Last updated on December 2018

ADDIA Proof-of-Performance Clinical Study


Brief description of study

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 Study 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 -amyloid (A) 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: A, total-Tau and p-tau biomarkers. Alternatively to absence of retrospective CSF data, retrospective A 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 A PET scan Tau PET scan and normal CSF A, 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 (A) peptide and protein kinase C (PKC).

ADDIA' blood cell-based A 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 A and/or PKC biomarkers will be correlated to the levels of CSF biomarkers A and tau or phospho-tau (or A 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 A 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 A 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 A 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 -80C at the clinical centres before being shipped at -80C 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 -80C at the clinical centres and shipped at -80C 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 A 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 A 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.

Clinical Study Identifier: NCT03030586

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Recruitment Status: Open


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