Trial document




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  DRKS00003705

Trial Description

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Title

Identification of biomarkers sensitive to disease progression in patients with Mild Cognitive Impairment. Two-Part Research: Part B

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Trial Acronym

WP5P001 - Part B

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URL of the Trial

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Brief Summary in Lay Language

Identification of biomarkers sensitive to disease progression in patients with Mild Cognitive Impairment. We conduct this study in patients with mild memory impairment (referred to in this study as "mild cognitive impairment" / MCI or amnestic MCI / aMCI). Mild memory impairment in older people can remain stable over time or worsen and progress to Alzheimer's disease. According to the current medical and scientific knowledge, it is assumed that people progressing to Alzheimer's disease do show abnormalities already in the state of MCI. Those abnormalities can be detected in neuroimaging scans and other biological markers. It is, however, still necessary to clarify which combinations of biomarkers present the highest predictive value. In addition, a biomarker that can monitor the course of progression of the disease over time is not yet known. However, this is of utmost importance to be able to develop effective drugs. A biomarker is a substance that can be measured in your body and gives evidence of a biological condition, in this case memory impairment. MCI patients are examined for 24 months to find out how useful biomarkers might be in the conduct of future studies, which aim to early detection and treatment of Alzheimer's disease. The aim of the study at hand is to collect data to be stored for future research. It includes repeated neuropsychological testing, blood sample tests, magnetic resonance imaging scans (MRI) of the brain, lumbar punctures and electroencephalogram (EEG) and actigraphy. For actigraphy a wristwatch-like instrument records the activation levels and the waking / sleeping pattern for several days / weeks. This study will possibly show which MCI patients have great chance to progresses to dementia and this knowledge might be used to improve the future treatment of MCI and Alzheimer's patients.

[Amendment shortening to 24 month EC approval march 2013]

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Brief Summary in Scientific Language

By collecting clinical, biochemical, neuroimaging, neuropsychological and neurophysiological data in Mild Cognitive Impairment patient, we aim to:

1.To develop a biomarker MATRIX (made of a combination of biological secondary endpoints) which is more sensitive than the changes observed in the loss of hippocampal volume (primary endpoint) and correlate with the neuropsychological progression and conversion (clinical secondary endpoints).
2.To develop a biomarker MATRIX (made of a combination of biological secondary endpoints) at baseline which is more predictive of the loss of hippocampal volume (primary endpoint) and neuropsychological progression (clinical secondary endpoint) in MCI patients.
3.To harmonize the biomarker MATRIX collection and qualify multiple centres across Europe

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Organizational Data

  •   DRKS00003705
  •   2012/04/17
  •   2011/08/12
  •   no
  •   Approved
  •   11-4807-BO, Ethik-Kommission der Medizinischen Fakultät der Universität Duisburg-Essen
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Secondary IDs

  •   NCT01425957  (CinicalTrials.gov )
  •   DRKS00003721  (DRKS-ID Part A)
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Health Condition or Problem studied

  •   Alzheimer's disease
  •   F00.0 -  Dementia in Alzheimer's disease with early onset
  •   F00.1 -  Dementia in Alzheimer's disease with late onset
  •   F00.2 -  Dementia in Alzheimer's disease, atypical or mixed type
  •   F00.9 -  Dementia in Alzheimer's disease, unspecified
  •   F06.7 -  Mild cognitive disorder
  •   Mild Cognitive Impairment
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Interventions/Observational Groups

  •   Longitudinal study in MCI patients (male/female) between 55-90 years.

    - boold samples
    - neuropsychological tests
    - MRIs of the brain
    - EEGs
    - Actigraphy
    - Lumbar puncture:All the patients will be divided in two groups based on their Aβ 1-42 levels measured in the cerebro-spinal fluid obtained form a lumbar puncture: in low Aβ1-42 (positive aMCI patients CSFP) and high Aβ1-42 (Negative aMCI patients CSFN). The threshold of Aβ1-42 used to divide the patient will be 500 (ng/L) based on Sjogren criteria (2001).



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Characteristics

  •   Non-interventional
  •   Other
  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Prognosis
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

Changes in the hippocampal volume [Time Frame: 3 times during 2 years (T0, T18, and T24)] measured with structural MRI.
The primary endpoint will be changes of the hippocampal volume between the two groups (differentiated by the level of amyloid β1-42 in the cerebro-spinal fluid) and within the same group over time.

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Secondary Outcome

Clinical assessment [Time frame: Every 6 months (screening/T0, T6, T12, T18 and T24)]

-Mini-Mental State Examination (MMSE) (general cognitive functioning);
-Clinical Dementia Rating (CDR);
-Medical History;
-physical exam;
-Neurological exams;
-Hachinski-Ischämie-Skala (differentiate Alzheimer#s type dementia and multi-infact dementia);
-Geriatric Depression Scale (Depressive symptoms);
-Functional Assessment Questionnaire (FAQ) (Activities of daily living);
-Neuropsychiatric Inventory Questionnaire (NPI-Q) (Behaviour).

Neuropsychologische Testbatterie: [Time frame: Every 6 months (screening/T0, T6, T12, T18 and T24)]

-ADAS-COG ;
-Clock Drawing and Copying test (Executive functions and planning abilities)
-Rey Auditory Verbal Test (AVLT)(Memory)
-Logical Memory Test I - Immediate Recall (Memory)
-Digit Span Forward (Memory);
-Digit Span Backward ((Memory));
-CANTAB-Testbatterie (visualspacial functions);
-Letter fluency (Language);
-Category Fluency (Language);
-Boston Naming Test (BNT) (Language);
-Trail Making Test (Attention);
-Digit Symbol Substitution Test (Processing speed).

Blutprobenentnahme :[every 6 months]

- ApoE (T0 only)
- β amyloid in Plasma (screening/T0, T6, T12, T18 and T24)
- Plasma and lymphocytes biomarker (T0, T12 und T24)
- PKC conformation (To und T24)
- amyloid β1-42 binding on erythrocytes (T0 und T24)
- Platelet APP-CTF (intracellular APP metabolites) (T0, T6, T12, T18, and T24)
- RNA splicing analysis (T0, T6, T12, T18, T24)

Lumbar puncture (Liquor): [Time frame: (screening/T0, T18 and T24)]

Magnetic Resonance Imagery (MRI) and functional MRI [Time frame: every 6 month(T0, T6, T12, T18, T24)]

- Protocol: localiser or scout run, 2 structural-volumetric MRI sequences (i.e. MPRAGE and FLAIR), one 2D structural analysis (i.e. T2*), a resting state functional MRI acquisition (i.e. rs-fMRI) and a diffusion tensor scan (i.e. DTI)

Electroencephalography (EEG) [Time frame: Every 6 months (T0, T6, T12, T18, T24)]

Adverse events [Time frame: Every 6 months (screening/T0, T6, T12, T18, T24)]

Any changes in chronicity, severity, action taken, seriousness of a symptom or adverse event will be recorded by a qualified clinician (MD).



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Countries of Recruitment

  •   Germany
  •   France
  •   Italy
  •   Spain
  •   Netherlands
  •   Greece
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2012/09/27
  •   150
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   55   Years
  •   90   Years
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Additional Inclusion Criteria

1. Written Informed Consent to participate in a 3 year imaging study
2. Male and female aged between 55-90 years
3. Memory complaint by patient or patner that is verified by a study partner.
4. Abnormal memory functions documented by scoring 1 SD below the age- and education-adjusted mean on the logical Memory II subscale, (Delayed Paragraph Recall) from the Wechsler Memory Scalee.
5. General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by site physician at the time of the screening visit.
6. Mini-Mental State Exam score between 24 and 30 (inclusive)
7. Clinical Dementia Rating = 0.5. Memory Box scoremust be at least 0.5.
8. Amnestic Mild Cognitive Impairment (MCI) (pure amnestic or multidomain)
9. Geriatric Depression Scale less than 6
10. Hachinski Modified Ischemic scale<to 4
11. Stabilitiy of Permitted Medications for 4 weeks
12. At least 5 grades education
13. Must speak German fluently
14. have a study partner with 10+ hr/wk contact (can be in person and telephone), accompanies to visits
15. Willing and able to comply with requirements of the study, as judged by the investigator



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Exclusion Criteria

1. Visual and auditory acuity inadequate for neuropsychological testing
2. Enrolment in other trails or studies not compatiple with study objectives (in particular, tzhose with experimental drugs
3. History of significant neurological or psychiatric illnesses or presence of other diseases precluding enrolment
4. Use of forbidden medications
5. Ferromagnetic implants and devices not eligible for MRI scanning. Brain malformation or other conditions that may complicate lumbar puncture
6. Excluded medication: Antidepressants with anti-cholinergic properties and within 4 weeks of the screening: Regular use of narcotic analgesics (>2 doses per week), Use of neuroleptics with anti-cholinergic properties (e.g., chlorpromazine, thioridazine), Chronic use of other medications with significant central nervous system anticholinergic activity (e.g., diphenhydramine), use of Anti-Parkinsonian medications (including sinemet, amantadine, bromocriiiptine, pergolide, selegiline), Participation in any other investigational drug study (individuals may not participate in any drug study while participating in this protocol). Diuretic drugs should not be startes or discontinued within 4 weeks prior to screening (Any change in diuretic medication during the study should be reported).

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Addresses

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    • QUALISSIMA
    • Mr.  Romain  Combalat 
    • 10, rue Clapier
    • 13001  MARSEILLE
    • France
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    • Universitätsklinikum Duisburg-Essen, LVR Essen
    • Ms.  Dr.  Jennifer  Arnold 
    • Wickenburgstr. 23
    • 45147  Essen
    • Germany
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    • Universitätsklinikum Duisburg-Essen, LVR Essen
    • Ms.  Dr.  Jennifer  Arnold 
    • Wickenburgstr. 23
    • 45147  Essen
    • Germany
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Sources of Monetary or Material Support

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    • Innovative Medicines Initiative (IMI)
    • Avenue de la Toison d'Or 56-60
    • B-1060   Brussels
    • Belgium
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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