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Role of ADA SNPs in Subjects With Relapsing Multiple Sclerosis (RMS)

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ClinicalTrials.gov Identifier: NCT04121065
Recruitment Status : Not yet recruiting
First Posted : October 9, 2019
Last Update Posted : October 9, 2019
Sponsor:
Information provided by (Responsible Party):
Diego Centonze, Neuromed IRCCS

Brief Summary:

Multiple Sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), which is highly heterogeneous in terms of clinical symptoms, MS subtypes and treatment response. In each patient with MS, inflammatory, neurodegenerative and reparative processes are intermingled in different proportions, making the disease course unpredictable and the treatment approach challenging.

Although MS etiology is still unclear, many studies have demonstrated that T and B cells are crucial cellular determinants of MS pathophysiological processes. Auto-reactive T lymphocytes have been also implicated in excitotoxic synaptopathy, an early hallmark of MS recently emerged to link inflammation and neurodegeneration in a complex and inter-regulated circuit. In addition, several reports published in the last few years show the presence of a link between metabolism and immune responses. Indeed, it is now clear that cell metabolism is able to control T cell survival, growth, activation and differentiation. It has been reported that distinct metabolic pathways are able to support specific T cell activities suggesting that the delicate balance among glycolysis, fatty acid oxidation (FAO) and mitochondrial respiration drives specific effector (Tconv) and regulatory T cell (Treg) differentiation and functions.

The individual response to treatment varies widely and their use may be burdened by side effects and major adverse events. An explanation of the clinical and pharmacological individual variability can be sought in the pathological heterogeneity and in different genetic, immunological and metabolomics profiles. With this perspective, the lack of a single predictive or diagnostic test remains a great obstacle in the management of MS at most stages and in the choice of the therapy. Consequently, the availability of biomarkers that reliably capture the different aspects of the disease could be extremely useful.


Condition or disease Intervention/treatment
Relapsing Multiple Sclerosis Procedure: Blood withdrawal

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Interventional Not Pharmacological Study to Investigate the Role of ADA in Multiple Sclerosis PatientsTreated With an Immune-Reconstitution Therapy (2-CdA)
Estimated Study Start Date : January 2020
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Relapsing MS patients
Single Arm: Relapsing Multiple Sclerosis patients ADA SNPs and other biomarkers analyses in blood samples.
Procedure: Blood withdrawal
Blood withdrawal of maximum 60 ml performed to each enrolled patient during the study for primary and secondary endpoints evaluation.




Primary Outcome Measures :
  1. 1. Evaluation of lymphopenia, measured by the number of lymphocytes per cubic millimeter (mm3) and associated to ADA polymorphism [ Time Frame: Month 0 enrollment compared to month 12; RMS patients ]

    Assessment of lymphopenia induced by oral Cladribine (2-CdA) treatment comparing the change in the number of pre-post treatment lymphocytes after oral Cladribine treatment at month 12 (compared with month 0), between two groups (associated with the genetic polymorphism of ADA).

    Changein the number of lymphocytes measured as number of cells per cubic millimeter (mm3), grades of lymphopenia will be assigned according to the common terminology criteria for adverse events: grade 1 (mild lymphopenia) ALC < lower limit of normal to 800/mm3, grade 2 (moderate lymphopenia) ALC < 800-500/mm3, and grade 3 (severe lymphopenia) ALC < 500-200/mm3.



Secondary Outcome Measures :
  1. Genotyping of SNPs and gene expression for correlation analysis with disease effectiveness of Cladribine treatment [ Time Frame: months 0, 6, 12 and 24 ]

    To investigate the association between SNPs, gene expression and clinical parameters (Expanded Disability Status Score (EDSS), Kurtzke Functional System Score (KFS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modality Test (SDMT), Annualized Relapses Rate (ARR) and the Percentage of "No Evidence of Disease acitivity (NEDA)) at months 0, 6, 12 and 24.

    Statistical correlations of minor allele presence of each screened SNP with gene expression and/or the clinical parameters. The significance level is established at p<0.05.


  2. Evaluation of DCK and 5'NT genes expression [ Time Frame: months 0, 6, 12 and 24 ]
    Evaluation of the ratio of DCK and 5'NT genes expression at months 0, 6, 12 and 24 through the mRNA quantification by ddPCR measuring the number of copies / microliter.

  3. Statistical correlation of EBV genotypes with responder or non-responder conditions [ Time Frame: month 0 ]
    Correlation of EBV genotypes with responder or non-responder conditions evaluated by clinical parameters (Expanded Disability Status Score (EDSS), Kurtzke Functional System Score (KFS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), Symbol Digit Modality Test (SDMT), Annualized Relapses Rate (ARR) and the Percentage of "No Evidence of Disease acitivity (NEDA)). Statistical correlations of specific EBV genotype with the clinical parameters. The significance level is established at p<0.05.

  4. Quantification of DCK and cytosolic forms of NT5 and evaluation of CD4+ enzyme activity [ Time Frame: months 0, 6, 12 and 24 ]
    Assessment of cellular content of DCK and cytosolic forms of NT5 and the activity of CD4+ enzymes at months 0, 6, 12 and 24, the protein quantification will be obtained by flow cytometry measuring the relative levels of MFI (mean fluorescence intensity) values. The CD4+ enzymes will be evaluated with the luminescence-based ADP detection, measuring the ADP, based on the detection by luminometer of ATP synthesized during a luciferase/luciferin reaction and the use of an ATP-to-ADP conversion curve.

  5. Genes expression [ Time Frame: months 0, 6, 12 and 24 ]
    Analysis of molecular and biochemical parameters (miRNA, mRNA and circulating exosomes), performed comparing patients responder and non-responder. miRNA and mRNA detection will be assessed by qRT-PCR, measuring the relative quantification by using the 2^(-ddCt) method.

  6. Measure of T cell extracellular acidification rate and mitochondrial respiration [ Time Frame: months 0, 6, 12 and 24 ]
    Measure of T cell glycolytic (Extracellular Acidification Rate, ECAR) and mitochondrial respiration (Measurement of Oxygen Consumption Rate, OCR) at months 0, 6, 12 and 24.

  7. Measure of metabolic profile [ Time Frame: months 0, 6, 12 and 24 ]
    Characterize the metabolic profile induced by Cladribine of responder/non-responder or to presence/absence of lymphopenia at months 0, 6, 12 and 24, performing a multivariate statistical analysis. The significance level is established at p<0.05.

  8. Blood levels of B-Cell Activating Factor (BAFF) and Proliferating-Inducing Ligand [ Time Frame: months 0, 6, 12 and 24 ]

    Establish the blood levels of B-Cell Activating Factor (BAFF) and Proliferating-Inducing Ligand (APRIL), which have a regulatory role in B cells biology, at months 0, 6, 12 and 24.

    The proteins quantification will be measured in picograms/ milliliter.


  9. Assessment of MFI (Mean Fluorescence Intensity) levels in NK, T and B cell subsets [ Time Frame: months 0, 6, 12 and 24 ]

    Assess whether Cladribine treatment affects effector and regulatory NK, T and B cell subsets at months 0, 6, 12 and 24.

    The composition of cell subpopulation will be measured by the levels of MFI.


  10. Assessment of synaptic alterations induced by T-cell-released cytokines [ Time Frame: month 12 ]
    Assess a possible neuroprotective action of Cladribine in counteracting synaptic excitotoxicity by modulation of T-cell-released cytokines at month 12. The variable assessed will be the spontaneous corticostriatal excitatory currents (sEPSCs) and the spontaneous corticostriatal inhibitory currents (sEPSCs).

  11. Assessment of disease progression measuring the change in the Expanded Disability Status Scale (EDSS)/Kurtzke [ Time Frame: months 0, 6, 12 and 24 ]
    Assessment of disease progression after oral Cladribine treatment by means of Expanded Disability Status Scale (EDSS)/Kurtzke at month 6, 12 and 24 compared to month 0. The variable assessed will be the change in Expanded Disability Status Scale (EDSS) compared to month 0.The EDSS is widely used in clinical trials to quantify disability and monitor the changes in the level of disability over time. The EDSS scale ranges from 0 to 10.

  12. Assessment of Kurtzke Functional System Score (KFS) evaluating the type and severity of neurologic impairment [ Time Frame: months 0, 6, 12 and 24 ]

    Assessment of Functional System (KFS) at month 6, 12 and 24 compared to month 0.

    KFSS is half of a 2-part system evaluating the type and severity of neurologic impairment in MS and is based on neurologic examination of independent functions. The KFSS rates 7 functional systems (plus "other"), including pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral (or mental), and other. Each of the FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6.


  13. Assessment of upper extremity (arm and hand) function performing the 9-Hole Peg Test (9HPT) [ Time Frame: months 0, 6, 12 and 24 ]
    Assessment of 9-Hole Peg Test (9HPT) at month 6, 12 and 24 compared to month 0. The 9-HPT is a quantitative measure of upper extremity (arm and hand) function. Both the dominant and non-dominant hands are tested twice. Two consecutive trials of the dominant hand, followed immediately by two consecutive trials of the non-dominant hand will be executed.

  14. Assessment of of lower extremity function, performing the Timed 25-Foot Walk test (T25FW) [ Time Frame: months 0, 6, 12 and 24 ]

    Assessment of Timed 25-Foot Walk (T25FW) at month 6, 12 and 24 compared to month 0.

    The Timed 25-Foot Walk is a quantitative measure of lower extremity function. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task. The average score of two 25-Foot Timed Walk trials will be measured.


  15. Assessment of attention and information processing speed, performing the Symbol Digit Modality Test (SDMT) [ Time Frame: months 0, 6, 12 and 24 ]

    Assessment of Symbol Digit Modality Test (SDMT) at month 6, 12 and 24 compared to month 0.

    The SDMT is designed to measure divided attention and information processing speed. The examinee has 90 seconds to pair specific numbers with given geometric figures by using a reference key. The SDMT score is the sum of the correct substitutions within the 90 second interval.


  16. Evaluation of the change in Annualized Relapse Rate (ARR). [ Time Frame: months 0, 6, 12 and 24 ]

    Evaluation of Annualized Relapse Rate (ARR) at month 6, 12 and 24 compared to month 0.

    Change in Annualized Relapse Rate (ARR) measured by the total number of relapses divided by the total person-time at risk of relapse.


  17. Evaluation of Disease Activity measuring the Percentage of "No Evidence of Disease Activity" (NEDA) . [ Time Frame: months 0, 6, 12 and 24 ]

    Evaluation of the Percentage of "No Evidence of Disease Activity" (NEDA) at month 6, 12 and 24 compared to month 0.

    No Evidence of Disease Activity" (NEDA) will be measured as number of NEDA subjects / total number of recruited patients *100


  18. Collection of safety and tolerability data: number of patients with treatment related adverse events classified by MedDRA [ Time Frame: months 0, 6, 12 and 24 ]
    Collection of safety and tolerability data on RMS patients treated with Cladribine. Number of patients with Adverse



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
subject with relapsing multiple sclerosis
Criteria

Inclusion Criteria:

  1. Male or female subjects ≥ 18 years old
  2. Subjects candidate to be treated with Cladribine (2-CdA) according to clinical practice and meeting the SmPc requirements:

    • Body weight ≥ 40 Kg
    • Highly active RMS as defined by: One relapse in the previous year and at least 1 T1 Gd+ lesion or 9 or more T2 lesions, while on therapy with other disease modifying drugs (DMDs); two or more relapses in the previous year, whether on DMD treatment or not;
  3. Normal lymphocyte count (absolute values 1.0-3.0×109/l) according to Cladribine local labelling;
  4. EDSS score ≤5.0.

Exclusion Criteria:

  1. Previous exposure to drugs such as fingolimod, natalizumab, alemtuzumab, mitoxantrone and ocrelizumab;
  2. Positive hepatitis C or hepatitis B surface antigen test and/or hepatitis B core antibody test for IgG and/or IgM;
  3. Current or previous history of immune deficiency disorders including a positive human immunodeficiency virus (HIV) result;
  4. Currently receiving immunosuppressive or myelosuppressive therapy with, e.g., monoclonal antibodies, methotrexate, cyclophosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids;
  5. History of tuberculosis, presence of active tuberculosis, or latent tuberculosis;
  6. Evidence or suspect of PML in MRI;
  7. Active malignancy or history of malignancy.
  8. Pregnant or lactating women
  9. Currently receiving interferon

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04121065


Contacts
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Contact: Diego Centonze, MD +39 3934444159 centonze@uniroma2.it
Contact: Mario Stampanoni Bassi, MD +39 2460181370 mario_sb@hotmail.it

Locations
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Italy
IRCCS Neuromed Not yet recruiting
Pozzilli, Isernia, Italy, 86077
Contact: Stefania Passarelli, Dr    +39 0865.915217    direzionescientifica@neuromed.it   
Sponsors and Collaborators
Neuromed IRCCS
Investigators
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Principal Investigator: Diego Centonze IRCCS Neuromed, Pozzilli, Isernia Italy

Publications:

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Responsible Party: Diego Centonze, Haed of Neurology Unit, Neuromed IRCCS
ClinicalTrials.gov Identifier: NCT04121065     History of Changes
Other Study ID Numbers: ADA-MS
First Posted: October 9, 2019    Key Record Dates
Last Update Posted: October 9, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Diego Centonze, Neuromed IRCCS:
ADA
Genetic polymorphism
Relapsing Multiple Sclerosis
Immune-reconstitution therapy
2-CdA
single nucleotide polymorphisms
lymphopenia induced by 2-CdA treatment
ADA genetic variant rs244072
non-risk/risk allele T/C
Additional relevant MeSH terms:
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Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases