<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03030586</url>
  </required_header>
  <id_info>
    <org_study_id>ST0056</org_study_id>
    <nct_id>NCT03030586</nct_id>
  </id_info>
  <brief_title>ADDIA Proof-of-Performance Clinical Study</brief_title>
  <acronym>ADDIA</acronym>
  <official_title>A Multi-centre Proof-of-performance Clinical Study to Validate Blood-based Biomarker Candidates for the Diagnosis of Alzheimer's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Amoneta Diagnostics SAS</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Commission</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Firalis SA</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Strasbourg</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centre Hospitalier Universitaire Vaudois</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>IRCCS Centro San Giovanni di Dio Fatebenefratelli</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hopitaux Civils de Colmar</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Istanbul University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Lille</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Geneva</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cliniques universitaires Saint-Luc- Université Catholique de Louvain</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Erasme University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Montpellier</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centre Hospitalier Universitaire de Besancon</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centre Hospitalier Universitaire de Nice</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Amoneta Diagnostics SAS</source>
  <brief_summary>
    <textblock>
      The objective of the ADDIA clinical Proof-of-Performance study is to validate the performance&#xD;
      of ADDIA' blood biomarkers for diagnosis of Alzheimer's disease (AD).&#xD;
&#xD;
      ADDIA clinical study is a multi-centre, non-interventional, prospective, proof-of-performance&#xD;
      study with only one visit.&#xD;
&#xD;
      About 800 well-characterized subjects will be recruited into 3 groups in 2:1:1 ratio, namely&#xD;
      patients with Alzheimer's disease (AD), patients with non-AD neurodegenerative disease (NAD)&#xD;
      and 200 control subjects (healthy as compared to their age).&#xD;
&#xD;
        -  400 patients with Alzheimer's disease (AD): 200 patients with mild AD, 200 patients with&#xD;
           moderate-to-severe AD,&#xD;
&#xD;
        -  200 patients with non-Alzheimer's neurodegenerative diseases (NAD),&#xD;
&#xD;
        -  200 controls (healthy as compared to their age).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      ADDIA study is dedicated to the proof-of-performance (PoP) of blood biomarkers for diagnosis&#xD;
      of Alzheimer's disease (AD) and will recruit approximately 800 subjects (400 AD and 400&#xD;
      non-AD).&#xD;
&#xD;
      CONTEXT OF USE:&#xD;
&#xD;
      To quantify the performance of ADDIA' blood biomarkers for AD diagnosis (yes/no).&#xD;
&#xD;
      Since the main objective of this study is to establish the performance of ADDIA' blood&#xD;
      cell-based biomarkers β-amyloid (Aβ) and protein kinase C (PKC) and corresponding assays and&#xD;
      to seek approval as In-Vitro Diagnosis (IVD) test(s) specific for diagnosis of AD, and to&#xD;
      validate the newly identified metabolomics and RNA signatures and selected protein biomarker&#xD;
      candidates, samples will be used from:&#xD;
&#xD;
        -  the patients recruited in the AD group and patients recruited in the non-AD&#xD;
           neurodegenerative disorders (NAD) group who are accurately diagnosed during the&#xD;
           pre-screening period, including by using three types of diagnostic methods: clinical&#xD;
           neuropsychological scores, neuroimaging (at least volumetric structural MRI) and&#xD;
           retrospective cerebrospinal (CSF) data: Aβ, total-Tau and p-tau biomarkers.&#xD;
           Alternatively to absence of retrospective CSF data, retrospective Aβ PET /Tau PET scans&#xD;
           can be used if compatible to diagnosis of respective diseases.&#xD;
&#xD;
        -  the subjects recruited in the control group have no objective memory loss, normal&#xD;
           results on neuropsychology tests, and normal neuroimaging findings for their age, as&#xD;
           well as normal Aβ PET scan Tau PET scan and normal CSF Aβ, total-Tau and p-Tau&#xD;
           concentration if retrospectively available.&#xD;
&#xD;
      For further validation of ADDIA' biomarkers, an integrative tool combining ADDIA' blood&#xD;
      biomarkers with cognitive scores and/or, neuroimaging (and/or retrospective CSF biomarker&#xD;
      data) will be used. The impact of polymorphisms associated with AD, such as APOE e4 (known to&#xD;
      be as risk factor of AD) on ADDIA' blood biomarkers will also be studied.&#xD;
&#xD;
      OBJECTIVES:&#xD;
&#xD;
      Objective 1: Validate the ADDIA biomarker candidates: two blood cell-based biomarkers&#xD;
      measured by flow cytometry using Amoneta Diagnostics' proprietary probes specific to&#xD;
      beta-Amyloid (Aβ) peptide and protein kinase C (PKC).&#xD;
&#xD;
      ADDIA' blood cell-based Aβ and/or PKC biomarkers will also be combined via an integrative&#xD;
      tool with clinical neuropsychological scores (MMSE, MoCA, FCSRT) and/or neuroimaging (at&#xD;
      least volumetric MRI) scores for diagnosis and/or differential diagnosis. The impact on these&#xD;
      ADDIA biomarkers of genotyping in particular polymorphisms known to be associated with AD&#xD;
      (e.g. APOE e4, e2 alleles) will also be tested. In addition, the levels of ADDIA' blood&#xD;
      cell-based Aβ and/or PKC biomarkers will be correlated to the levels of CSF biomarkers Aβ and&#xD;
      tau or phospho-tau (or Aβ PET and TAU PET levels).&#xD;
&#xD;
      Objective 2: ADDIA clinical PoP study will also validate additional new biomarker candidates&#xD;
      (identified previously and/or under analytical validation in the ADKIT study and&#xD;
      chronobiological studies) for AD diagnosis in peripheral body fluids; in particular, studies&#xD;
      on a set of proteins (using immuno-detection methods), metabolomics/lipidomics signatures&#xD;
      (using e.g. LC-HRMS method) and miRNA signature (using e.g. qPCR, HTG-NGS methods) are&#xD;
      planned. These new biomarkers may be used if needed to further enhance the accuracy of ADDIA'&#xD;
      blood-based Aβ and PKC biomarker test for diagnosis or differential diagnosis.&#xD;
&#xD;
      STUDY DESIGN&#xD;
&#xD;
      ADDIA clinical study is a multi-centre, non-interventional, prospective, proof-of-performance&#xD;
      group study without a clinical follow-up. About 800 well characterized subjects will be&#xD;
      enrolled into 3 groups in 2:1:1 ratio, namely Alzheimer's disease, non-AD neurodegenerative&#xD;
      diseases and controls (healthy as compared to their age). The number of subjects is divided&#xD;
      into 3 groups as following:&#xD;
&#xD;
        -  400 patients with Alzheimer's disease (AD),&#xD;
&#xD;
        -  200 patients with non-Alzheimer's neurodegenerative diseases (NAD),&#xD;
&#xD;
        -  200 controls (CC).&#xD;
&#xD;
      All groups will be age-matched and mean age similar in the three groups.&#xD;
&#xD;
      ADDIA clinical study needs to recruit well characterized subjects in each group, therefore a&#xD;
      pre-screening or a diagnostic workup of the subjects needs to be performed by the clinical&#xD;
      centres before the start of the clinical study (during Visit 0). In ADDIA clinical study,&#xD;
      only one visit (Visit 1) is required for the subjects without any follow-up, in which the&#xD;
      subjects will be recruited and sampling of blood and urine will be done in the same Visit 1.&#xD;
      The following data sets will be collected:&#xD;
&#xD;
        1. Data set 1 and samples available from visit 0 collected in the e-CRF after informed&#xD;
           consent signature:&#xD;
&#xD;
           • Data from all subjects of the three groups include neuropsychological scores (MMSE,&#xD;
           MoCA, FCSRT scores), neuroimaging (at least structural MRI volumetric scores, and other&#xD;
           neuroimaging as needed for diagnosis) and laboratory data (haematology, biochemistry)&#xD;
           related to pre-screening and diagnosis. CSF samples obtained retrospectively by clinical&#xD;
           centres are needed if available.&#xD;
&#xD;
        2. Data set 2 and samples from Visit 1 include in all three groups clinical MMSE, FCSRT,&#xD;
           MoCA tests (MMSE and MoCA tests to be redone on Visit 1 if older than 3 months) and&#xD;
           laboratory data (haematology, biochemistry), and blood and urine (and saliva and tear as&#xD;
           optional) collected during Visit 1 (clinical centres). The clinical centres equipped&#xD;
           with flow cytometry can perform experiments on ADDIA blood cell-based biomarkers&#xD;
           utilizing Amoneta' proprietary Aβ and PKC probes.&#xD;
&#xD;
      Data set 3 will be obtained at the end of ADDIA clinical study (Amoneta Diagnostics/Firalis)&#xD;
      and will comprise data on the performance of ADDIA biomarkers as described in details in&#xD;
      objectives 1, 2.&#xD;
&#xD;
      SUBJECT RECRUITMENT AND SAMPLING&#xD;
&#xD;
      The subjects who meet the inclusion and exclusion criteria prior to the inclusion in the&#xD;
      study (as checked by the clinical centres during Visit 0) will be enrolled in the ADDIA study&#xD;
      after the informed consent signatures. Sampling will be performed for the following body&#xD;
      fluids during Visit 1: blood (11 tubes, 2.5, 4 or 5 mL each) and urine (1 tube, 5 mL) from&#xD;
      all subjects. Saliva (1 tube, 4 mL) and tear (2 tubes, 0.15 mL each) samples are optional.&#xD;
&#xD;
      Eleven tubes of blood and spot urine will be collected from each subject that has fasted for&#xD;
      &gt; 12 hours. The samples will be used as follows:&#xD;
&#xD;
        -  2 (two) tubes will be used at the participating clinical centres for routine lab tests,&#xD;
           haematology and biochemistry.&#xD;
&#xD;
        -  9 (nine) tubes will be sent to Amoneta facilities in the following format:&#xD;
&#xD;
        -  3 (three) fresh whole blood samples (3 Li-heparin tubes), 1 tube will be sent in the&#xD;
           morning immediately after sampling to the flow cytometry laboratory (Amoneta&#xD;
           laboratories or another laboratory chosen by Amoneta which can be a laboratory of the&#xD;
           clinical centre if equipped with flow cytometry platform) to quantify the performance of&#xD;
           ADDIA assays based on blood cell-based biomarkers Aβ and PKC for AD diagnosis and 2&#xD;
           tubes will be used to fix or prepare cells that will be later analysed by flow cytometry&#xD;
           at Amoneta laboratories.&#xD;
&#xD;
        -  6 (six) fresh blood samples will be prepared on-site to obtain serum (dry tube), plasma&#xD;
           (EDTA and Li-Heparin tubes), PAXgene and PAXRNA samples and PBMC (Li-Heparin tube)&#xD;
           samples, which will be aliquoted and stored immediately at -80°C at the clinical centres&#xD;
           before being shipped at -80°C later on Amoneta/Firalis central laboratory for testing:&#xD;
           genotyping and gene, RNA expression (2 blood tubes), protein expression and&#xD;
           metabolomics/lipidomics (1 Li-Heparin and 1 EDTA tubes of plasma, 1 dry tube of serum,&#xD;
           and 1 Li-Heparin tube of PBMCs) during the ADDIA program and for validating the emerging&#xD;
           biomarkers and for replication studies during or after the ADDIA program (as may be&#xD;
           requested by regulatory authorities for IVD product approval).&#xD;
&#xD;
        -  Urine samples (and saliva, tear samples as optional) will be aliquoted and frozen&#xD;
           immediately at -80°C at the clinical centres and shipped at -80°C to Amoneta/Firalis&#xD;
           central laboratory for testing in selected assays based on results that will be obtained&#xD;
           on blood samples.&#xD;
&#xD;
      ENDPOINTS&#xD;
&#xD;
        -  Performance evaluation of the ADDIA blood biomarkers Aβ and PKC (IVD) kit by AD&#xD;
           diagnosis in the form of binary outcome (Yes/No) after quantification of sensitivity &amp;&#xD;
           specificity of these biomarkers. This will be also achieved by using the integrative&#xD;
           tool enabling comparison of ADDIA blood-based biomarkers Aβ and PKC to and combination&#xD;
           with standard clinical diagnosis tests: cognitive scores, neuroimaging scores (and CSF&#xD;
           Biomarkers if possible).&#xD;
&#xD;
        -  Performance evaluation of the ADDIA' additional new biomarkers (RNA signature,&#xD;
           metabolomics signature and/or other peripheral biomarkers) for AD diagnosis in the form&#xD;
           of binary outcome (Yes/No) after quantification of sensitivity &amp; specificity of these&#xD;
           biomarkers.&#xD;
&#xD;
      STATISTICAL CONSIDERATIONS&#xD;
&#xD;
      Primary consideration (for the evaluation of the diagnostic performance) will be the&#xD;
      comparisons between the following groups:&#xD;
&#xD;
        -  AD (Mild AD + Moderate-to-severe AD) versus healthy controls, and/or&#xD;
&#xD;
        -  Mild AD versus healthy controls, and/or&#xD;
&#xD;
        -  Moderate-to-severe AD versus healthy controls, and/or&#xD;
&#xD;
        -  AD versus healthy controls+NAD groups.&#xD;
&#xD;
      Secondary considerations (for the evaluation of the differential diagnostic performance) will&#xD;
      be the comparisons between the following groups:&#xD;
&#xD;
        -  AD (Mild AD + Moderate-to-severe AD) versus NAD and/or&#xD;
&#xD;
        -  Mild AD versus NAD and/or&#xD;
&#xD;
        -  Moderate-to-severe AD versus NAD and/or&#xD;
&#xD;
        -  Mild AD versus Moderate-to-severe AD Tertiary considerations will explore potential&#xD;
           differences between NAD versus healthy controls and the subgroups of NAD (FTD, LBD, PDD,&#xD;
           PSP, CBD) two by two as well as versus healthy controls and AD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 1, 2016</start_date>
  <completion_date type="Anticipated">June 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Blood cell biomarkers for diagnosis of Alzheimer</measure>
    <time_frame>18 Months</time_frame>
    <description>Proof of Performance of ADDIA' blood biomarker-based test</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Biomarkers circulating in body fluids for diagnosis of Alzheimer and/or other dementia type</measure>
    <time_frame>18 months</time_frame>
    <description>Validation of biomarkers circulating in peripheral body fluids</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">800</enrollment>
  <condition>Alzheimer Disease (AD)</condition>
  <condition>Frontotemporal Lobar Degeneration</condition>
  <condition>Dementia With Lewy Bodies (DLB)</condition>
  <condition>Parkinson Disease Dementia (PDD)</condition>
  <condition>Progressive Supranuclear Palsy (PSP)</condition>
  <condition>Corticobasal Degeneration (CBD)</condition>
  <arm_group>
    <arm_group_label>Alzheimer</arm_group_label>
    <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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-Alzheimer neurodegenerative disease</arm_group_label>
    <description>200 patients comprising:&#xD;
75 patients with behavioural variant of Fronto-Temporal Lobe Degeneration (FTD),&#xD;
50 patients with Parkinson's disease dementia (PDD),&#xD;
50 patients with Dementia with Lewy Bodies (DLB) and&#xD;
25 patients with Progressive Supranuclear Palsy (PSP) or cortico-basal degeneration (CBD)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <description>200 healthy subjects</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        About 800 well characterized subjects will be enrolled into 3 groups in 2:1:1 ratio, namely&#xD;
        patients with Alzheimer's disease (AD), patients with non-AD neurodegenerative disease&#xD;
        (NAD) and control subjects (healthy as compared to their age). The number of subjects is&#xD;
        divided into 3 groups as following:&#xD;
&#xD;
          -  400 patients with AD (50% with mild AD and 50% of with moderate to severe AD),&#xD;
&#xD;
          -  200 patients with non-Alzheimer's neurodegenerative diseases (NAD): this group will&#xD;
             comprise 75 patients with behavioural variant of Fronto-Temporal Lobe Degeneration&#xD;
             (FTD) recruited according to Rascovsky et al., 2011; 50 patients with Parkinson's&#xD;
             disease dementia (PDD), 50 patients with Lewy Body dementia (DLB) recruited according&#xD;
             to McKeith et al., 2005 criteria; 25 patients with Progressive Supranuclear Palsy&#xD;
             (PSP) or cortico-basal degeneration (CBD).&#xD;
&#xD;
          -  200 controls (healthy as compared to their age).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        For all groups:&#xD;
&#xD;
          -  Female and male subjects aged 40 to 85 years.&#xD;
&#xD;
          -  Dated and signed informed consent by the subject (or its legal representative if&#xD;
             applicable in accordance with the local regulations).&#xD;
&#xD;
          -  AD, NAD patients and control subjects will be age-matched and mean age similar in the&#xD;
             three groups.&#xD;
&#xD;
          -  Able to comply with all study procedures.&#xD;
&#xD;
        For AD group:&#xD;
&#xD;
          -  Diagnosis of AD: typical and atypical AD.&#xD;
&#xD;
          -  MMSE score (measured in the last 3 months): &lt; 21 for patients with moderate to severe&#xD;
             AD. MMSE score &gt; 21 in subjects with mild AD with sporadic or a familial form of AD&#xD;
             due to mutation in APP or PSEN1 or PSEN2 genes.&#xD;
&#xD;
          -  FCSRT, MoCA tests (MoCA measured in the last 3 months).&#xD;
&#xD;
          -  Neuroimaging compatible with a diagnosis of AD:&#xD;
&#xD;
               -  At least quantitative volumetric structural MRI: volumes of hippocampus and&#xD;
                  cortical areas.&#xD;
&#xD;
               -  Visual semi-quantitative MRI if practiced shall show medial temporal lobe atrophy&#xD;
                  (MTA) and parietal atrophy with visual rating (semi-quantitative) on the&#xD;
                  MTA-score (e.g. Scheltens' scores 0-4). MTA score must be ≥ 2 in patients aged&#xD;
                  40-75 years and ≥ 3 in patients aged above 75 years. For patients younger than 60&#xD;
                  years, and with familial form of AD, who may have normal MTA-scores, Koedam score&#xD;
                  (0-3) for Parietal Atrophy showing atrophy of the precuneus characteristic of AD&#xD;
                  may be used with a Koedam score from 1 to 3.&#xD;
&#xD;
        Other neuroimaging data (retrospectively available) including PET Amyloid scan and FDG PET&#xD;
        are desired if practiced by clinical centres and if available.&#xD;
&#xD;
        - Cerebrospinal fluid biomarker data (retrospectively available) showing positive levels of&#xD;
        at least 2 out of 3 biomarkers: i.e. Aβ1-42 and tau (phosphorylated-Tau and/or total-Tau).&#xD;
        Note: If retrospective CSF data are not available, retrospective Aβ PET and Tau PET data&#xD;
        can be used.&#xD;
&#xD;
        For NAD group:&#xD;
&#xD;
        For all patients of the group NAD, except PSP subgroup (when PSP has a clear-cut typical&#xD;
        phenotype, sometimes called Steele-Richardson phenotype), the CSF biomarker data must show&#xD;
        levels for CSF biomarkers Aβ1-42, phosphorylated-Tau and total-Tau, compatible with the&#xD;
        respective NAD subgroup. If retrospective CSF data are not available, retrospective Aβ PET&#xD;
        and Tau PET data can be used.&#xD;
&#xD;
        Fronto-temporal dementia (FTD)&#xD;
&#xD;
          -  Diagnosis of probable behavioural FTD (bvFTD) for all subjects of this FTD subgroup,&#xD;
             whether with familial or non-familial forms. If with familial form, the subject must&#xD;
             be a member of family with a known mutation in one of the FTD related genes: MAPT,&#xD;
             PGRN. The predominant phenotype in the kindred must be cognitive/behavioural (i.e.&#xD;
             kindred in whom Parkinsonism or Amyotrophic Lateral Sclerosis is the predominant&#xD;
             clinical phenotype among affected relatives is excluded).&#xD;
&#xD;
          -  Centrally rated frontal and/or anterior temporal atrophy score of 2 or greater on&#xD;
             brain MRI.&#xD;
&#xD;
          -  MMSE score compatible. If currently taking an acetylcholinesterase inhibitor and/or&#xD;
             memantine, the subject must have been taking such medication(s) for ≥3 months.&#xD;
&#xD;
        Dementia Lewy body (DLB)&#xD;
&#xD;
          -  DLB should be diagnosed when dementia occurs before or concurrently with Parkinsonism.&#xD;
&#xD;
          -  Patients diagnosed with probable DLB. Probable DLB can be made with the presence of&#xD;
             two core features out of the following:&#xD;
&#xD;
               -  Fluctuating cognition with pronounced variations in attention and alertness,&#xD;
&#xD;
               -  Recurrent visual hallucinations that are typically well formed and detailed,&#xD;
&#xD;
               -  Spontaneous features of Parkinsonism.&#xD;
&#xD;
        Probable DLB is diagnosed with the presence of one or more of the above core features and&#xD;
        one or more of the following suggestive features. Probable DLB should not be diagnosed on&#xD;
        the basis of suggestive features alone:&#xD;
&#xD;
          -  REM sleep behaviour disorder,&#xD;
&#xD;
          -  Severe neuroleptic sensitivity,&#xD;
&#xD;
          -  Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging&#xD;
             (if data retrospectively available).&#xD;
&#xD;
        Supportive diagnosis:&#xD;
&#xD;
          -  Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity (if&#xD;
             data retrospectively available),&#xD;
&#xD;
          -  Abnormal (low uptake) MIBG myocardial scintigraphy,&#xD;
&#xD;
          -  Prominent slow wave activity on EEG with temporal lobe transient sharp waves.&#xD;
&#xD;
               -  MRI: Relative preservation of medial temporal lobe structures on CT/MRI scan.&#xD;
&#xD;
               -  Clinical Dementia Rating (CDR) score is greater than or equal to 0.5.&#xD;
&#xD;
               -  MMSE score compatible.&#xD;
&#xD;
               -  Patients with familial forms caused by mutation in genes SNCA, SNCB.&#xD;
&#xD;
        Parkinson's disease dementia (PDD)&#xD;
&#xD;
          -  Subjects with Parkinson's Disease Dementia (PDD) must have dementia after (not before)&#xD;
             developing Parkinson's disease (PD).&#xD;
&#xD;
          -  PD is diagnosed by the 3 typical PD symptomatic findings:&#xD;
&#xD;
               -  tremor,&#xD;
&#xD;
               -  rigidity, and&#xD;
&#xD;
               -  slowed movement (bradykinesia).&#xD;
&#xD;
          -  Subjects with dementia and with LRRK2 gene mutation (or with mutation in one of the&#xD;
             following genes: PARK2 or SNCA, VPS35, PINK1, DJ1, ATP13A2, FBX07, SLC6A3, TAF1 are&#xD;
             also included.&#xD;
&#xD;
          -  L-DOPA responsive (a good response to levodopa as practiced by clinical investigator,&#xD;
             retrospectively to the study).&#xD;
&#xD;
          -  MMSE score &lt; 21 for moderate to severe PDD and &gt; 21 for mild PDD.&#xD;
&#xD;
          -  MRI: evidence of relevant structural abnormality (i.e. basal ganglia for Parkinsonism&#xD;
             and potentially medio-temporal or cortical findings that may be related to dementia).&#xD;
             Functional imaging techniques such as fluoro-dopa PET, FDG PET or SPECT to document&#xD;
             the presence of dopaminergic dysfunction if retrospectively available.&#xD;
&#xD;
        Progressive Supranuclear Palsy (PSP)&#xD;
&#xD;
          -  Diagnosis of probable or possible PSP as defined by the National Institute of&#xD;
             Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy&#xD;
             (NINDS-SPSP) diagnostic criteria, and as summarized by Armstrong et al. (2013) for the&#xD;
             conclusions on CBD criteria from an international consortium of behavioural neurology,&#xD;
             neuropsychology, and movement disorders specialists):&#xD;
&#xD;
               -  Gradually progressive disorder,&#xD;
&#xD;
               -  Onset at age 40 or later,&#xD;
&#xD;
               -  Vertical (upward or downward gaze) supranuclear palsy and prominent postural&#xD;
                  instability with tendency to fall in the first year of disease onset,&#xD;
&#xD;
               -  No evidence of other diseases that could explain the foregoing features, as&#xD;
                  indicated by mandatory exclusion criteria.&#xD;
&#xD;
          -  Brain MRI at Screening consistent with PSP: neuroradiologic evidence of relevant&#xD;
             structural abnormality in the midbrain and frontal lobes (i.e. basal ganglia, lobar&#xD;
             atrophy).&#xD;
&#xD;
          -  MMSE score compatible.&#xD;
&#xD;
          -  Be able to ambulate and stand unassisted for 5 minutes.&#xD;
&#xD;
          -  Be able to cooperate with gait and balance testing.&#xD;
&#xD;
        Corticobasal degeneration (CBD)&#xD;
&#xD;
        • Diagnosis of possible CBD. Inclusion clinical criteria for possible CBD, with features of&#xD;
        Cortico-Basal Syndrome (CBS); familial forms related to MAPT included, Progressive&#xD;
        Supranuclear Palsy Syndrome (PSPS) phenotype included.&#xD;
&#xD;
          -  Features of CBS: a) limb rigidity or akinesia, b) limb dystonia, c) limb myoclonus&#xD;
             plus 1 of: d) orobuccal or limb apraxia, e) cortical sensory deficit, f) alien limb&#xD;
             phenomena (more than simple levitation).&#xD;
&#xD;
          -  Features of PSPS: Three of: a) axial or symmetric limb rigidity or akinesia, b)&#xD;
             postural instability or falls, c) urinary incontinence, d) behavioural changes, e)&#xD;
             supranuclear vertical gaze palsy or decreased velocity of vertical saccades.&#xD;
&#xD;
        Note: subjects with probable sporadic CBD (no familial form) are excluded.&#xD;
&#xD;
          -  MRI findings: parietal cortical atrophy (asymmetric).&#xD;
&#xD;
          -  MMSE score compatible.&#xD;
&#xD;
        Controls&#xD;
&#xD;
          -  Normal cognitive performance with normal scores of neuropsychological tests for their&#xD;
             age.&#xD;
&#xD;
          -  MMSE &gt;26 (performed in less than 3 months).&#xD;
&#xD;
          -  At least volumetric structural MRI with normal findings. Normal retrospective finding&#xD;
             in β-amyloid PET scan, FDG PET scan if practiced by clinical centres.&#xD;
&#xD;
          -  If retrospectively available, normal CSF biomarkers concentrations: negative levels&#xD;
             for all three CSF biomarkers Aβ1-42, phosphorylated-Tau and total-Tau.&#xD;
&#xD;
          -  If retrospectively available, Aβ PET and/or Tau PET scan(s) shall be negative.&#xD;
&#xD;
          -  Able to comply with the study procedures.&#xD;
&#xD;
        EXCLUSION CRITERIA for all subjects:&#xD;
&#xD;
        The following exclusion criteria apply to all subjects:&#xD;
&#xD;
          -  Neutropenia (Neutrophils: &lt; 1,500/mm3 according to ethnic group).&#xD;
&#xD;
          -  Thrombocytopenia (platelets: &lt; 100,000/mm3, rule out EDTA-induced&#xD;
             pseudo-thrombocytopenia).&#xD;
&#xD;
          -  Subjects with less than an elementary education are excluded.&#xD;
&#xD;
          -  Subject with no medical insurance are excluded in the countries where medical&#xD;
             insurance is mandatory such as in France. In the countries where medical insurance is&#xD;
             not mandatory, subjects with no medical insurance may not be excluded.&#xD;
&#xD;
          -  Psychiatric history: schizophrenia, psychosis.&#xD;
&#xD;
          -  Vascular dementia.&#xD;
&#xD;
          -  Infection diseases, chronic inflammatory diseases that affect blood cells, patients&#xD;
             with an active infection/ immunosuppressive disorders/ treatment with&#xD;
             immunosuppressive or immunomodulatory medication.&#xD;
&#xD;
          -  Current malignancy or past diagnosis of malignancy affecting blood cells under&#xD;
             treatment or with treatment stopped only during last 3 months.&#xD;
&#xD;
          -  Medication interfering with cognitive functions and ADDIA biomarkers (i.e. kinase&#xD;
             inhibitors and beta-amyloid and tau passive and active immunizations).&#xD;
&#xD;
          -  Major sensory deficits that could interfere with cognitive assessment (visual and&#xD;
             auditory).&#xD;
&#xD;
          -  Epilepsy.&#xD;
&#xD;
          -  Patients with known contraindication for MRI imaging such as MRI-incompatible stent or&#xD;
             MRI-incompatible endoprosthesis.&#xD;
&#xD;
        EXCLUSION CRITERIA for AD group&#xD;
&#xD;
          -  Mixed dementia.&#xD;
&#xD;
          -  Vascular dementia.&#xD;
&#xD;
          -  Other dementia type.&#xD;
&#xD;
          -  Other neurodegenerative disease.&#xD;
&#xD;
          -  Absence of CSF biomarker data and/or amyloid PET data is an exclusive criterion for&#xD;
             all subjects with sporadic forms of AD, but it is not an exclusive criterion for&#xD;
             subjects with a familial form of AD that is due to a mutation of a gene among APP,&#xD;
             PSEN1, PSEN2.&#xD;
&#xD;
        EXCLUSION CRITERIA for NAD group&#xD;
&#xD;
          -  AD diagnosis.&#xD;
&#xD;
          -  Mixed dementia.&#xD;
&#xD;
          -  Vascular dementia.&#xD;
&#xD;
          -  Absence of either CSF biomarker data or amyloid PET data is an exclusive criterion for&#xD;
             all subjects in sporadic DLB, PDD, FTD and CBD (but not for subjects with PSP when PSP&#xD;
             has a clear-cut typical phenotype, sometimes called Steele-Richardson phenotype).&#xD;
             However, absence of CSF biomarker and/or amyloid PET data is not an exclusive&#xD;
             criterion for subjects with a familial form of NAD that is due to a mutation of a gene&#xD;
             among MAPT, PGRN, SNCA, SNCB, PARK2 or SNCA, VPS35, PINK1, DJ1, ATP13A2, FBX07, SLC6A3&#xD;
             or TAF1, TREM2.&#xD;
&#xD;
        EXCLUSION CRITERIA for Control group&#xD;
&#xD;
          -  AD patients.&#xD;
&#xD;
          -  Dementia patients.&#xD;
&#xD;
          -  Cognitive impairments.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Frédéric Blanc, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hôpitaux Universitaires Strasbourg</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jean-François Démonet, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre hospitalier universitaire vaudois, Lausanne</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hakan Gurvit, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Istanbul University, Istanbul</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Moira Marizzoni, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Centro San Giovanni di Dio Fatenenefratelli, Bressia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>François Sellal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hôpitaux Civils (Hopital Louis Pasteur) de Colmar</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Frisoni Giovanni, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hôpitaux universitaires de Genève</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Florence Pasquier, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre Hospitalier Régional, Universitaire de Lille</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Adrian Ivanoiu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cliniques Universitaires Saint-Luc, Brussels</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Bruno Dubois, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jean-Christophe Bier, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hopital ERASME, Brussels</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Audrey Gabelle, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Montpellier</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Eloi Magnin, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre Hospitalier Universitaire de Besançon</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Renaud David, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Centre Hospitalier Universitaire de Nice</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Saliha Moussaoui, PhD</last_name>
    <phone>33389911321</phone>
    <email>saliha.moussaoui@firalis.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hüseyin Firat, MD</last_name>
    <phone>33389911321</phone>
    <email>hueseyin.firat@firalis.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Cliniques Universitaires Saint-Luc</name>
      <address>
        <city>Brussels</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>ERASME Hospital</name>
      <address>
        <city>Brussels</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Hopitaux Universitaires de Strasbourg</name>
      <address>
        <city>Strasbourg</city>
        <state>Alsace</state>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Frédéric Blanc, MD</last_name>
      <phone>33388115858</phone>
      <email>frederic.blanc@chru-strasbourg.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Besançon</name>
      <address>
        <city>Besançon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Hôpitaux Civils (Hopital Louis Pasteur) de Colmar</name>
      <address>
        <city>Colmar</city>
        <country>France</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Régional Universitaire de Lille</name>
      <address>
        <city>Lille</city>
        <country>France</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Montpellier</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Nice</name>
      <address>
        <city>Nice</city>
        <country>France</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>APHP-Hôpitaux Universitaires Pitié Salpêtrière</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>IRCCS Centro San Giovanni di Dio Fatenenefratelli</name>
      <address>
        <city>Brescia</city>
        <country>Italy</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Hôpitaux Universitaires de Genève</name>
      <address>
        <city>Genève</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire Vaudois</name>
      <address>
        <city>Lausanne</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Istanbul University Hospital</name>
      <address>
        <city>Istanbul</city>
        <country>Turkey</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
    <country>Italy</country>
    <country>Switzerland</country>
    <country>Turkey</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>January 23, 2017</study_first_submitted>
  <study_first_submitted_qc>January 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 25, 2017</study_first_posted>
  <last_update_submitted>July 7, 2020</last_update_submitted>
  <last_update_submitted_qc>July 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Blood cell biomarkers, peripheral circulating biomarkers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parkinson Disease</mesh_term>
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Dementia</mesh_term>
    <mesh_term>Supranuclear Palsy, Progressive</mesh_term>
    <mesh_term>Lewy Body Disease</mesh_term>
    <mesh_term>Frontotemporal Lobar Degeneration</mesh_term>
    <mesh_term>Corticobasal Degeneration</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03030586
org study id: ST0056
nct id: NCT03030586
lead sponsor: 
collaborator: 
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collaborator: 
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).
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.
observational model: Cohort
time perspective: Prospective
measure: Blood cell biomarkers for diagnosis of Alzheimer
time frame: 18 Months
description: Proof of Performance of ADDIA' blood biomarker-based test
measure: Biomarkers circulating in body fluids for diagnosis of Alzheimer and/or other dementia type
time frame: 18 months
description: Validation of biomarkers circulating in peripheral body fluids
arm group label: 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
arm group label: Non-Alzheimer neurodegenerative disease
description: 200 patients comprising:
75 patients with behavioural variant of Fronto-Temporal Lobe Degeneration (FTD),
50 patients with Parkinson's disease dementia (PDD),
50 patients with Dementia with Lewy Bodies (DLB) and
25 patients with Progressive Supranuclear Palsy (PSP) or cortico-basal degeneration (CBD)
arm group label: Healthy Controls
description: 200 healthy subjects
Blood
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 40 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Frédéric Blanc, MD
role: Principal Investigator
affiliation: Hôpitaux Universitaires Strasbourg
last name: Jean-François Démonet, MD
role: Principal Investigator
affiliation: Centre hospitalier universitaire vaudois, Lausanne
last name: Hakan Gurvit, MD
role: Principal Investigator
affiliation: Istanbul University, Istanbul
last name: Moira Marizzoni, PhD
role: Principal Investigator
affiliation: IRCCS Centro San Giovanni di Dio Fatenenefratelli, Bressia
last name: François Sellal, MD
role: Principal Investigator
affiliation: Hôpitaux Civils (Hopital Louis Pasteur) de Colmar
last name: Frisoni Giovanni, MD
role: Principal Investigator
affiliation: Hôpitaux universitaires de Genève
last name: Florence Pasquier, MD
role: Principal Investigator
affiliation: Centre Hospitalier Régional, Universitaire de Lille
last name: Adrian Ivanoiu, MD
role: Principal Investigator
affiliation: Cliniques Universitaires Saint-Luc, Brussels
last name: Bruno Dubois, MD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Jean-Christophe Bier, MD
role: Principal Investigator
affiliation: Hopital ERASME, Brussels
last name: Audrey Gabelle, MD
role: Principal Investigator
affiliation: University Hospital, Montpellier
last name: Eloi Magnin, MD
role: Principal Investigator
affiliation: Centre Hospitalier Universitaire de Besançon
last name: Renaud David, MD
role: Principal Investigator
affiliation: Centre Hospitalier Universitaire de Nice
last name: Saliha Moussaoui, PhD
phone: 33389911321
email: saliha.moussaoui@firalis.com
last name: Hüseyin Firat, MD
phone: 33389911321
email: hueseyin.firat@firalis.com
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Recruiting
contact: 
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
facility: 
status: Completed
country: Belgium
country: France
country: Italy
country: Switzerland
country: Turkey
responsible party type: Sponsor
mesh term: Parkinson Disease
mesh term: Alzheimer Disease
mesh term: Dementia
mesh term: Supranuclear Palsy, Progressive
mesh term: Lewy Body Disease
mesh term: Frontotemporal Lobar Degeneration
mesh term: Corticobasal Degeneration
sharing ipd: No