Dementia, Mild Cognitive Impairment
Conditions
Keywords
Mild Cognitive Impairment, Early Stage Dementia, Conversion to Alzheimer's disease, Memory Impairment
Brief summary
The purpose of this study is to determine whether treatment with the investigational drug ladostigil will delay the onset of Alzheimer's disease(AD) in patients with Mild Cognitive Impairment (MCI). MCI is now recognized as a precursor to AD and clinical tools are available to assess cognitive performance at this earlier stage. Ladostigil is currently under investigation for the treatment of AD. In this study, the investigators will be examining ladostigil at a lower dose level. At this dose level, ladostigil has been shown to reduce signs of early memory loss in animals. Thus, in this study the investigators are attempting to determine if earlier invention with a lower dose of ladostigil will significantly reduce initial memory loss and delay the subsequent progression to more serious cognitive dysfunction.
Detailed description
Ladostigil shows neuroprotective activity, reducing oxidative stress, activating microglia, and inhibiting pro-inflammatory cytokines in pre-clinical models. Study assessed its safety and potential efficacy in a 3-year, randomised, double-blind, placebo-controlled, phase 2 clinical trial in patients with mild cognitive impairment (MCI). Patients from 16 centers in Austria, Germany and Israel with MCI (Albert et al 2011), Clinical Dementia Rating (CDR) = 0.5, Mini-Mental State Examination (MMSE) \> 24, Wechsler Memory Scale - Revised Verbal Paired Associates ≤ 18, and medial temporal lobe atrophy were stratified by APOE4 genotype and randomly assigned (1:1 allocation) using blocks of 4, to receive either ladostigil, 10 mg per day, or placebo as identically-appearing capsules. The primary endpoint was onset of Alzheimer's disease (AD). Secondary endpoints were the NTB, DAD, and GDS. Exploratory outcomes were MRI-derived whole brain, hippocampus, and entorhinal cortex volumes; the NeuroTrax Mindstreams computerized cognitive battery; and the CDR. Between February 17, 2012 and August 1, 2013, we randomly allocated 210 patients to placebo (107 patients) or ladostigil (103 patients); 4 patients in each group lacked post baseline assessments. After 36 months 20.4% (21 of 103 patients) of the placebo group and 14.1% (14 of 99 patients) of the ladostigil group progressed to AD (log-rank test p=.16). There were no significant effects on NTB, DAD, or GDS outcomes. There was less decline in whole brain volume in the ladostigil group as compared to placebo (p\<.02), but not hippocampus and entorhinal cortex volumes, and CDR and a trend for less decline on the RAVLT total delayed score component of the NTB (p=.09). Fourteen patients taking placebo and 21 taking ladostigil discontinued treatment because of adverse events. Serious adverse events were reported by 26 (25.2%) patients in the ladostigil group and 28 (26.2%) patients in the placebo group. Ladostigil appeared safe, well-tolerated, and may have potential for improving memory and delaying progression to dementia.
Interventions
10mg ladostigil base administered once daily as hard gelatin capsule
DRUGPlacebo
Placebo comparator
Sponsors
Avraham Pharmaceuticals Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Men and women (non-childbearing potential) with a diagnosis of Mild Cognitive Impairment (MCI) according to consensus criteria as defined by Petersen * Abnormal memory function will be evaluated by Verbal Paired Associates from the Wechsler Memory Scale - Revised. Norm values for healthy adults in two age cohorts are: a) 50-70 years 19.7 (SD=2.9) and b) 75-95 years 18.3 (SD=2.8). Patients that score \< or = 23 will be included. * Clinical Dementia Rating (CDR) score of 0.5 (Memory box score 0.5 or 1, no box score \> 1) * Mini Mental State Examination (MMSE) \> 24 and \< or = 30 * General cognition and functional performance is sufficiently preserved such that a diagnosis of AD can be excluded by the site physician at the time of the screening visit. * No significant cerebrovascular disease indicated by Modified Hackinski Ischaemic Score equal to or below 4 * Age 55-85 years based upon correlation of cognition and Scheltens score observed in this age range * Geriatric Depression Scale (GDS) of \< or = 5 * An informer who has frequent contact with the subject (e.g. an average of 10 hours per week or more) is available and agrees to monitor administration of study drug, to observe the subject for adverse events and to accompany the subject to clinical visits during the trial, if the presence of the informer is required. * All patients have to undergo an MRI scan after the screening visit, i.e. during the screening visit, irrespective of MRIs having been performed prior to entry into the study. MRI findings have to be consistent with a diagnosis of MCI. * Central rating of medial temporal lobe according to Scheltens scale. The right and left medial temporal structures will be rated separately and an overall estimate will be deduced using the average of the two ratings. An average score \> 1 is required to make patients eligible for the study. * Adequate visual and auditory acuity must be demonstrated to allow for neuropsychological testing. * Good general health status acceptable for participation in a 36-month clinical trial, with no additional diseases expected to interfere with the study * ECG without clinically significant abnormalities according to
Exclusion criteria
listed below * Subject is not pregnant, lactating or of childbearing potential (i.e. women must be two years post menopausal or surgically sterile) * Signed informed consent by patient and informer prior to any study specific procedure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo | 3,6,12,18,24,30 and 36 months | Total number of conversions from Mild Cognitive Impairment to Alzheimer's disease across entire 3 year study period. Conversion is determined, or defined, by a Clinical Dementia Rating (CDR) score of greater than or equal to one. Composite rating ranges from 0 no symptoms of dementia to 3 Severe symptoms of dementia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population | 3,6,12,18,24,30 and 36 months | Mean value change (from baseline) in Geriatric Depression Scale (GDS) across entire study period. The GDS ranges from 0 to 30. Scores of 0-9 are considered normal, 10-19 mildly depressed, and 20-30 severely depressed. |
| Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population | 3,6,12,18,24,30 and 36 months | Mean value change (from baseline) in Neuropsychiatric Test Battery (NTB) across entire study period. The NTB included the following well known cognitive tests: Rey Auditory Verbal Learning Test (RAVLT), Controlled Word Association Test (COWAT), Category Fluency Test (CFT), WMS-R Digit Span, and Trail Making Part A and B. The mean value was comprised of the z score of each of these tests with all z scores in the direction of higher scores better functioning. Range -3 to +3. |
| Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population | 3,6,12,18,24,30 and 36 months | Mean value change (from baseline) in Disability Assessment in Dementia (DAD) across entire study period. DAD evaluates the basic and instrumental activities in daily activities of elderly people with dementia. Higher scores reflect better functioning. DAD ranges from 0 to 100. |
Countries
Austria, Germany, Israel
Participant flow
Recruitment details
Recruitment between Feb. 17, 2012 and August 1, 2013.
Participants by arm
| Arm | Count |
|---|---|
| Ladostigil Hemitartrate 10mg ladostigil base
ladostigil hemitartrate: 10mg ladostigil base administered once daily as hard gelatin capsule | 103 |
| Placebo Control drug product excipients
Placebo: Placebo comparator | 107 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 14 |
| Overall Study | Assorted | 1 | 2 |
| Overall Study | Conversion to Alzheimer's disease | 14 | 21 |
| Overall Study | Death | 1 | 0 |
| Overall Study | No post baseline data | 4 | 4 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Protocol Violation | 3 | 2 |
| Overall Study | Withdrawal by Subject | 19 | 13 |
Baseline characteristics
| Characteristic | Ladostigil Hemitartrate | Placebo Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 88 Participants | 91 Participants | 179 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 16 Participants | 31 Participants |
| Age, Continuous | 71.3 years STANDARD_DEVIATION 6.3 | 71.4 years STANDARD_DEVIATION 6.8 | 71.35 years STANDARD_DEVIATION 6.54 |
| Region of Enrollment Austria | 23 participants | 24 participants | 47 participants |
| Region of Enrollment Germany | 33 participants | 33 participants | 66 participants |
| Region of Enrollment Israel | 47 participants | 50 participants | 97 participants |
| Sex: Female, Male Female | 36 Participants | 41 Participants | 77 Participants |
| Sex: Female, Male Male | 67 Participants | 66 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 103 | 0 / 107 |
| other Total, other adverse events | 56 / 103 | 59 / 107 |
| serious Total, serious adverse events | 26 / 103 | 28 / 107 |
Outcome results
Primary
Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo
Total number of conversions from Mild Cognitive Impairment to Alzheimer's disease across entire 3 year study period. Conversion is determined, or defined, by a Clinical Dementia Rating (CDR) score of greater than or equal to one. Composite rating ranges from 0 no symptoms of dementia to 3 Severe symptoms of dementia.
Time frame: 3,6,12,18,24,30 and 36 months
Population: All randomized subjects with at least one post-baseline visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ladostigil Hemitartrate | Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo | 14 Participants |
| Placebo Control | Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo | 21 Participants |
p-value: <0.1695% CI: [0.74, 3.25]Log Rank
Secondary
Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population
Mean value change (from baseline) in Disability Assessment in Dementia (DAD) across entire study period. DAD evaluates the basic and instrumental activities in daily activities of elderly people with dementia. Higher scores reflect better functioning. DAD ranges from 0 to 100.
Time frame: 3,6,12,18,24,30 and 36 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ladostigil Hemitartrate | Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population | -0.77 Change from basline on units on a scale | Standard Deviation 8.43 |
| Placebo Control | Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population | -0.40 Change from basline on units on a scale | Standard Deviation 5.11 |
p-value: <0.97Mixed Models Analysis
Secondary
Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population
Mean value change (from baseline) in Geriatric Depression Scale (GDS) across entire study period. The GDS ranges from 0 to 30. Scores of 0-9 are considered normal, 10-19 mildly depressed, and 20-30 severely depressed.
Time frame: 3,6,12,18,24,30 and 36 months
Population: Modified Intent to Treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ladostigil Hemitartrate | Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population | .084 Change from basline on units on a scale | Standard Deviation 1.7 |
| Placebo Control | Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population | .242 Change from basline on units on a scale | Standard Deviation 1.87 |
p-value: <0.61Mixed Models Analysis
Secondary
Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population
Mean value change (from baseline) in Neuropsychiatric Test Battery (NTB) across entire study period. The NTB included the following well known cognitive tests: Rey Auditory Verbal Learning Test (RAVLT), Controlled Word Association Test (COWAT), Category Fluency Test (CFT), WMS-R Digit Span, and Trail Making Part A and B. The mean value was comprised of the z score of each of these tests with all z scores in the direction of higher scores better functioning. Range -3 to +3.
Time frame: 3,6,12,18,24,30 and 36 months
Population: Modified Intent to treat (all randomized subject with at least one post baseline assessment)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ladostigil Hemitartrate | Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population | .21 Change from basline on units on a scale | Standard Deviation 0.55 |
| Placebo Control | Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population | .17 Change from basline on units on a scale | Standard Deviation 0.43 |
p-value: <0.32Mixed Models Analysis