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

NCT04121065 | Recruiting

• 1 other identifier: ADA-MS
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 1

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.

Conditions

Relapsing Multiple Sclerosis

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 1. Evaluation of lymphopenia, measured by the number of lymphocytes per cubic millimeter (mm3) and associated to ADA polymorphism

  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.

  Month 0 enrollment compared to month 12; RMS patients

Secondary Outcomes (18)

• Genotyping of SNPs and gene expression for correlation analysis with disease effectiveness of Cladribine treatment

  months 0, 6, 12 and 24

• Evaluation of DCK and 5'NT genes expression

  months 0, 6, 12 and 24

• Statistical correlation of EBV genotypes with responder or non-responder conditions

  month 0

• Quantification of DCK and cytosolic forms of NT5 and evaluation of CD4+ enzyme activity

  months 0, 6, 12 and 24

• Genes expression

  months 0, 6, 12 and 24

Study Arms (1)

Relapsing MS patients

Single Arm: Relapsing Multiple Sclerosis patients ADA SNPs and other biomarkers analyses in blood samples.

Procedure: Blood withdrawal

Interventions

Blood withdrawal PROCEDURE

Blood withdrawal of maximum 60 ml performed to each enrolled patient during the study for primary and secondary endpoints evaluation.

Relapsing MS patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

subject with relapsing multiple sclerosis

You may qualify if:

• Male or female subjects ≥ 18 years old
• 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;
• Normal lymphocyte count (absolute values 1.0-3.0×109/l) according to Cladribine local labelling;
• EDSS score ≤5.0.

You may not qualify if:

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

Sponsors & Collaborators

• Neuromed IRCCS: lead

Study Sites (1)

IRCCS Neuromed

Pozzilli, Isernia, 86077, Italy

RECRUITING

Related Publications (21)

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Study Officials

• Diego Centonze

  IRCCS Neuromed, Pozzilli, Isernia Italy

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Diego Centonze, MD

CONTACT

+39 3934444159; centonze@uniroma2.it

Mario Stampanoni Bassi, MD

CONTACT

+39 2460181370; mario_sb@hotmail.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Haed of Neurology Unit

Study Record Dates

• First Submitted: September 26, 2019
• First Posted: October 9, 2019
• Study Start: September 7, 2020
• Primary Completion: October 1, 2024
• Study Completion: June 1, 2025
• Last Updated: March 29, 2024

Record last verified: 2024-03

Locations

IT (1)