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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Ipsen
ClinicalTrials.gov Identifier:
NCT00814346
First received: December 23, 2008
Last updated: February 26, 2016
Last verified: February 2016
  Purpose
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.

Condition Intervention Phase
Alzheimer's Disease
Cognitive Impairment
Drug: EGb761®
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Ipsen:

Primary Outcome Measures:
  • Change in Brain Glucose Metabolism Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography (18FDG-PET) [ Time Frame: From Baseline (Month 0) to Week 4 (Month 1) - Double blind phase ] [ Designated as safety issue: No ]

    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)



Secondary Outcome Measures:
  • Change in Brain Glucose Metabolism in the MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]

    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


  • Change in Cognitive Tests-Clinical Dementia Rating (CDR) Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]
    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).

  • Change in Cognitive Tests-Geriatric Depression Scale (GDS) Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]
    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.

  • Change in Cognitive Tests-Verbal Fluency in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]

    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.


  • Change in Cognitive Tests-Mini Mental Status Examination (MMSE) Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]
    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.

  • Change in Cognitive Tests-Clock Drawing Test Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]
    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.

  • Change in Cognitive Tests-Cube Drawing Test Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]

    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.


  • 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) [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]

    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).


  • Change in Cognitive Tests-Age-Adjusted Logical Memory (MEM III) in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]

    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).


  • Change in Cognitive Tests-Age-Adjusted Wechsler Adult Intelligence Scale (WAIS) in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]

    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.


  • Change in Cognitive Tests-Time to Perform Trail Making Test (TMT) in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 9 ] [ Designated as safety issue: No ]

    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.


  • Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to the DSM IV (Diagnostic of Dementia) [ Time Frame: At Month 9 ] [ Designated as safety issue: No ]

    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)


  • Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to NINCDS-ADRDA (Diagnostic of Alzheimer's) [ Time Frame: At Month 9 ] [ Designated as safety issue: No ]
    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.

  • Change in Cognitive Tests-CDR Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]
    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)

  • Change in Cognitive Tests-GDS Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]
    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.

  • Change in Cognitive Tests-Verbal Fluency in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]

    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.


  • Change in Cognitive Tests-MMSE Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]
    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.

  • Change in Cognitive Tests-Clock Drawing Test Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]
    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.

  • Change in Cognitive Tests-Cube Drawing Test Score in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]

    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.


  • Change in Cognitive Tests in MC and CNE Groups - Total Immediate Recall and Delayed Recall Scores of FCSRT [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]

    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).


  • Change in Cognitive Tests-Age-Adjusted Logical Memory (MEM III) in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]

    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).


  • Change in Cognitive Tests-Age-Adjusted WAIS in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]

    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.


  • Change in Cognitive Tests-Time to Perform TMT in MC and CNE Groups [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]

    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.


  • Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to the DSM IV (Diagnostic of Dementia) [ Time Frame: At Month 18 ] [ Designated as safety issue: No ]
    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.

  • Number of Subjects Conversion to Alzheimer's Dementia Diagnosed According to NINCDS-ADRDA (Diagnostic of Alzheimer's) [ Time Frame: At Month 18 ] [ Designated as safety issue: No ]
    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.

  • Incidence of Adverse Events (AEs) [ Time Frame: Up to Month 18 ] [ Designated as safety issue: Yes ]

    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.


  • Change in Brain Morphology in the MC and CNE Groups as Determined by the Change in Voxel Size [ Time Frame: From Baseline (Month 0) to Month 18 ] [ Designated as safety issue: No ]
    Evolution of brain morphology (degree of cortical atrophy) after 18 months with EGb761, using MRI voxel based morphometry


Enrollment: 49
Study Start Date: October 2008
Study Completion Date: July 2012
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: EGb 120 mg Drug: EGb761®
Four weeks for AD patients, 18 months for MC and CNE patients
Placebo Comparator: Placebo Drug: Placebo
Placebo 1 tablet BID

  Eligibility

Ages Eligible for Study:   65 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00814346

Locations
France
Hôpital Corentin Celton 4 parvis Corentin Celton
Issy-Les-Moulineaux, France
Hôpital de Juvisy
Juvisy sur Orge, France
CMPI "Les Rives de Seine"
Le Vesinet, France
Centre Hospitalier d'Orsay 4 place du Général Leclerc
Orsay, France
Private practice
Paris, France, 75009
Hôpital Broca 54-56 rue Pascal
Paris, France, 75013
Observatoire de l'âge
Paris, France
Hôpital Paul Brousse 12 av Paul-Vaillant-Couturier
Villejuif, France
Sponsors and Collaborators
Ipsen
Investigators
Study Director: Hélène Mathiex-Fortunet, M.D. Ipsen
  More Information

Responsible Party: Ipsen
ClinicalTrials.gov Identifier: NCT00814346     History of Changes
Other Study ID Numbers: 2-39-00240-134  2007-005377-63 
Study First Received: December 23, 2008
Results First Received: September 11, 2015
Last Updated: February 26, 2016
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Ipsen:
Mild Alzheimer's disease (AD) patients
Memory complaint patients with cognitive impairment (MC)
Memory complaint patients cognitively normal (CNE)

Additional relevant MeSH terms:
Alzheimer Disease
Cognition Disorders
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders

ClinicalTrials.gov processed this record on December 06, 2016