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

MILD COGNITIVE IMPAIRMENT Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01425957
• Other study ID #: WP5P001
• Secondary ID: 2011-A00985-36
• Status: Completed
• Phase: N/A
• First received: August 26, 2011
• Last updated: October 30, 2015
• Start date: December 2011
• Est. completion date: October 2015

Study information

• Verified date: October 2015
• Source: Qualissima
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Comité de protection des personnes Sud-Mediterannée 1 (Approval reference 1142)France: ANSM - 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 andrelated disorders (Thessaloniki: 284/2012 AI)The Netherlands: Medisch Ethische Toetsingscommissie (Amsterdam: NL43073.029.13)Italy (under IRCCS-FBF sponsorship): Ethics Committee
• Study type: Interventional

Clinical Trial Summary

THE STUDY WILL BE A TWO-PART RESEARCH

PART A and PART A extended:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 229
• Est. completion date: October 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 50 Years to 90 Years

Eligibility

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).

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Cognition Disorders
• Disease Progression
• Mild Cognitive Impairment

Intervention

Procedure:
• Lumbar puncture
All the patients will be divided in two groups based on their Aß 1-42 levels measured in the cerebro-spinal fluid obtained form a lumbar puncture: in low Aß1-42 (positive aMCI patients CSFP) and high Aß1-42 (Negative aMCI patients CSFN). The threshold of Aß1-42 used to divide the patient will be 500 (ng/L) based on Sjogren criteria (2001). Timeframe of lumbar punctures: every 18 months during 2 years (T0 and T18) or 3 years (T0, T18 and T36).

Locations

Country	Name	City	State
France	Université Lille 2, UL2 - Centre d'investigation clinique / Centre de Ressources biologiques 9301 - INSERM - Centre Hospitalier Régional et Universitaire de LILLE	Lille
France	APHM, Hopital de la Timone, Service de Neurologie et Neuropsychologie	Marseille
France	INSERM - CHU Purpan	Toulouse
Germany	Hospital and Institute of the University of Duisburg and Essen - Department for Psychiatry and Psychotherapy, LVR Hospital Essen	Essen
Germany	University Hospital of Leipzig - Department of Psychiatry	Leipzig
Greece	Aristotle University of Thessaloniki, Greek Association of Alzheimer's disease and related disorders, Thessaloniki, Greece	Thessaloniki
Italy	IRCCS-FBF - Ordine Ospedaliero San Giovanni di Dio, Fatebenefratelli, Istituto di Ricovero e Cura a Carattere Scientifico	Brescia	Provincia Lombardo-Veneta
Italy	Neurofisiologia Clinica IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Padiglione Specialita' piano Fondi	Genoa
Italy	IRCCS Fondazione SDN per la Ricerca e l'Alta Formazione in Diagnostica Nucleare di Napoli	Napoli
Italy	Dipartimento di Specialità medico-chirurgiche e Sanità Pubblica, Sezione di Clinica Neurologica, Centro Disturbi della Memoria, Perugia, Italy	Perugia
Italy	Università Cattolica del Sacro Cuore - Policlinico Agostino Gemelli Istituto di Neurologia - Neuropsychological and Neurorehabilitation Unit	Roma
Netherlands	VUmc Alzheimercentrum	Amsterdam
Spain	Institut d'Investigacions Biomèdiques August Pi I Sunyer, IDIBAPS	Barcelona	Catalunya

Sponsors (2)

Lead Sponsor	Collaborator
Qualissima	European Union

Countries where clinical trial is conducted

France,  Germany,  Greece,  Italy,  Netherlands,  Spain, 

References & Publications (1)

Grady CL, Haxby JV, Horwitz B, Sundaram M, Berg G, Schapiro M, Friedland RP, Rapoport SI. Longitudinal study of the early neuropsychological and cerebral metabolic changes in dementia of the Alzheimer type. J Clin Exp Neuropsychol. 1988 Oct;10(5):576-96. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Magnetic Resonance Imagery protocol	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), a diffusion tensor scan (i.e. DTI) that will be conducted at the magnetic field strength of 3T and a quantitative assessment of brain perfusion changes with a sequence of Arterial Spin Labelling (i.e. ASL) . 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).	Two times: One measure at day 1	No
Primary	Part B: Changes of the hippocampal volume	The primary endpoint will be changes of the hippocampal volume between the two groups (differentiated by the level of amyloid ß1-42 in the cerebro-spinal fluid) and within the same group over time.	2 or 3 times: every 18 months during 2 or 3 years (T0, T18 and/or T36)	No
Secondary	Part B: Clinical assessment	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)	Every 6 months (screening, T6, T12, T18, T24, T30 and T36)	No
Secondary	Part B: Neuropsychology	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)	Every 6 months (screening, T6, T12, T18, T24, T30 and T36)	No
Secondary	Part B: Neurophysiology	Electro-Encephalography in several conditions	Every 6 months (T0, T6, T12, T18, T24, T30 and T36)	No
Secondary	Part B: Magnetic Resonance Imagery and functional MRI	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), a diffusion tensor scan (i.e. DTI) that will be conducted at the magnetic field strength of 3T and a quantitative assessment of brain perfusion changes with a sequence of Arterial Spin Labelling (i.e. ASL only in T18 and T24 timepoints for available patients).	Every 6 months (screening, T0, T6, T12, T18, T24, T30 and T36)	No
Secondary	Part B: Blood drawing	ApoE (T0 only); ß 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 ß1-42 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)	Every 6 months	No
Secondary	Part B: Actigraphy	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.	Every 6 months (T0, T6, T12, T18, T24, T30 and T36)	No
Secondary	Adverse events	Any changes in the chronicity, severity, action taken, seriousness of a symptom or adverse event will be recorded by a qualified clinician (MD).	Every 6 months (T0, T6, T12, T18, T24, T30 and T36)	Yes

External Links

•   The Alzheimer-Europe announcement webpage dedicated to PharmaCog project