Clinical trial NCT03834402: INTERCEPTOR Project: From MCI to Dementia
Official title: Interceptor Project: On Early Diagnosis Of The Prodromal Stage Of Alzheimer Disease. The Progression From Mild Cognitive Impairment (Mci) To Dementia: The Role Of Biomarkers In Early Interception Of Patients Candidate For Prescription Of Future Disease-Modifying Drugs
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Mild Cognitive Impairment
Alzheimer Disease
Keywords: Mild Cognitive Impairment
Alzheimer Disease
Lead sponsor: Catholic University of the Sacred Heart
Sponsor class: OTHER
Collaborators: name: Ministry of Health, Italy
name: Agenzia Italiana del Farmaco
First posted: 2019-02-08
Enrollment: 500
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: MCI subjects

Brief summary: In the next years a number of phase 2-3 trials which utilize experimental drugs possibly disease modifying for Alzheimer Dementia will reach their conclusion. This dense clinical trials activity has triggered a fundamental question both from Patients and Scientific Communities and Health Authorities/Insurances: on which basis will the new drugs -if effective-be distributed to patients or at-risk population? This question mainly deals with the "MCI prodromal to AD"condition since the MCI population actually includes about 50% of those who will progress to AD (the real "prodromic to AD" MCI form) while the remaining 50% will never convert to AD.

The INTERCEPTOR project is focused on the prodromic AD condition (IWG2) or the MCI condition (NIA-AA) which form the neuropsychological point of view and is characterized by means of: cognitive questionnaires, screening test (MMSE), extended neuropsychological evaluation.

The study is an observational, longitudinal cohort one, in which the baseline clinical and biomarkers characteristics of the enrolled MCI subjects at baseline will be compared for those classified as "AD converters" after 3.0 years of follow-up with respect to those "non-converters". MCI subjects who will convert to other forms of dementia will be examined separately. It will be considered the conversion to Alzheimer's disease within 3.0 years after diagnosis of MCI, together with the assessment of those who remain in a stable condition and those who have a reversion to normal cognitive profile. People with MCI who convert to other forms of dementia will be considered separately. The biomarker or a set of biomarkers that can predict the conversion to Alzheimer's disease with higher accuracy will be evaluated.

Detailed description: In the next 8 years a number of phase 2-3 trials will end up which utilize experimental drugs possibly disease modifying for Alzheimer Dementia. They target different disease stages: mild-moderate AD, 'early' AD, MCI prodromic to AD (MCI + for biomarkers heralding progression to AD), pre-symptomatic AD in pathogenetic gene mutation carriers of familiar AD forms. This dense clinical trials activity has triggered a fundamental question both from Patients and Scientific Communities and Health Authorities/Insurances: on which basis will the new drugs -if effective-be distributed to patients or at-risk population? This question mainly deals with the "MCI prodromal to AD"condition since the MCI population actually includes about 50% of those who will progress to AD (the real "prodromic to AD" MCI form) while the remaining 50% will never convert to AD. Since the new drugs -if effective- will carry both elevated unit costs and not marginal side-effects, they should be administered selectively to those MCI with a severely high risk of conversion (i.e. 90% or more) and particularly to those with a highrisk of rapid conversion (1-2 years from diagnosis of the MCI condition).

The INTERCEPTOR project is focused on the prodromic AD condition (IWG2) or the MCI condition (NIA-AA) which form the neuropsychological point of view and is characterized by means of: cognitive questionnaire, screening test (MMSE), extended neuropsychological evaluation (incl. 2 episodic memory tests, language test, visuo-spatial abilities evaluation, behavioural scales, functional scales (Annex), full neurological examination. CDR must be 0.5. Atypical types of clinical presentations must be particularly considered (i.e. non amnesic debut) for a differential diagnosis where the role of biomarkers is pivotal.

In Italy, according to a recent study, an MCI prevalence of 5.9% has been evaluated in over 60 yrs population, with an increase of 4.5% between 60 \& 69 yrs, of 5.8% between 70 \& 79 yrs, and up to 7.1% in the 80 - 89 yrs range. On this epidemiological basis about 735.000 MCI cases are estimated for 2016in the resident Italian population. Multicentric non therapeutic cohort study in subjects fulfilling the MCI "core" criteria as defined by the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. The study design reflect a longitudinal cohort study in which the baseline clinical and biomarkers characteristics of the enrolled MCI subjects at baseline will be compared for those classified as "AD converters" after 3.0 years of follow-up with respect to those "non-converters". MCI subjects who will convert to other forms of dementia will be examined separately.

All the medications at baseline are allowed without modifications for the whole protocol except for urgencies.

Neuropsychological follow-up tests will be carried out at 6 months intervals (total 7 from T0= baseline to T6= 42 months).

Within 60 days from T0 biomarkers must be carried out/collected including:

MMSE \& DRF - FCSRT) DNA extraction and ApoE typing Lumbar Puncture for Beta/Tau metabolites EEG for brain connectivity with graph theory MRI + hippocampal volumetry (18F)FDG-PET

Eligibility criteria: Inclusion Criteria:

1. age between 50 and 85 years;
2. age and education corrected Mini Mental State Examination score equal or superior to 24/30;
3. Clinical Dementia Rating (CDR) global score of 0.5;
4. concerns about cognitive modifications, expressed as subjective complaints by the subject, or by impression by a close acquaintance or an expert clinician;
5. defective performance with reference to age and education matched controls in one cognitive domain (memory, executive function, attention, language, visuospatial function): if repeated assessments are available, evidence of performance decline;
6. preserved functional autonomy: the subject remains fully independent, even if specific performances may be slower, less efficient than usual level, with occasional errors;
7. no dementia: the cognitive modifications do not significantly hamper social function or work activities.

Exclusion Criteria:

1. history of cerebrovascular disease (i.e. stroke episodes), alcohol abuse, severe medical disorders associated with cognitive impairment (organ failures, endocrine disorders, in particular thyroid disease and B12/folates deficiency); neuroimaging evidence of other potential causes of cognitive decline (e.g. subdural haematoma, malignancy etc.); chronic treatment with psychotropic drugs; women in reproductive age;
2. history of malignancy \< 5 years;
3. contraindications for Magnetic Resonance Imaging (MRI): pacemaker; spinal stimulators; defibrillator; any other condition incompatible with MRI acquisition;
4. presence of spinal malformations or any other contraindications to lumbar puncture, according to the investigator's judgement;
5. HIV infection;
6. use of drugs potentially affecting cognitive function, according to the investigator's judgement;
7. subjects are not allowed to participate in any trial with experimental drug;

Exclusion criteria specific to lumbar puncture:

Patients who refuse to or cannot temporarily interrupt antiplatelet or anticoagulant therapy 14 days prior to sampling visit.

Primary outcomes:
measure: MCI converting to AD
timeFrame: 3 years
Secondary outcomes:
measure: PREDICTING BIOMARKERS
timeFrame: 4.5 years
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Policlinico Agostino Gemelli
Study officials:
affiliation: Catholic University of Sacred Heart
name: Paolo Maria Rossini, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. doi: 10.1016/j.jalz.2011.03.008. Epub 2011 Apr 21.
citation: Appollonio I, Leone M, Isella V, Piamarta F, Consoli T, Villa ML, Forapani E, Russo A, Nichelli P. The Frontal Assessment Battery (FAB): normative values in an Italian population sample. Neurol Sci. 2005 Jun;26(2):108-16. doi: 10.1007/s10072-005-0443-4.
citation: Arevalo-Rodriguez I, Smailagic N, Roque I Figuls M, Ciapponi A, Sanchez-Perez E, Giannakou A, Pedraza OL, Bonfill Cosp X, Cullum S. Mini-Mental State Examination (MMSE) for the detection of Alzheimer's disease and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2015 Mar 5;2015(3):CD010783. doi: 10.1002/14651858.CD010783.pub2.