ADDIA Proof-of-Performance Clinical Study

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Brief Title

ADDIA Proof-of-Performance Clinical Study

Official Title

A Multi-centre Proof-of-performance Clinical Study to Validate Blood-based Biomarker Candidates for the Diagnosis of Alzheimer's Disease

Brief Summary

      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).

        -  400 patients with Alzheimer's disease (AD): 200 patients with mild AD, 200 patients with
           moderate-to-severe AD,

        -  200 patients with non-Alzheimer's neurodegenerative diseases (NAD),

        -  200 controls (healthy as compared to their age).
    

Detailed 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:

        -  the patients recruited in the AD group and patients recruited in the non-AD
           neurodegenerative disorders (NAD) group who are accurately diagnosed during the
           pre-screening period, including by using three types of diagnostic methods: clinical
           neuropsychological scores, neuroimaging (at least volumetric structural MRI) and
           retrospective cerebrospinal (CSF) data: Aβ, total-Tau and p-tau biomarkers.
           Alternatively to absence of retrospective CSF data, retrospective Aβ PET /Tau PET scans
           can be used if compatible to diagnosis of respective diseases.

        -  the subjects recruited in the control group have no objective memory loss, normal
           results on neuropsychology tests, and normal neuroimaging findings for their age, as
           well as normal Aβ PET scan Tau PET scan and normal CSF Aβ, total-Tau and p-Tau
           concentration if retrospectively available.

      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:

        -  400 patients with Alzheimer's disease (AD),

        -  200 patients with non-Alzheimer's neurodegenerative diseases (NAD),

        -  200 controls (CC).

      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:

        1. 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.

        2. 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:

        -  2 (two) tubes will be used at the participating clinical centres for routine lab tests,
           haematology and biochemistry.

        -  9 (nine) tubes will be sent to Amoneta facilities in the following format:

        -  3 (three) fresh whole blood samples (3 Li-heparin tubes), 1 tube will be sent in the
           morning immediately after sampling to the flow cytometry laboratory (Amoneta
           laboratories or another laboratory chosen by Amoneta which can be a laboratory of the
           clinical centre if equipped with flow cytometry platform) to quantify the performance of
           ADDIA assays based on blood cell-based biomarkers Aβ and PKC for AD diagnosis and 2
           tubes will be used to fix or prepare cells that will be later analysed by flow cytometry
           at Amoneta laboratories.

        -  6 (six) fresh blood samples will be prepared on-site to obtain serum (dry tube), plasma
           (EDTA and Li-Heparin tubes), PAXgene and PAXRNA samples and PBMC (Li-Heparin tube)
           samples, which will be aliquoted and stored immediately at -80°C at the clinical centres
           before being shipped at -80°C later on Amoneta/Firalis central laboratory for testing:
           genotyping and gene, RNA expression (2 blood tubes), protein expression and
           metabolomics/lipidomics (1 Li-Heparin and 1 EDTA tubes of plasma, 1 dry tube of serum,
           and 1 Li-Heparin tube of PBMCs) during the ADDIA program and for validating the emerging
           biomarkers and for replication studies during or after the ADDIA program (as may be
           requested by regulatory authorities for IVD product approval).

        -  Urine samples (and saliva, tear samples as optional) will be aliquoted and frozen
           immediately at -80°C at the clinical centres and shipped at -80°C to Amoneta/Firalis
           central laboratory for testing in selected assays based on results that will be obtained
           on blood samples.

      ENDPOINTS

        -  Performance evaluation of the ADDIA blood biomarkers Aβ and PKC (IVD) kit by AD
           diagnosis in the form of binary outcome (Yes/No) after quantification of sensitivity &
           specificity of these biomarkers. This will be also achieved by using the integrative
           tool enabling comparison of ADDIA blood-based biomarkers Aβ and PKC to and combination
           with standard clinical diagnosis tests: cognitive scores, neuroimaging scores (and CSF
           Biomarkers if possible).

        -  Performance evaluation of the ADDIA' additional new biomarkers (RNA signature,
           metabolomics signature and/or other peripheral biomarkers) for AD diagnosis in the form
           of binary outcome (Yes/No) after quantification of sensitivity & specificity of these
           biomarkers.

      STATISTICAL CONSIDERATIONS

      Primary consideration (for the evaluation of the diagnostic performance) will be the
      comparisons between the following groups:

        -  AD (Mild AD + Moderate-to-severe AD) versus healthy controls, and/or

        -  Mild AD versus healthy controls, and/or

        -  Moderate-to-severe AD versus healthy controls, and/or

        -  AD versus healthy controls+NAD groups.

      Secondary considerations (for the evaluation of the differential diagnostic performance) will
      be the comparisons between the following groups:

        -  AD (Mild AD + Moderate-to-severe AD) versus NAD and/or

        -  Mild AD versus NAD and/or

        -  Moderate-to-severe AD versus NAD and/or

        -  Mild AD versus Moderate-to-severe AD Tertiary considerations will explore potential
           differences between NAD versus healthy controls and the subgroups of NAD (FTD, LBD, PDD,
           PSP, CBD) two by two as well as versus healthy controls and AD.
    


Study Type

Observational


Primary Outcome

Blood cell biomarkers for diagnosis of Alzheimer

Secondary Outcome

 Biomarkers circulating in body fluids for diagnosis of Alzheimer and/or other dementia type

Condition

Alzheimer Disease (AD)


Study Arms / Comparison Groups

 Alzheimer
Description:  400 patients in total, with approximately 200 patients with mild Alzheimer's disease and 200 patients with moderate to severe Alzheimer's disease will be recruited for sampling blood, urine (and other peripheral body fluids: tears and saliva as optional) for validation of biomarkers

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

800

Start Date

September 1, 2016

Completion Date

June 30, 2021

Primary Completion Date

June 30, 2021

Eligibility Criteria

        Inclusion Criteria:

        For all groups:

          -  Female and male subjects aged 40 to 85 years.

          -  Dated and signed informed consent by the subject (or its legal representative if
             applicable in accordance with the local regulations).

          -  AD, NAD patients and control subjects will be age-matched and mean age similar in the
             three groups.

          -  Able to comply with all study procedures.

        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:

               -  At least quantitative volumetric structural MRI: volumes of hippocampus and
                  cortical areas.

               -  Visual semi-quantitative MRI if practiced shall show medial temporal lobe atrophy
                  (MTA) and parietal atrophy with visual rating (semi-quantitative) on the
                  MTA-score (e.g. Scheltens' scores 0-4). MTA score must be ≥ 2 in patients aged
                  40-75 years and ≥ 3 in patients aged above 75 years. For patients younger than 60
                  years, and with familial form of AD, who may have normal MTA-scores, Koedam score
                  (0-3) for Parietal Atrophy showing atrophy of the precuneus characteristic of AD
                  may be used with a Koedam score from 1 to 3.

        Other neuroimaging data (retrospectively available) including PET Amyloid scan and FDG PET
        are desired if practiced by clinical centres and if available.

        - Cerebrospinal fluid biomarker data (retrospectively available) showing positive levels of
        at least 2 out of 3 biomarkers: i.e. Aβ1-42 and tau (phosphorylated-Tau and/or total-Tau).
        Note: If retrospective CSF data are not available, retrospective Aβ PET and Tau PET data
        can be used.

        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)

          -  Diagnosis of probable behavioural FTD (bvFTD) for all subjects of this FTD subgroup,
             whether with familial or non-familial forms. If with familial form, the subject must
             be a member of family with a known mutation in one of the FTD related genes: MAPT,
             PGRN. The predominant phenotype in the kindred must be cognitive/behavioural (i.e.
             kindred in whom Parkinsonism or Amyotrophic Lateral Sclerosis is the predominant
             clinical phenotype among affected relatives is excluded).

          -  Centrally rated frontal and/or anterior temporal atrophy score of 2 or greater on
             brain MRI.

          -  MMSE score compatible. If currently taking an acetylcholinesterase inhibitor and/or
             memantine, the subject must have been taking such medication(s) for ≥3 months.

        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:

               -  Fluctuating cognition with pronounced variations in attention and alertness,

               -  Recurrent visual hallucinations that are typically well formed and detailed,

               -  Spontaneous features of Parkinsonism.

        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:

          -  REM sleep behaviour disorder,

          -  Severe neuroleptic sensitivity,

          -  Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging
             (if data retrospectively available).

        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.

               -  MRI: Relative preservation of medial temporal lobe structures on CT/MRI scan.

               -  Clinical Dementia Rating (CDR) score is greater than or equal to 0.5.

               -  MMSE score compatible.

               -  Patients with familial forms caused by mutation in genes SNCA, SNCB.

        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:

               -  tremor,

               -  rigidity, and

               -  slowed movement (bradykinesia).

          -  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):

               -  Gradually progressive disorder,

               -  Onset at age 40 or later,

               -  Vertical (upward or downward gaze) supranuclear palsy and prominent postural
                  instability with tendency to fall in the first year of disease onset,

               -  No evidence of other diseases that could explain the foregoing features, as
                  indicated by mandatory exclusion criteria.

          -  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.

          -  Features of CBS: a) limb rigidity or akinesia, b) limb dystonia, c) limb myoclonus
             plus 1 of: d) orobuccal or limb apraxia, e) cortical sensory deficit, f) alien limb
             phenomena (more than simple levitation).

          -  Features of PSPS: Three of: a) axial or symmetric limb rigidity or akinesia, b)
             postural instability or falls, c) urinary incontinence, d) behavioural changes, e)
             supranuclear vertical gaze palsy or decreased velocity of vertical saccades.

        Note: subjects with probable sporadic CBD (no familial form) are excluded.

          -  MRI findings: parietal cortical atrophy (asymmetric).

          -  MMSE score compatible.

        Controls

          -  Normal cognitive performance with normal scores of neuropsychological tests for their
             age.

          -  MMSE >26 (performed in less than 3 months).

          -  At least volumetric structural MRI with normal findings. Normal retrospective finding
             in β-amyloid PET scan, FDG PET scan if practiced by clinical centres.

          -  If retrospectively available, normal CSF biomarkers concentrations: negative levels
             for all three CSF biomarkers Aβ1-42, phosphorylated-Tau and total-Tau.

          -  If retrospectively available, Aβ PET and/or Tau PET scan(s) shall be negative.

          -  Able to comply with the study procedures.

        EXCLUSION CRITERIA for all subjects:

        The following exclusion criteria apply to all subjects:

          -  Neutropenia (Neutrophils: < 1,500/mm3 according to ethnic group).

          -  Thrombocytopenia (platelets: < 100,000/mm3, rule out EDTA-induced
             pseudo-thrombocytopenia).

          -  Subjects with less than an elementary education are excluded.

          -  Subject with no medical insurance are excluded in the countries where medical
             insurance is mandatory such as in France. In the countries where medical insurance is
             not mandatory, subjects with no medical insurance may not be excluded.

          -  Psychiatric history: schizophrenia, psychosis.

          -  Vascular dementia.

          -  Infection diseases, chronic inflammatory diseases that affect blood cells, patients
             with an active infection/ immunosuppressive disorders/ treatment with
             immunosuppressive or immunomodulatory medication.

          -  Current malignancy or past diagnosis of malignancy affecting blood cells under
             treatment or with treatment stopped only during last 3 months.

          -  Medication interfering with cognitive functions and ADDIA biomarkers (i.e. kinase
             inhibitors and beta-amyloid and tau passive and active immunizations).

          -  Major sensory deficits that could interfere with cognitive assessment (visual and
             auditory).

          -  Epilepsy.

          -  Patients with known contraindication for MRI imaging such as MRI-incompatible stent or
             MRI-incompatible endoprosthesis.

        EXCLUSION CRITERIA for AD group

          -  Mixed dementia.

          -  Vascular dementia.

          -  Other dementia type.

          -  Other neurodegenerative disease.

          -  Absence of CSF biomarker data and/or amyloid PET data is an exclusive criterion for
             all subjects with sporadic forms of AD, but it is not an exclusive criterion for
             subjects with a familial form of AD that is due to a mutation of a gene among APP,
             PSEN1, PSEN2.

        EXCLUSION CRITERIA for NAD group

          -  AD diagnosis.

          -  Mixed dementia.

          -  Vascular dementia.

          -  Absence of either CSF biomarker data or amyloid PET data is an exclusive criterion for
             all subjects in sporadic DLB, PDD, FTD and CBD (but not for subjects with PSP when PSP
             has a clear-cut typical phenotype, sometimes called Steele-Richardson phenotype).
             However, absence of CSF biomarker and/or amyloid PET data is not an exclusive
             criterion for subjects with a familial form of NAD that is due to a mutation of a gene
             among MAPT, PGRN, SNCA, SNCB, PARK2 or SNCA, VPS35, PINK1, DJ1, ATP13A2, FBX07, SLC6A3
             or TAF1, TREM2.

        EXCLUSION CRITERIA for Control group

          -  AD patients.

          -  Dementia patients.

          -  Cognitive impairments.
      

Gender

All

Ages

40 Years - 85 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Frédéric Blanc, MD, 33389911321, [email protected]

Location Countries

Belgium

Location Countries

Belgium

Administrative Informations


NCT ID

NCT03030586

Organization ID

ST0056


Responsible Party

Sponsor

Study Sponsor

Amoneta Diagnostics SAS

Collaborators

 European Commission

Study Sponsor

Frédéric Blanc, MD, Principal Investigator, Hôpitaux Universitaires Strasbourg


Verification Date

July 2020