Effect of EGb761® on Brain Glucose Metabolism in Three Groups of Elderly Defined by Cognitive Functions

Study Overview
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Brief Summary
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The aim of the study is to evaluate the effect of EGb761®, in comparison to placebo, on cerebral glucose metabolism, in three groups of elderly patients: newly diagnosed mild Alzheimer's disease (AD), memory complaint patients with cognitive impairment (MC) and memory complaint patients cognitively normal (CNE). The first phase includes four weeks treatment with EGb761® for all groups, with change in brain glucose metabolism at month 1 using 18 FDG-PET, as primary endpoint which will be followed by an open 17 months follow-up (FU) period with EGb761® treatment in MC and CNE patients.

Official Title
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Effect of Oral EGb761® on Brain Glucose Metabolism in Three Groups of Elderly With Memory Complaint, Mild Alzheimer's Disease, and Cognitively Normal Elderly. Phase II, Randomised, Double-blind, Parallel Groups, Placebo-controlled Study

Conditions
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Alzheimer's Disease, Cognitive Impairment

Intervention / Treatment
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* Drug: EGb761®
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Group Specific Inclusion Criteria: Cognitively normal elderly (CNE) Spontaneous memory complaint by patient, Mini-Mental State Exam score ≥ 28. Clinical Dementia Rating = 0. No Diagnostic And Statistical Manual Of Mental Disorders, Fourth Edition (DSMIV) criteria for Dementia. Memory complaints (MC) : Spontaneous memory complaint by patient Mini-Mental State Exam score ≥ 25 Clinical Dementia Rating 0.5. No DSMIV criteria for Dementia. Mild Alzheimer's Disease (AD): Mini Mental Status Examination (MMSE) between 20 and 28 (inclusive). Clinical Dementia Rating ≥ 1.0 DSMIV criteria for Dementia. National Institute of Neurological and Communicative Diseases and Stroke / Alzheimer's Disease and Related Disorders Association(NINCDS/ADRDA) criteria for probable AD. Newly diagnosed patients without treatment by Cholinesterase Inhibitors or Memantine. ≥ 65 years of age, both sex Geriatric Depression Scale (GDS) < 15 Informed consent signed by the patient or, if necessary by legal representative Exclusion Criteria: Contraindication to Magnetic Resonance Imaging (MRI) and/or Positron-Emission Tomography (PET) scan Forbidden Concomitant medications (Cholinesterase inhibitors and memantine, Specific psychoactive medications,e.g., neuroleptics, chronic anxiolytics including meprobamate, or sedative hypnotics other than benzodiazepines, Monoamine oxidase inhibitors (MAOIs) including selective MAOIs. Drugs acting on cerebral nervous system, Antidiabetes medications , Antioxidants medications, Medications known to interfere with cognitive evaluations Significant neurological disease and psychiatric disorders/psychotic feature Significant medical illness

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EGb 120 mg<br> | Drug: EGb761®<br>* Four weeks for AD patients, 18 months for MC and CNE patients<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo 1 tablet BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brain Glucose Metabolism Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET) | Following statistical parametric mapping (SPM) analyses were performed by the Commissariat à l'Energie Atomique (CEA): The comparison between treatment groups separately for each group of elderly subjects (CNE and MC groups only) The comparison between the two groups of elderly subjects (CNE and MC groups only) by treatment group FDG PET demonstrates reductions in the cerebral glucose metabolism that may occur a few years before the overt clinical manifestation of disease. SUVBSA2 = [Brain radioactivity (Bq/cc)] / [Injected dose (MBq)/BSA2] x [Blood glucose (g/l)] BSA2(m^2) = 0.007184 x Height (cm)^0.35 x weight (kg)^0.80 Standardized Uptake Value (SUV) Body Surface Area (BSA) | From Baseline (Month 0) to Week 4 (Month 1) - Double blind phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brain Glucose Metabolism in the MC and CNE Groups | Brain glucose metabolism measured by 18FDG PET SUVBSA2 = [Brain radioactivity (Bq/cc)] / [Injected dose (MBq)/BSA2] x [Blood glucose (g/l)] BSA2(m^2) = 0.007184 x Height (cm)^0.35 x weight (kg)^0.80 | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-Clinical Dementia Rating (CDR) Score in MC and CNE Groups | CDR is a structured interview to collect information regarding subject's memory in a standard way from both the patient and the helper. Scores are calculated using below scale; q CDR=No dementia (score: 0), q CDR=Very mild dementia (score: 0.5), q CDR=Mild dementia (score: 1), q CDR=Moderate dementia (score: 2) and q CDR=Severe dementia (score: 3). | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Geriatric Depression Scale (GDS) Score in MC and CNE Groups | The Geriatric Depression Scale is a self-administered depression scale, which was developed as a basic screening measure for depression in older adults. By yes or no answers, scores permit to classify patients into groups of severely depressed (score of 21 to 30), moderately depressed (score of 11 to 20) and normal (score of 0 to10). It takes10 to 15 minutes to administer. | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Verbal Fluency in MC and CNE Groups | Subjects completed a verbal fluency test. Higher scores represent higher levels of verbal fluency. Minimum score=0 and Maximum score= N/A. Letter fluency: this task consists of enouncing as many words as possible that begin with a given letter of the alphabet. Participants are not allowed to use proper names. Categorical fluency: in this task participants are asked to list as many words as possible that belong to a given semantic category (e.g. animals, fruits, towns) Each condition foresees 60 sec of word generation time. The score corresponds to the number of words correctly given. The verbal fluency task measures semantic storage and executive retrieval functions. | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Mini Mental Status Examination (MMSE) Score in MC and CNE Groups | MMSE is a brief screening instrument used to assess cognitive function in elderly participants. It assesses orientation, memory, attention, ability to name objects, follow verbal and written commands, write a sentence, and copy figures. Total score ranges from 0 to 30, with a lower score indicating greater disease severity. | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Clock Drawing Test Score in MC and CNE Groups | Clock drawing test is a visuo-constructive task, where subjects are asked to draw the face of a clock in a pre-drawn circle and then to draw in the arms to denote 16:45 (a quarter to five). The drawing can then be evaluated by a quantitative scoring method, which is based on the degree of completion of the drawing. The scoring system ranges from 0 to 6 with higher scores reflecting a greater number of errors and more impairment. | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Cube Drawing Test Score in MC and CNE Groups | Cube drawing: Subjects are asked to draw a cube by heart. In case of failure, a model of a cube is given to the subjects to copy. The score system ranges from 0 (worse score) to 6 (best score). Score calculation is following: 1 point by face with 4 sides, 2 points for each face where each angle should be respected. | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests in MC and CNE Groups - Total Immediate Recall and Delayed Recall Scores of the Free and Cued Selective Reminding Test (FCSRT) | Free and Cued Selective Reminding Test (FCSRT) Assessment of verbal episodic memory. By this test performances in free recalls, cued recalls and in a recognition task can be analysed, because the process of encoding is controlled. Subjects are asked to remember a list of 16 words. Three tasks of free and cued recalls, as well as one recognition task and one delayed recall give the scores. Total recall is obtained by the addition of cued recalls to free recalls. Maximum score is 48 for immediate: 16 words X 3 corresponding to immediate free recall + immediate cued recall + immediate recognition test. Maximum score is 64 (better score) when delayed recall : 16 words X 4 . The minimum score is 0 (worse). | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Age-Adjusted Logical Memory (MEM III) in MC and CNE Groups | Subjects are asked to memorize two short stories, one consisting of 24, the other one of 26 information units. After the stories have been read aloud by the investigator, subjects are asked to enounce all items of information they can remember (free recall). Correctly reported items are added for each story. This test applies analytical capacities, as well as auditive and verbal synthesis, working memory and episodic memory. Score range from 0(worst) to 75 (better). | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Age-Adjusted Wechsler Adult Intelligence Scale (WAIS) in MC and CNE Groups | Wechsler Adult Intelligence Scale (WAIS) In this test subjects are asked to say how two seemingly dissimilar items might in fact be similar (14 item couples). This test involves especially abstract thinking and concept capacities. Cognitive Tests-Age-Adjusted Wechsler Adult Intelligence Scale (WAIS): 19 tests on similarities. The items 1 to 5 are graded from 1 (good) to 0 (bad), and the items 6 to 19 are graded from 2 (good) to 0 (bad). Item 6 and 7 can be repeated. At the end, the worst total score is 0, the best total score is 33. | From Baseline (Month 0) to Month 9 | 
| Change in Cognitive Tests-Time to Perform Trail Making Test (TMT) in MC and CNE Groups | TMT is a neuropsychological test of visual attention and task switching. The task requires a subject to 'connect-the-dots' of 25 consecutive numbers (1,2,3,etc.) on a sheet of paper or computer screen. The goal of the subject is to finish the test as quickly as possible and the time taken to complete the test is used as the primary performance metric (in seconds). The maximum time allowed is 300 seconds. A negative change score indicates improvement. First, in the TMT A, the subject has to connect numbers increasingly as fast as possible. The TMT B requires the subject to connect and letters in an alternating pattern (1-A-2-B-3-C, etc.) in as little time as possible. | From Baseline (Month 0) to Month 9 | 
| Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to the DSM IV (Diagnostic of Dementia) | The Diagnostic and Statistical Manual of Mental Disorders: 4th Edition of the American Psychiatric Association (DSM-IV, 1994) also outlines diagnostic criteria for dementia of the Alzheimer's type that are generally consistent with the NINCDS-ADRDA criteria. National Institute of Neurological and Communicative Diseases and Stroke / Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) | At Month 9 | 
| Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to NINCDS-ADRDA (Diagnostic of Alzheimer's) | The most widely accepted diagnostic criteria for probable AD are those offered by the National Institute of Neurological and Communicative Disorders and Stroke and by the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA; McKhann et al., 1984). These criteria include the presence of dementia established by clinical examination and confirmed by neuropsychological testing. The dementia is described as involving multiple, progressive cognitive deficits in older persons in the absence of disturbances of consciousness, presence of psychoactive substances, or any other medical, neurological, or psychiatric conditions that might in and of themselves account for these progressive deficits. | At Month 9 | 
| Change in Cognitive Tests-CDR Score in MC and CNE Groups | CDR is a structured interview to collect information regarding subject's memory in a standard way from both the patient and the helper. Scores are calculated using below scale; q CDR=No dementia (score: 0), q CDR=Very mild dementia (score: 0.5), q CDR=Mild dementia (score: 1), q CDR=Moderate dementia (score: 2) and q CDR=Severe dementia (score: 3) | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-GDS Score in MC and CNE Groups | The Geriatric Depression Scale is a self-administered depression scale, which was developed as a basic screening measure for depression in older adults. By yes or no answers, scores permit to classify patients into groups of severely depressed (score of 21 to 30), moderately depressed (score of 11 to 20) and normal (score of 0 to10). It takes10 to 15 minutes to administer. | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-Verbal Fluency in MC and CNE Groups | Subjects completed a verbal fluency test. Higher scores represent higher levels of verbal fluency. Minimum score=0 and Maximum score= N/A. Letter fluency: this task consists of enouncing as many words as possible that begin with a given letter of the alphabet. Participants are not allowed to use proper names. Categorical fluency: in this task participants are asked to list as many words as possible that belong to a given semantic category (e.g. animals, fruits, towns) Each condition foresees 60 sec of word generation time. The score corresponds to the number of words correctly given. The verbal fluency task measures semantic storage and executive retrieval functions. | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-MMSE Score in MC and CNE Groups | MMSE is a brief screening instrument used to assess cognitive function in elderly participants. It assesses orientation, memory, attention, ability to name objects, follow verbal and written commands, write a sentence, and copy figures. Total score ranges from 0 to 30, with a lower score indicating greater disease severity. | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-Clock Drawing Test Score in MC and CNE Groups | Clock drawing test is a visuo-constructive task, where subjects are asked to draw the face of a clock in a pre-drawn circle and then to draw in the arms to denote 16:45 (a quarter to five). The drawing can then be evaluated by a quantitative scoring method, which is based on the degree of completion of the drawing. The scoring system ranges from 0 to 6 with higher scores reflecting a greater number of errors and more impairment. | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-Cube Drawing Test Score in MC and CNE Groups | Cube drawing: Subjects are asked to draw a cube by heart. In case of failure, a model of a cube is given to the subjects to copy. The score system ranges from 0 (worse score) to 6 (best score). Score calculation is following: 1 point by face with 4 sides, 2 points for each face where each angle should be respected. | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests in MC and CNE Groups - Total Immediate Recall and Delayed Recall Scores of FCSRT | Free and Cued Selective Reminding Test (FCSRT) Assessment of verbal episodic memory. By this test performances in free recalls, cued recalls and in a recognition task can be analysed, because the process of encoding is controlled. Subjects are asked to remember a list of 16 words. Three tasks of free and cued recalls, as well as one recognition task and one delayed recall give the scores. Total recall is obtained by the addition of cued recalls to free recalls. Maximum score is 48 for immediate: 16 words X 3 corresponding to immediate free recall + immediate cued recall + immediate recognition test. Maximum score is 64 (better score) when delayed recall : 16 words X 4 . The minimum score is 0 (worse). | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-Age-Adjusted Logical Memory (MEM III) in MC and CNE Groups | Subjects are asked to memorize two short stories, one consisting of 24, the other one of 26 information units. After the stories have been read aloud by the investigator, subjects are asked to enounce all items of information they can remember (free recall). Correctly reported items are added for each story. This test applies analytical capacities, as well as auditive and verbal synthesis, working memory and episodic memory. Score range from 0(worst) to 75 (better). | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-Age-Adjusted WAIS in MC and CNE Groups | Wechsler Adult Intelligence Scale (WAIS) In this test subjects are asked to say how two seemingly dissimilar items might in fact be similar (14 item couples). This test involves especially abstract thinking and concept capacities. Cognitive Tests-Age-Adjusted Wechsler Adult Intelligence Scale (WAIS): 19 tests on similarities. The items 1 to 5 are graded from 1 (good) to 0 (bad), and the items 6 to 19 are graded from 2 (good) to 0 (bad). Item 6 and 7 can be repeated. At the end, the worst total score is 0, the best total score is 33. | From Baseline (Month 0) to Month 18 | 
| Change in Cognitive Tests-Time to Perform TMT in MC and CNE Groups | TMT is a neuropsychological test of visual attention and task switching. The task requires a subject to 'connect-the-dots' of 25 consecutive numbers (1,2,3,etc.) on a sheet of paper or computer screen. The goal of the subject is to finish the test as quickly as possible and the time taken to complete the test is used as the primary performance metric (in seconds). The maximum time allowed is 300 seconds. A negative change score indicates improvement. First, in the TMT A, the subject has to connect numbers increasingly as fast as possible.The TMT B requires the subject to connect and letters in an alternating pattern (1-A-2-B-3-C, etc.) in as little time as possible. | From Baseline (Month 0) to Month 18 | 
| Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to the DSM IV (Diagnostic of Dementia) | The Diagnostic and Statistical Manual of Mental Disorders: 4th Edition of the American Psychiatric Association (DSM-IV, 1994) also outlines diagnostic criteria for dementia of the Alzheimer's type that are generally consistent with the NINCDS-ADRDA criteria. | At Month 18 | 
| Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to NINCDS-ADRDA (Diagnostic of Alzheimer's) | The most widely accepted diagnostic criteria for probable AD are those offered by the National Institute of Neurological and Communicative Disorders and Stroke and by the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA; McKhann et al., 1984). These criteria include the presence of dementia established by clinical examination and confirmed by neuropsychological testing. The dementia is described as involving multiple, progressive cognitive deficits in older persons in the absence of disturbances of consciousness, presence of psychoactive substances, or any other medical, neurological, or psychiatric conditions that might in and of themselves account for these progressive deficits. | At Month 18 | 
| Incidence of Adverse Events (AEs) | The relationship of an adverse event to the study medication will be classified according to the following criteria: Related : reports including good reasons and sufficient information (e.g. temporal relationship, dose-response relationship, pharmacology, positive de-challenge and/or re-challenge) to assume a causal relationship with the study drug in the sense that it is plausible, conceivable, or likely Not related: reports including good reasons and sufficient information (e.g. no temporal relationship and/or attributable to concurrent disease or other drugs) to rule out a causal relationship with the study drug. | Up to Month 18 | 
| Change in Brain Morphology in the MC and CNE Groups as Determined by the Change in Voxel Size | Evolution of brain morphology (degree of cortical atrophy) after 18 months with EGb761, using MRI voxel based morphometry | From Baseline (Month 0) to Month 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mild Alzheimer's disease (AD) patients, Memory complaint patients with cognitive impairment (MC), Memory complaint patients cognitively normal (CNE)