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The objective of the ADDIA clinical Proof-of-Performance study is to validate the performance of ADDIA' blood biomarkers for diagnosis of Alzheimer's disease (AD).
ADDIA clinical study is a multi-centre, non-interventional, prospective, proof-of-performance study with only one visit.
About 800 well-characterized subjects will be recruited into 3 groups in 2:1:1 ratio, namely patients with Alzheimer's disease (AD), patients with non-AD neurodegenerative disease (NAD) and 200 control subjects (healthy as compared to their age).
Full description
ADDIA study is dedicated to the proof-of-performance (PoP) of blood biomarkers for diagnosis of Alzheimer's disease (AD) and will recruit approximately 800 subjects (400 AD and 400 non-AD).
CONTEXT OF USE:
To quantify the performance of ADDIA' blood biomarkers for AD diagnosis (yes/no).
Since the main objective of this study is to establish the performance of ADDIA' blood cell-based biomarkers β-amyloid (Aβ) and protein kinase C (PKC) and corresponding assays and to seek approval as In-Vitro Diagnosis (IVD) test(s) specific for diagnosis of AD, and to validate the newly identified metabolomics and RNA signatures and selected protein biomarker candidates, samples will be used from:
For further validation of ADDIA' biomarkers, an integrative tool combining ADDIA' blood biomarkers with cognitive scores and/or, neuroimaging (and/or retrospective CSF biomarker data) will be used. The impact of polymorphisms associated with AD, such as APOE e4 (known to be as risk factor of AD) on ADDIA' blood biomarkers will also be studied.
OBJECTIVES:
Objective 1: Validate the ADDIA biomarker candidates: two blood cell-based biomarkers measured by flow cytometry using Amoneta Diagnostics' proprietary probes specific to beta-Amyloid (Aβ) peptide and protein kinase C (PKC).
ADDIA' blood cell-based Aβ and/or PKC biomarkers will also be combined via an integrative tool with clinical neuropsychological scores (MMSE, MoCA, FCSRT) and/or neuroimaging (at least volumetric MRI) scores for diagnosis and/or differential diagnosis. The impact on these ADDIA biomarkers of genotyping in particular polymorphisms known to be associated with AD (e.g. APOE e4, e2 alleles) will also be tested. In addition, the levels of ADDIA' blood cell-based Aβ and/or PKC biomarkers will be correlated to the levels of CSF biomarkers Aβ and tau or phospho-tau (or Aβ PET and TAU PET levels).
Objective 2: ADDIA clinical PoP study will also validate additional new biomarker candidates (identified previously and/or under analytical validation in the ADKIT study and chronobiological studies) for AD diagnosis in peripheral body fluids; in particular, studies on a set of proteins (using immuno-detection methods), metabolomics/lipidomics signatures (using e.g. LC-HRMS method) and miRNA signature (using e.g. qPCR, HTG-NGS methods) are planned. These new biomarkers may be used if needed to further enhance the accuracy of ADDIA' blood-based Aβ and PKC biomarker test for diagnosis or differential diagnosis.
STUDY DESIGN
ADDIA clinical study is a multi-centre, non-interventional, prospective, proof-of-performance group study without a clinical follow-up. About 800 well characterized subjects will be enrolled into 3 groups in 2:1:1 ratio, namely Alzheimer's disease, non-AD neurodegenerative diseases and controls (healthy as compared to their age). The number of subjects is divided into 3 groups as following:
All groups will be age-matched and mean age similar in the three groups.
ADDIA clinical study needs to recruit well characterized subjects in each group, therefore a pre-screening or a diagnostic workup of the subjects needs to be performed by the clinical centres before the start of the clinical study (during Visit 0). In ADDIA clinical study, only one visit (Visit 1) is required for the subjects without any follow-up, in which the subjects will be recruited and sampling of blood and urine will be done in the same Visit 1. The following data sets will be collected:
Data set 1 and samples available from visit 0 collected in the e-CRF after informed consent signature:
• Data from all subjects of the three groups include neuropsychological scores (MMSE, MoCA, FCSRT scores), neuroimaging (at least structural MRI volumetric scores, and other neuroimaging as needed for diagnosis) and laboratory data (haematology, biochemistry) related to pre-screening and diagnosis. CSF samples obtained retrospectively by clinical centres are needed if available.
Data set 2 and samples from Visit 1 include in all three groups clinical MMSE, FCSRT, MoCA tests (MMSE and MoCA tests to be redone on Visit 1 if older than 3 months) and laboratory data (haematology, biochemistry), and blood and urine (and saliva and tear as optional) collected during Visit 1 (clinical centres). The clinical centres equipped with flow cytometry can perform experiments on ADDIA blood cell-based biomarkers utilizing Amoneta' proprietary Aβ and PKC probes.
Data set 3 will be obtained at the end of ADDIA clinical study (Amoneta Diagnostics/Firalis) and will comprise data on the performance of ADDIA biomarkers as described in details in objectives 1, 2.
SUBJECT RECRUITMENT AND SAMPLING
The subjects who meet the inclusion and exclusion criteria prior to the inclusion in the study (as checked by the clinical centres during Visit 0) will be enrolled in the ADDIA study after the informed consent signatures. Sampling will be performed for the following body fluids during Visit 1: blood (11 tubes, 2.5, 4 or 5 mL each) and urine (1 tube, 5 mL) from all subjects. Saliva (1 tube, 4 mL) and tear (2 tubes, 0.15 mL each) samples are optional.
Eleven tubes of blood and spot urine will be collected from each subject that has fasted for > 12 hours. The samples will be used as follows:
ENDPOINTS
STATISTICAL CONSIDERATIONS
Primary consideration (for the evaluation of the diagnostic performance) will be the comparisons between the following groups:
Secondary considerations (for the evaluation of the differential diagnostic performance) will be the comparisons between the following groups:
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Inclusion Criteria:
For all groups:
For AD group:
Diagnosis of AD: typical and atypical AD.
MMSE score (measured in the last 3 months): < 21 for patients with moderate to severe AD. MMSE score > 21 in subjects with mild AD with sporadic or a familial form of AD due to mutation in APP or PSEN1 or PSEN2 genes.
FCSRT, MoCA tests (MoCA measured in the last 3 months).
Neuroimaging compatible with a diagnosis of AD:
Other neuroimaging data (retrospectively available) including PET Amyloid scan and FDG PET are desired if practiced by clinical centres and if available.
For NAD group:
For all patients of the group NAD, except PSP subgroup (when PSP has a clear-cut typical phenotype, sometimes called Steele-Richardson phenotype), the CSF biomarker data must show levels for CSF biomarkers Aβ1-42, phosphorylated-Tau and total-Tau, compatible with the respective NAD subgroup. If retrospective CSF data are not available, retrospective Aβ PET and Tau PET data can be used.
Fronto-temporal dementia (FTD)
Dementia Lewy body (DLB)
DLB should be diagnosed when dementia occurs before or concurrently with Parkinsonism.
Patients diagnosed with probable DLB. Probable DLB can be made with the presence of two core features out of the following:
Probable DLB is diagnosed with the presence of one or more of the above core features and one or more of the following suggestive features. Probable DLB should not be diagnosed on the basis of suggestive features alone:
Supportive diagnosis:
Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity (if data retrospectively available),
Abnormal (low uptake) MIBG myocardial scintigraphy,
Prominent slow wave activity on EEG with temporal lobe transient sharp waves.
Parkinson's disease dementia (PDD)
Subjects with Parkinson's Disease Dementia (PDD) must have dementia after (not before) developing Parkinson's disease (PD).
PD is diagnosed by the 3 typical PD symptomatic findings:
Subjects with dementia and with LRRK2 gene mutation (or with mutation in one of the following genes: PARK2 or SNCA, VPS35, PINK1, DJ1, ATP13A2, FBX07, SLC6A3, TAF1 are also included.
L-DOPA responsive (a good response to levodopa as practiced by clinical investigator, retrospectively to the study).
MMSE score < 21 for moderate to severe PDD and > 21 for mild PDD.
MRI: evidence of relevant structural abnormality (i.e. basal ganglia for Parkinsonism and potentially medio-temporal or cortical findings that may be related to dementia). Functional imaging techniques such as fluoro-dopa PET, FDG PET or SPECT to document the presence of dopaminergic dysfunction if retrospectively available.
Progressive Supranuclear Palsy (PSP)
Diagnosis of probable or possible PSP as defined by the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy (NINDS-SPSP) diagnostic criteria, and as summarized by Armstrong et al. (2013) for the conclusions on CBD criteria from an international consortium of behavioural neurology, neuropsychology, and movement disorders specialists):
Brain MRI at Screening consistent with PSP: neuroradiologic evidence of relevant structural abnormality in the midbrain and frontal lobes (i.e. basal ganglia, lobar atrophy).
MMSE score compatible.
Be able to ambulate and stand unassisted for 5 minutes.
Be able to cooperate with gait and balance testing.
Corticobasal degeneration (CBD)
• Diagnosis of possible CBD. Inclusion clinical criteria for possible CBD, with features of Cortico-Basal Syndrome (CBS); familial forms related to MAPT included, Progressive Supranuclear Palsy Syndrome (PSPS) phenotype included.
Note: subjects with probable sporadic CBD (no familial form) are excluded.
Controls
EXCLUSION CRITERIA for all subjects:
The following exclusion criteria apply to all subjects:
EXCLUSION CRITERIA for AD group
EXCLUSION CRITERIA for NAD group
EXCLUSION CRITERIA for Control group
821 participants in 3 patient groups
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Central trial contact
Saliha Moussaoui, PhD; Hüseyin Firat, MD
Data sourced from clinicaltrials.gov
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