Identification of Biomarkers Sensitive to Disease Progression in Patients With Mild Cognitive Impairment

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 by Qualissima
Sponsor:
Collaborator:
European Union
Information provided by (Responsible Party):
Qualissima
ClinicalTrials.gov Identifier:
NCT01425957
First received: August 26, 2011
Last updated: June 18, 2013
Last verified: June 2013
  Purpose

THE STUDY WILL BE A TWO-PART RESEARCH

PART A:

  1. To implement a "common" MRI acquisition protocol in multiple centers across Europe (Pharma-COG partners).
  2. Apply the common MRI protocol on phantoms and human subjects to characterize, compare and minimize test-retest variability across the MR sites of WP5 for all the quantitative metrics that will be later assessed on patients.

PART B: 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

Condition Intervention
MILD COGNITIVE IMPAIRMENT
Procedure: Lumbar puncture

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Identification of Biomarkers Sensitive to Disease Progression in Patients With Mild Cognitive Impairment: a Two-part Clinical Study. PartA: Multisite MRI Acquisition, Protocol Harmonization. PartB: Identification of Biomarkers Sensitive to Disease Progression in Patients With Mild Cognitive Impairment: a Clinical Study

Resource links provided by NLM:


Further study details as provided by Qualissima:

Primary Outcome Measures:
  • Part A: Magnetic Resonance Imagery protocol [ Time Frame: Two times: One measure at day 1 ] [ Designated as safety issue: No ]

    The Magnetic Resonance Imagery protocol comprises a localiser or scout run, 4 structural-volumetric MRI sequences (i.e. 2 MP-RAGE, 1 FLAIR and 1 T2*), a resting state functional MRI acquisition (i.e. rsfMRI) and a diffusion tensor scan (i.e. DTI) that will be conducted at the magnetic field strength of 3T. The field map will be used for geometric distortion correction of the fMRI data.

    The main parameter of "efficacy" will be the reliability of the acquired MRI data (in terms of their correct acquisition and limited variability).


  • Part B: Changes of the hippocampal volume [ Time Frame: 2 or 3 times: every 18 months during 2 or 3 years (T0, T18 and/or T36) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Part B: Clinical assessment [ Time Frame: Every 6 months (screening, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]
    • Mini-Mental State Examination (MMSE) (general cognitive functioning)
    • Clinical Dementia Rating (CDR)
    • Medical History
    • Physical exam
    • Neurological exams
    • Hachinski ischemic scale (differentiate Alzheimer's type dementia and multi-infarct dementia)
    • Geriatric Depression Scale (Depressive symptoms)
    • Functional Assessment Questionnaire (FAQ) (Activities of daily living)
    • Neuropsychiatric Inventory Questionnaire (NPI-Q) (Behaviour)

  • Part B: Neuropsychology [ Time Frame: Every 6 months (screening, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]
    • 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 Battery (visuospatial functions)
    • Letter fluency (Language)
    • Category Fluency (Language)
    • Boston Naming Test (BNT) (Language)
    • Trail Making Test (Attention)
    • Digit Symbol Substitution Test (Processing speed)

  • Part B: Neurophysiology [ Time Frame: Every 6 months (T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]
    Electro-Encephalography in several conditions

  • Part B: Magnetic Resonance Imagery and functional MRI [ Time Frame: Every 6 months (screening, T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]
    The protocol comprises a 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) that will be conducted at the magnetic field strength of 3T.

  • Part B: Blood drawing [ Time Frame: Every 6 months ] [ Designated as safety issue: No ]
    • ApoE (T0 only)
    • β amyloid in plasma (T0, T6, T12, T18, T24, T30 and T36)
    • Plasma and lymphocytes biomarkers (T0, T6, T12, T18, T24, T30 and T36)
    • PKC conformation (T0 and T18/T36)
    • amyloid β1-42 binding on erythrocytes (T0 and T18/T36)
    • Platelet APP-CTF (intracellular APP metabolites)(T0, T6, T12, T18, T24, T30 and T36)
    • RNA splicing analysis (T0, T6, T12, T18, T24, T30 and T36)

  • Part B: Actigraphy [ Time Frame: Every 6 months (T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: No ]
    Assessment of changes in position and acceleration for up to several weeks providing measures of activity. Additionally, sleep/wake and circadian rhythmicity can objectively be estimated from the recorded data by algorithms.

  • Adverse events [ Time Frame: Every 6 months (T0, T6, T12, T18, T24, T30 and T36) ] [ Designated as safety issue: Yes ]
    Any changes in the chronicity, severity, action taken, seriousness of a symptom or adverse event will be recorded by a qualified clinician (MD).


Estimated Enrollment: 210
Study Start Date: December 2011
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Mild Cognitive Impairment Patient
PartB: Patients affected by amnestic Mild Cognitive Impairment (aMCI).
Procedure: 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).

Timeframe of lumbar punctures: every 18 months during 2 or 3 years (T0, T18 and/or T36).

Other Name: Cerebrospinal fluid puncture

  Eligibility

Ages Eligible for Study:   50 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • PART A:

Participants will be (i) healthy volunteers (between 50 and 80 years old) and/or (ii) subjects (between 50 and 80 years old), who will perform a 3T-MRI for reasons such as migraine, headache, auditory or visual symptoms, paresthesias, and whose scan will be negative (see exclusion criteria below). Such subjects will be selected and asked to perform additional sequences according to the part A study protocol.

  • PART B:

Specific inclusion criteria:

  1. Written Informed Consent to participate in a up to 3 year imaging study
  2. Male and female aged between 55-90 years
  3. Memory complaint by patient or partner that is verified by a physician. (Memory complains expressed by the patients or their informant that the examiner considers to be relevant and exceed those expected for a patient of their age. The patient may or may not have symptoms of deficiency in other cognitive areas.)
  4. Abnormal memory functions documented by scoring 1 SD below the age-adjusted mean on the Logical Memory II subscale, (Delayed Paragraph Recall) from the Wechsler Memory Scale.
  5. General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the 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 score must 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. Patient is untreated or under a permitted medication (Cholinesterase inhibitors and memantine, before the enrolment and newly prescriptions during the study, are permitted for aMCI patients.)
  12. At least 5 grades education
  13. Must speak (language) 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 the requirements of the study, as judged by the investigator

Exclusion Criteria:

  • PART A:

    1. Ischaemic lesions already detected in a previous scan
    2. Head injury with loss of consciousness > 24 hours
    3. Current substance abuse
    4. Current therapy with steroids or current chemotherapy
    5. Loss of weight > 5 kg in the last 6 months
    6. Systemic disease with frequent involvement of the CNS (lupus, HIV, rheumatoid arthritis)
    7. CNS disease diagnosed by a specialist or in treatment (such as epilepsy, ictus)
    8. Cerebral metastasis or CNS primary tumour still benign (except for pituitary microadenoma)
    9. Suspected multiple sclerosis + MRI evidence of white matter lesions
    10. Suspected recent stroke + MRI evidence of infarct
    11. Aneurysm > 10 mm and arteriovenous malformations (except for venous angioma)
    12. Dysgenesia of central nervous system
  • PART B:

    1. Visual and auditory acuity inadequate for neuropsychological testing
    2. Enrolment in other trials or studies not compatible with study objectives (in particular, those 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, bromocriptine, 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 started or discontinued within 4 weeks prior to screening (Any change in diuretic medication during the study should be reported).
  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: NCT01425957

Contacts
Contact: Giovanni Frisoni, MD, MP 0039 030 35 01 261 gfrisoni@fatebenefratelli.it
Contact: Severine Pitel, Director 0334 91 50 40 39 severine.pitel@qualissima.com

Locations
France
Université Lille 2, UL2 - Centre d'investigation clinique / Centre de Ressources biologiques 9301 - INSERM - Centre Hospitalier Régional et Universitaire de LILLE Recruiting
Lille, France, 59307
Contact: Regis Bordet, MD    0033320445449    bordet@univ-lille2.fr   
Sub-Investigator: Florence Pasquier, MD         
APHM, Hopital de la Timone, Service de Neurologie et Neuropsychologie Recruiting
Marseille, France, 13385
Contact: Mira Didic, MD    0033491384717    mira.didic@ap-hm.fr   
Principal Investigator: Mira Didic, MD         
INSERM - CHU Purpan Recruiting
Toulouse, France, 31059
Contact: Pierre Payoux, MD    0033561772129    payoux.p@chu-toulouse.fr   
Principal Investigator: Pierre Payoux, MD, PD         
Germany
Hospital and Institute of the University of Duisburg and Essen - Department for Psychiatry and Psychotherapy, LVR Hospital Essen Recruiting
Essen, Germany, 45147
Contact: Jens Wiltfang, MD    0049-201-7227-200    jens.wiltfang@uni-due.de   
Principal Investigator: Jens Wiltfang, MD         
University Hospital of Leipzig - Department of Psychiatry Recruiting
Leipzig, Germany, 04103
Contact: Peter Schönknecht, MD, PD    0049-341-9724506    peter.schoenknecht@medizin.uni-leipzig.de   
Principal Investigator: Peter Schönknecht, MD         
Greece
Aristotle University of Thessaloniki, Greek Association of Alzheimer's disease and related disorders, Thessaloniki, Greece Recruiting
Thessaloniki, Greece, 54643
Contact: Magda Tsolaki, MD    0030 694 29 18 933    tsolakim@med.auth.gr   
Principal Investigator: Magda Tsolaki, MD         
Italy
IRCCS-FBF - Ordine Ospedaliero San Giovanni di Dio, Fatebenefratelli, Istituto di Ricovero e Cura a Carattere Scientifico Recruiting
Brescia, Provincia Lombardo-Veneta, Italy, 25125
Contact: Giovanni Frisoni, MD, PD    00390303501261    gfrisoni@fatebenefratelli.it   
Principal Investigator: Giovanni Frisoni, MD, PD         
Neurofisiologia Clinica IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Padiglione Specialita' piano Fondi Recruiting
Genoa, Italy, 16132
Contact: Flavio Mariano Nobili, MD    +39 0103537568    flaviomariano.nobili@hsanmartino.it   
Principal Investigator: Flavio Mariano Nobili, MD         
IRCCS Fondazione SDN per la Ricerca e l'Alta Formazione in Diagnostica Nucleare di Napoli Recruiting
Napoli, Italy, 80143
Contact: Andrea Soricelli, MD    0039 081 24 08 260    soricelli@uniparthenope.it   
Principal Investigator: Andrea Soricelli, MD         
Dipartimento di Specialità medico-chirurgiche e Sanità Pubblica, Sezione di Clinica Neurologica, Centro Disturbi della Memoria, Perugia, Italy Recruiting
Perugia, Italy, 06132
Contact: Lucilla Parnetti, MD    0039 075 57 83 545    parnetti@unipg.it   
Principal Investigator: Lucilla Parnetti, MD         
Università Cattolica del Sacro Cuore - Policlinico Agostino Gemelli Istituto di Neurologia - Neuropsychological and Neurorehabilitation Unit Recruiting
Roma, Italy, 00168
Contact: Paolo Maria Rossini, MD    0039 063 01 54 303    paolomaria.rossini@afar.it   
Principal Investigator: Paolo Maria Rossini, MD         
Netherlands
VUmc Alzheimercentrum Recruiting
Amsterdam, Netherlands, 1007MB
Contact: Pieter J Visser, MD    0031 204 440 183    PJ.Visser@vumc.nl   
Contact: Nienke Scheltens    0031 204 440 183    n.scheltens@vumc.nl   
Sub-Investigator: Pieter J Visser, MD         
Spain
Institut d'Investigacions Biomèdiques August Pi I Sunyer, IDIBAPS Recruiting
Barcelona, Catalunya, Spain, 08036
Contact: Jose-Luis Molinuevo, PhD    0034932275414    JLMOLI@clinic.ub.es   
Principal Investigator: Jose Luis Molinuevo, MD, PD         
Sponsors and Collaborators
Qualissima
European Union
Investigators
Study Director: Giovanni Frisoni, MD, MP Istituto di Ricovero e Cura a Carattere Scientifico, San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Principal Investigator: Mira Didic, MD Université de la Méditerranée, Service de Neurologie et Neuropsychologie, Marseille France
Principal Investigator: Jose-Luis Molinuevo, PhD Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain
Principal Investigator: Regis Bordet, MD Université Lille 2, Lille, France
Principal Investigator: Pierre Payoux, MD Institut National de la Santé et de la Recherche Médicale, Toulouse, France
Principal Investigator: Peter Schönknecht, MD Universitätsklinikum Leipzig, Department of Psychiatry and Nuclear Medicine, Leipzig, Germany
Principal Investigator: Jens Wiltfang, MD Universitaet Duisburg-Essen, Department of Psychiatry and Nuclear Medicine, Duisburg-Essen, Germany
Principal Investigator: Flavio Mariano Nobili, MD IRCCS Azienda Ospedaliera Universitaria San Martino-IST
Principal Investigator: Magda Tsolaki, MD Greek Association of Alzheimer's disease and related disorders, Thessaloniki, Greece
Principal Investigator: Lucilla Parnetti, MD Università di Perugia, Clinica Neurologica, Centro Disturbi della Memoria, Perugia, Italy
Principal Investigator: Paolo Maria Rossini, MD Università Cattolica del Sacro Cuore, Policlinico Agostino Gemelli, Istituto di Neurologia, Roma, Italy
Principal Investigator: Andrea Soricelli, MD Istituto di Ricerca Diagnostica e Nucleare, University of Naples Parthenope, Napoli, Italy
Principal Investigator: Philip Scheltens, MD VUmc Alzheimercentrum
  More Information

Additional Information:
Publications:
Responsible Party: Qualissima
ClinicalTrials.gov Identifier: NCT01425957     History of Changes
Other Study ID Numbers: WP5P001, 2011-A00985-36
Study First Received: August 26, 2011
Last Updated: June 18, 2013
Health Authority: France: Comité de protection des personnes Sud-Mediterannée 1 (Approval reference 1142)
France: Afssaps - French Health Products Safety Agency (AEC/B111094-90)
Germany: Ethics Commission (Essen: 11-4807-BO; Leipzig: 290-11-22082011)
Spain: Ethics Committee (Barcelona: 2011-6861)
Greece: Scientific Committee of the Greek Association of Alzheimer's disease and
related disorders (Thessaloniki: 284/2012 AI)
The Netherlands: Medisch Ethische Toetsingscommissie (Amsterdam: NL43073.029.13)
Italy (under IRCCS-FBF sponsorship): Ethics Committee

Keywords provided by Qualissima:
MEMORY and COGNITIVE IMPAIRMENT
ALZHEIMER DISEASE CONVERSION
Amyloid beta-Peptides

Additional relevant MeSH terms:
Disease Progression
Cognition Disorders
Disease Attributes
Pathologic Processes
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders

ClinicalTrials.gov processed this record on July 26, 2014