. The executive interview EXIT25 (0 to 50) high scores indicate more executive impairment. A modified unified Parkinson's disease rating scale UPDRS (0-199) high scores indicate worse disability. Boston naming test (0-15) low scores indicate more retrieval difficulties. |
| Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Baseline and 26 Weeks | Letter fluency, score is number of words recalled starting with a specified letter for 60 seconds. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials for the score. Low scores indicate high impairment Category fluency, score is number of items generated belonging to a specific category (such as animals) in 60 seconds, low scores indicate high impairment. Digit symbol, score is number of symbols that correctly corresponded to the random numerals entered in the form in 90 seconds. Participants are given a table of numerals with matching symbols, and a form with random numerals with open spaces. Low scores indicate high impairment. Digits backwards, score is number of digits backwards recalled (range: 0-14), The participant hears a list of digits and is asked to repeat the digits backwards. Low scores indicate high impairment. |
| Number of Participants Starting Antipsychotic Therapy | 26 weeks | — |
Countries
United States
Participant flow
Recruitment details
We recruited patients from nine US academic dementia research centres with expertise in the diagnosis of FTD. Study visits occurred between December 12, 2007, and May 7, 2012.
Pre-assignment details
100 subjects were assessed for eligibility. 19 were excluded prior to randomization. 81 were randomized. 16 subjects did not meet inclusion criteria and 3 declined to participate.
Participants by arm
| Arm | Count |
|---|---|
| Memantine Memantine 10mg administered orally twice daily | 39 |
| Placebo Placebo (inactive tablets identical to memantine 10mg tablets) | 42 |
| Total | 81 |
Baseline characteristics
| Characteristic | Memantine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 17 Participants | 38 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 25 Participants | 43 Participants |
| Age, Continuous | 65.8 years STANDARD_DEVIATION 2.8 | 66.2 years STANDARD_DEVIATION 2.3 | 66.0 years STANDARD_DEVIATION 2.5 |
| Region of Enrollment United States | 39 participants | 42 participants | 81 participants |
| Sex: Female, Male Female | 20 Participants | 10 Participants | 30 Participants |
| Sex: Female, Male Male | 19 Participants | 32 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 39 | 28 / 42 |
| serious Total, serious adverse events | 1 / 39 | 2 / 42 |
Outcome results
Primary
Change in Neuropsychiatric Inventory (NPI)
NPI:12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, nighttime behavior. A screening question is asked about each sub-domain. If the responses to these questions indicate that the patient has problems with a particular sub-domain of behavior, the caregiver is only then asked all the questions about that domain, rating the frequency of the symptoms on a 4-point scale, their severity on a 3-point scale, and the distress the symptom causes them on a 5-point scale. Severity(1=Mild to 3=Severe),frequency(1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score(range 0-12). Total score=sum of each domain score(range 0-144);higher score=greater behavioral disturbances;negative change score from baseline=improvement.
Time frame: Baseline, 26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Memantine | Change in Neuropsychiatric Inventory (NPI) | -1.9 units on a scale |
| Placebo | Change in Neuropsychiatric Inventory (NPI) | 0.3 units on a scale |
Primary
Clinical Global Impression of Change (CGIC)
The scale is rated on a 7-point scale, using a range of responses from 1 (very much improved) through 7 (very much worse). The clinician compares the participant's current condition to the condition at admission to the project.
Time frame: 26 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Memantine | Clinical Global Impression of Change (CGIC) | 4.4 units on a scale |
| Placebo | Clinical Global Impression of Change (CGIC) | 4.8 units on a scale |
Secondary
Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test
Clinical dementia rating sum of boxes CDR-SB (0-18) high scores indicate high impairment. Functional activities questionnaire FAQ (0-30) high scores indicate high impairment. Texas functional living scale TFLS (0 to 52) high scores suggest better instrumental activities of daily living functioning. Mini-Mental State Examination MMSE (0-30) low scores indicate low cognition. The executive interview EXIT25 (0 to 50) high scores indicate more executive impairment. A modified unified Parkinson's disease rating scale UPDRS (0-199) high scores indicate worse disability. Boston naming test (0-15) low scores indicate more retrieval difficulties.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | EXIT25 | 1.9 units on a scale |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | CDR-SB | 1.5 units on a scale |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | FAQ | 4.3 units on a scale |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | TFLS | -3.7 units on a scale |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | MMSE | -1.2 units on a scale |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | UPDRS | 1.7 units on a scale |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | Boston naming test | -1.4 units on a scale |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | UPDRS | 1.4 units on a scale |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | MMSE | -0.9 units on a scale |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | CDR-SB | 1.5 units on a scale |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | EXIT25 | 0.7 units on a scale |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | FAQ | 2.9 units on a scale |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | Boston naming test | 0.7 units on a scale |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: CDR-SB, FAQ, TFLS, MMSE, EXIT25, UPDRS, Boston Naming Test | TFLS | -2.8 units on a scale |
Secondary
Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards
Letter fluency, score is number of words recalled starting with a specified letter for 60 seconds. There are 3 trials, with 3 different letters. The total number of correct responses is totaled for all 3 trials for the score. Low scores indicate high impairment Category fluency, score is number of items generated belonging to a specific category (such as animals) in 60 seconds, low scores indicate high impairment. Digit symbol, score is number of symbols that correctly corresponded to the random numerals entered in the form in 90 seconds. Participants are given a table of numerals with matching symbols, and a form with random numerals with open spaces. Low scores indicate high impairment. Digits backwards, score is number of digits backwards recalled (range: 0-14), The participant hears a list of digits and is asked to repeat the digits backwards. Low scores indicate high impairment.
Time frame: Baseline and 26 Weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Letter fluency | -0.1 number of items recalled |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Category fluency | -0.5 number of items recalled |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Digit symbol | -3.9 number of items recalled |
| Memantine | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Digits backwards | 0.1 number of items recalled |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Digits backwards | -0.2 number of items recalled |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Letter fluency | -0.3 number of items recalled |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Digit symbol | 4.2 number of items recalled |
| Placebo | Longitudinal Changes From Baseline to 26 Weeks for Test Battery: Letter Fluency, Category Fluency, Digit Symbol, Digits Backwards | Category fluency | -0.7 number of items recalled |
Secondary
Number of Participants Starting Antipsychotic Therapy
Time frame: 26 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Memantine | Number of Participants Starting Antipsychotic Therapy | 1 Participants |
| Placebo | Number of Participants Starting Antipsychotic Therapy | 2 Participants |