Role of ADA SNPs in Subjects With Relapsing Multiple Sclerosis (RMS)
NCT ID: NCT04121065
Last Updated: 2024-03-29
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
RECRUITING
Total Enrollment
150 participants
Study Classification
OBSERVATIONAL
Study Start Date
2020-09-07
Study Completion Date
2025-06-30
Brief Summary
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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.
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.
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Detailed Description
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The therapeutic landscape for multiple sclerosis (MS) is rapidly evolving. For the past 25 years, there has been an accelerating inclusion of new immunomodulating drugs. MS immunotherapies may also be classified in a different way, into treatments that are given continuously (chronic treatments) and medications that are applied intermittently (immune reconstitution therapies \[IRTs\]). The principle behind the latter is depletion of the immune system that allows it to rebuild itself. An IRT by definition is given at short intermittent courses and not continuously. IRT modalities were shown to induce long-term remission of MS that, in some cases, is close to the definition of a "cure".
Most importantly, IRT using these modalities causes substantial changes in the lymphocyte repertoire after the reconstitution phase.
This is particularly true for Cladribine (2-CdA), a high efficacy therapy that selectively depletes peripheral lymphocytes, recently approved by the European Medicine Agencies for RMS patients with high activity of disease.
Lymphocytes have a high intracellular ratio of DCK to 5'-NTs compared with other cell types. Specifically, levels of DCK and the ratio of DCK to 5'-NT are high in T cells (CD4+ and CD8+), B cells, and dendritic cells but are very low in numerous non-hematologic cell types (http://biogps.gnf.org). This makes lymphocytes, mainly memory B cells, particularly sensitive to the accumulation of 2-CdA nucleotides. The intracellular accumulation of 2-CdATP leads to the incorporation of 2-CdATP into cellular DNA, disrupting the double helix structure and leading to a failure of DNA repair and synthesis. The resulting DNA strand breaks alter the cell cycle progression inducing cell death mediated by apoptosis. Although apoptosis is the most prominent mechanism of action of 2-CdA, additional mechanisms cannot be excluded. Many evidences shown that nucleotide signaling governs some of the most essential responses in immunity, ranging from antigen-driven T lymphocyte proliferation to T helper 1 (Th1) and Th2 cell differentiation, from neutrophil and macrophage chemotaxis to intracellular pathogen killing, and from NADPH-oxidase activation to IL-1β maturation and release. In addition, an analysis of lymphocytes subsets collected in the pivotal phase III trial of Cladribine showed that while T cells reduction shows some Cladribine-dose dependency, B cells have a similar reduction with both dosing schedules in the trial. Moreover, the mean number of T and B cells do not differ between patients remaining free from relapses and patients developing relapses, suggesting that efficacy of Cladribine is not strictly dependent on reduction of lymphocyte count. On the other hand, a lower lymphocyte count has been correlated with a higher risk of developing an Herpes Zoster infection, with all the events restricted and dermatomal, and most of them graded as mild or moderate. Thus, severe lymphopenia is also an important identified risk for safety. In phase III clinical trials (RCTs), 20-25% of the subjects treated with 3.5mg/kg of oral 2-CdA developed transient Grade 3-4 lymphopenia. The rate of patients who discontinued the treatment for lymphopenia was highest (12.4%) in the group that received the greatest cumulative dose of 2-CdA (CC 8.75 mg/kg) at the end of the extension phase of the CLARITY study (22). This effect has been also correlated in others disease with a reduced level of DCK mRNA and a higher level of 5'NT mRNA in lymphocytes. Though the biological activation of 2-CdA needs DCK function independently of ADA action, it cannot be excluded ADA participation in other aspects of 2-CdA mechanism of action, taking in consideration ADA crucial role in lymphocytes activation and function.
In line with this, it has been recently identified an ADA genetic variant (rs244072, non-risk/risk allele: T/C) linked to brain inflammation and MS disease severity (article in preparation), by screening more than 50 SNPs in MS-related genes of 514 MS patients and looking for association with clinical and biochemical parameters. The most striking result observed was a direct correlation between the presence of at least one risk allele and EDSS score, namely CT/CC patients show higher values of EDSS than TT patients (p=0.016).
Therefore, we hypothesize that the genetic polymorphism of ADA gene, found to correlate with MS disease severity, can also influence the 2-CdA response in term of drug sensitivity/resistance as well as side effects, like lymphocytopenia. According to the rationale, in the panorama of the current therapeutic options available to the patient MRS, Cladribine is the only immune-reconstitution therapy to have an action mechanism that interferes with that of the ADA and for this it has been selected the Cladribine as a reference treatment in clinical practice for this study.
Subjects candidate to be treated with Cladribine according to clinical practice and meeting the SmPc requirements during a pre-baseline screening period of up to -3 months before baseline (month 0), will receive an initial treatment course in week 1 and week 5 (W1-W5) as per clinical practice.
Subjects will attend visits for blood sample as per mandatory monitoring before initiating Cladribine in year 1, before initiating Cladribine in year 2, and 2 and 6 months after start of treatment in each treatment year.
The study will last 2 years for each subjects, providing five visits: screening, at month 0, at month 6, at month 12 and at month 24, according to clinical practice for MS subjects monitoring.
The primary objective of the study is to evaluate the influence of the ADA SNP rs244072 (non-risk/risk allele: T/C) on lymphopenia induced by Cladribine (2-CdA) in real world setting in patients with relapsing multiple sclerosis (RMS).
The secondary objectives are:
* To evaluate molecular, metabolic and immunological factors involved in the mode of action of Cladribine, that can influence patients' response to treatment, focusing in particular on lymphopenia;
* To collect safety and tolerability data on RMS patients treated with Cladribine;
* To assess the effect of Cladribine on progression of disability and incidence of relapses.
The study will include the collection of blood samples to investigate the primary and secondary endpoints. For these analyses, a maximum of 60 ml of blood will be collected at month 0, month 6, month 12 and month 24.
Quantitative variables will be reported as mean and standard deviation (SD) or median and Interquartile Range (Q1-Q3), Categorical variables will be reported as number (n) and percentage (%) Primary endpoints and clinical endpoints will be evaluated on all sample. Others secondary endpoint will evaluate on patients of each center unless otherwise indicated.
T Student test or Mann Whitney test will be used to compare baseline characteristics of two groups (associated with the genetic polymorphism of ADA), Chi square test o Fisher exact test when necessary, will be used for categorical variables. Shapiro Wilk test and graphics methods will be use to assess normality assumptions.
In primary endpoint analysis paired t test will be used to evaluate change in lymphocytes in each group separately. Linear mixed model will be used to compare change in two groups taking in account repetitive data for each patient (patient as random effect) group, time and group per time as fixed effects. Model assumptions will be checked, in case of they are not support logarithm data or other models will be used.
Different mixed models will be used to evaluate clinical endpoint on all sample during time.
A p value \< 0.05 will be statistically significant.
Most importantly, IRT using these modalities causes substantial changes in the lymphocyte repertoire after the reconstitution phase.
This is particularly true for Cladribine (2-CdA), a high efficacy therapy that selectively depletes peripheral lymphocytes, recently approved by the European Medicine Agencies for RMS patients with high activity of disease.
Lymphocytes have a high intracellular ratio of DCK to 5'-NTs compared with other cell types. Specifically, levels of DCK and the ratio of DCK to 5'-NT are high in T cells (CD4+ and CD8+), B cells, and dendritic cells but are very low in numerous non-hematologic cell types (http://biogps.gnf.org). This makes lymphocytes, mainly memory B cells, particularly sensitive to the accumulation of 2-CdA nucleotides. The intracellular accumulation of 2-CdATP leads to the incorporation of 2-CdATP into cellular DNA, disrupting the double helix structure and leading to a failure of DNA repair and synthesis. The resulting DNA strand breaks alter the cell cycle progression inducing cell death mediated by apoptosis. Although apoptosis is the most prominent mechanism of action of 2-CdA, additional mechanisms cannot be excluded. Many evidences shown that nucleotide signaling governs some of the most essential responses in immunity, ranging from antigen-driven T lymphocyte proliferation to T helper 1 (Th1) and Th2 cell differentiation, from neutrophil and macrophage chemotaxis to intracellular pathogen killing, and from NADPH-oxidase activation to IL-1β maturation and release. In addition, an analysis of lymphocytes subsets collected in the pivotal phase III trial of Cladribine showed that while T cells reduction shows some Cladribine-dose dependency, B cells have a similar reduction with both dosing schedules in the trial. Moreover, the mean number of T and B cells do not differ between patients remaining free from relapses and patients developing relapses, suggesting that efficacy of Cladribine is not strictly dependent on reduction of lymphocyte count. On the other hand, a lower lymphocyte count has been correlated with a higher risk of developing an Herpes Zoster infection, with all the events restricted and dermatomal, and most of them graded as mild or moderate. Thus, severe lymphopenia is also an important identified risk for safety. In phase III clinical trials (RCTs), 20-25% of the subjects treated with 3.5mg/kg of oral 2-CdA developed transient Grade 3-4 lymphopenia. The rate of patients who discontinued the treatment for lymphopenia was highest (12.4%) in the group that received the greatest cumulative dose of 2-CdA (CC 8.75 mg/kg) at the end of the extension phase of the CLARITY study (22). This effect has been also correlated in others disease with a reduced level of DCK mRNA and a higher level of 5'NT mRNA in lymphocytes. Though the biological activation of 2-CdA needs DCK function independently of ADA action, it cannot be excluded ADA participation in other aspects of 2-CdA mechanism of action, taking in consideration ADA crucial role in lymphocytes activation and function.
In line with this, it has been recently identified an ADA genetic variant (rs244072, non-risk/risk allele: T/C) linked to brain inflammation and MS disease severity (article in preparation), by screening more than 50 SNPs in MS-related genes of 514 MS patients and looking for association with clinical and biochemical parameters. The most striking result observed was a direct correlation between the presence of at least one risk allele and EDSS score, namely CT/CC patients show higher values of EDSS than TT patients (p=0.016).
Therefore, we hypothesize that the genetic polymorphism of ADA gene, found to correlate with MS disease severity, can also influence the 2-CdA response in term of drug sensitivity/resistance as well as side effects, like lymphocytopenia. According to the rationale, in the panorama of the current therapeutic options available to the patient MRS, Cladribine is the only immune-reconstitution therapy to have an action mechanism that interferes with that of the ADA and for this it has been selected the Cladribine as a reference treatment in clinical practice for this study.
Subjects candidate to be treated with Cladribine according to clinical practice and meeting the SmPc requirements during a pre-baseline screening period of up to -3 months before baseline (month 0), will receive an initial treatment course in week 1 and week 5 (W1-W5) as per clinical practice.
Subjects will attend visits for blood sample as per mandatory monitoring before initiating Cladribine in year 1, before initiating Cladribine in year 2, and 2 and 6 months after start of treatment in each treatment year.
The study will last 2 years for each subjects, providing five visits: screening, at month 0, at month 6, at month 12 and at month 24, according to clinical practice for MS subjects monitoring.
The primary objective of the study is to evaluate the influence of the ADA SNP rs244072 (non-risk/risk allele: T/C) on lymphopenia induced by Cladribine (2-CdA) in real world setting in patients with relapsing multiple sclerosis (RMS).
The secondary objectives are:
* To evaluate molecular, metabolic and immunological factors involved in the mode of action of Cladribine, that can influence patients' response to treatment, focusing in particular on lymphopenia;
* To collect safety and tolerability data on RMS patients treated with Cladribine;
* To assess the effect of Cladribine on progression of disability and incidence of relapses.
The study will include the collection of blood samples to investigate the primary and secondary endpoints. For these analyses, a maximum of 60 ml of blood will be collected at month 0, month 6, month 12 and month 24.
Quantitative variables will be reported as mean and standard deviation (SD) or median and Interquartile Range (Q1-Q3), Categorical variables will be reported as number (n) and percentage (%) Primary endpoints and clinical endpoints will be evaluated on all sample. Others secondary endpoint will evaluate on patients of each center unless otherwise indicated.
T Student test or Mann Whitney test will be used to compare baseline characteristics of two groups (associated with the genetic polymorphism of ADA), Chi square test o Fisher exact test when necessary, will be used for categorical variables. Shapiro Wilk test and graphics methods will be use to assess normality assumptions.
In primary endpoint analysis paired t test will be used to evaluate change in lymphocytes in each group separately. Linear mixed model will be used to compare change in two groups taking in account repetitive data for each patient (patient as random effect) group, time and group per time as fixed effects. Model assumptions will be checked, in case of they are not support logarithm data or other models will be used.
Different mixed models will be used to evaluate clinical endpoint on all sample during time.
A p value \< 0.05 will be statistically significant.
Conditions
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Relapsing Multiple Sclerosis
Study Design
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Observational Model Type
COHORT
Study Time Perspective
PROSPECTIVE
Study Groups
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Relapsing MS patients
Single Arm: Relapsing Multiple Sclerosis patients ADA SNPs and other biomarkers analyses in blood samples.
Blood withdrawal
Intervention Type
PROCEDURE
Blood withdrawal of maximum 60 ml performed to each enrolled patient during the study for primary and secondary endpoints evaluation.
Interventions
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Blood withdrawal
Blood withdrawal of maximum 60 ml performed to each enrolled patient during the study for primary and secondary endpoints evaluation.
Intervention Type
PROCEDURE
Eligibility Criteria
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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.
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
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
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Neuromed IRCCS
OTHER
Sponsor Role
lead
Responsible Party
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Diego Centonze
Haed of Neurology Unit
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Diego Centonze
Role: PRINCIPAL_INVESTIGATOR
IRCCS Neuromed, Pozzilli, Isernia Italy
Locations
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IRCCS Neuromed
Pozzilli, Isernia, Italy
Site Status
RECRUITING
Countries
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Italy
Central Contacts
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Facility Contacts
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References
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Mandolesi G, Gentile A, Musella A, Fresegna D, De Vito F, Bullitta S, Sepman H, Marfia GA, Centonze D. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol. 2015 Dec;11(12):711-24. doi: 10.1038/nrneurol.2015.222. Epub 2015 Nov 20.
Reference Type
BACKGROUND
Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V, Galgani M, Faicchia D, Marone G, Tramontano D, Corona M, Alviggi C, Porcellini A, La Cava A, Mauri P, Matarese G. The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements. Immunity. 2016 Feb 16;44(2):406-21. doi: 10.1016/j.immuni.2016.01.028.
Reference Type
BACKGROUND
Price AM, Dai J, Bazot Q, Patel L, Nikitin PA, Djavadian R, Winter PS, Salinas CA, Barry AP, Wood KC, Johannsen EC, Letai A, Allday MJ, Luftig MA. Epstein-Barr virus ensures B cell survival by uniquely modulating apoptosis at early and late times after infection. Elife. 2017 Apr 20;6:e22509. doi: 10.7554/eLife.22509.
Reference Type
BACKGROUND
Mechelli R, Manzari C, Policano C, Annese A, Picardi E, Umeton R, Fornasiero A, D'Erchia AM, Buscarinu MC, Agliardi C, Annibali V, Serafini B, Rosicarelli B, Romano S, Angelini DF, Ricigliano VA, Buttari F, Battistini L, Centonze D, Guerini FR, D'Alfonso S, Pesole G, Salvetti M, Ristori G. Epstein-Barr virus genetic variants are associated with multiple sclerosis. Neurology. 2015 Mar 31;84(13):1362-8. doi: 10.1212/WNL.0000000000001420. Epub 2015 Mar 4.
Reference Type
BACKGROUND
Cekic C, Linden J. Purinergic regulation of the immune system. Nat Rev Immunol. 2016 Mar;16(3):177-92. doi: 10.1038/nri.2016.4.
Reference Type
BACKGROUND
Samuraki M, Sakai K, Odake Y, Yoshita M, Misaki K, Nakada M, Yamada M. Multiple sclerosis showing elevation of adenosine deaminase levels in the cerebrospinal fluid. Mult Scler Relat Disord. 2017 Apr;13:44-46. doi: 10.1016/j.msard.2017.02.005. Epub 2017 Feb 6.
Reference Type
BACKGROUND
Dong K, Gao ZW, Zhang HZ. The role of adenosinergic pathway in human autoimmune diseases. Immunol Res. 2016 Dec;64(5-6):1133-1141. doi: 10.1007/s12026-016-8870-2.
Reference Type
BACKGROUND
Giovannoni G. Cladribine to Treat Relapsing Forms of Multiple Sclerosis. Neurotherapeutics. 2017 Oct;14(4):874-887. doi: 10.1007/s13311-017-0573-4.
Reference Type
BACKGROUND
Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 5;4(4):e360. doi: 10.1212/NXI.0000000000000360. eCollection 2017 Jul.
Reference Type
BACKGROUND
Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, Lock H, Longhurst HJ, Giovannoni G, Schmierer K. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J Neurol. 2018 May;265(5):1199-1209. doi: 10.1007/s00415-018-8830-y. Epub 2018 Mar 17.
Reference Type
BACKGROUND
Siddiqui MK, Khurana IS, Budhia S, Hettle R, Harty G, Wong SL. Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing-remitting multiple sclerosis. Curr Med Res Opin. 2018 Aug;34(8):1361-1371. doi: 10.1080/03007995.2017.1407303. Epub 2017 Nov 28.
Reference Type
BACKGROUND
Karussis D, Petrou P. Immune reconstitution therapy (IRT) in multiple sclerosis: the rationale. Immunol Res. 2018 Dec;66(6):642-648. doi: 10.1007/s12026-018-9032-5.
Reference Type
BACKGROUND
De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C, Romano A, De Simone S, Procaccini C, La Rocca C, Carrieri PB, Maniscalco GT, Salvetti M, Buscarinu MC, Franzese A, Mozzillo E, La Cava A, Matarese G. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol. 2015 Nov;16(11):1174-84. doi: 10.1038/ni.3269. Epub 2015 Sep 28.
Reference Type
BACKGROUND
Wekerle H. B cells in multiple sclerosis. Autoimmunity. 2017 Feb;50(1):57-60. doi: 10.1080/08916934.2017.1281914.
Reference Type
BACKGROUND
An M, Wu J, Zhu J, Lubman DM. Comparison of an Optimized Ultracentrifugation Method versus Size-Exclusion Chromatography for Isolation of Exosomes from Human Serum. J Proteome Res. 2018 Oct 5;17(10):3599-3605. doi: 10.1021/acs.jproteome.8b00479. Epub 2018 Sep 19.
Reference Type
BACKGROUND
Mandolesi G, De Vito F, Musella A, Gentile A, Bullitta S, Fresegna D, Sepman H, Di Sanza C, Haji N, Mori F, Buttari F, Perlas E, Ciotti MT, Hornstein E, Bozzoni I, Presutti C, Centonze D. miR-142-3p Is a Key Regulator of IL-1beta-Dependent Synaptopathy in Neuroinflammation. J Neurosci. 2017 Jan 18;37(3):546-561. doi: 10.1523/JNEUROSCI.0851-16.2016.
Reference Type
BACKGROUND
Parodi B, Rossi S, Morando S, Cordano C, Bragoni A, Motta C, Usai C, Wipke BT, Scannevin RH, Mancardi GL, Centonze D, Kerlero de Rosbo N, Uccelli A. Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. Acta Neuropathol. 2015 Aug;130(2):279-95. doi: 10.1007/s00401-015-1422-3. Epub 2015 Apr 29.
Reference Type
BACKGROUND
Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, Piras E, Gargano F, Borsellino G, Battistini L, Schubart A, Mandolesi G, Centonze D. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016 Aug 26;13(1):207. doi: 10.1186/s12974-016-0686-4.
Reference Type
BACKGROUND
Harris VK, Sadiq SA. Biomarkers of therapeutic response in multiple sclerosis: current status. Mol Diagn Ther. 2014 Dec;18(6):605-17. doi: 10.1007/s40291-014-0117-0.
Reference Type
BACKGROUND
Comabella M, Montalban X. Body fluid biomarkers in multiple sclerosis. Lancet Neurol. 2014 Jan;13(1):113-26. doi: 10.1016/S1474-4422(13)70233-3.
Reference Type
BACKGROUND
Polachini CR, Spanevello RM, Casali EA, Zanini D, Pereira LB, Martins CC, Baldissareli J, Cardoso AM, Duarte MF, da Costa P, Prado AL, Schetinger MR, Morsch VM. Alterations in the cholinesterase and adenosine deaminase activities and inflammation biomarker levels in patients with multiple sclerosis. Neuroscience. 2014 Apr 25;266:266-74. doi: 10.1016/j.neuroscience.2014.01.048. Epub 2014 Feb 5.
Reference Type
BACKGROUND
Other Identifiers
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ADA-MS
Identifier Type: -
Identifier Source: org_study_id
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NCT01056471
COMPLETED
PHASE1/PHASE2
MEsenchymal StEm Cells for Multiple Sclerosis
NCT01854957
UNKNOWN
PHASE1/PHASE2
A Study to Assess the Effects of MK0812 on Disease Activity in Patients With Relapsing-Remitting Multiple Sclerosis as Measured by Magnetic Resonance Imaging (MRI)(0812-003)(COMPLETED)
NCT00239655
TERMINATED
PHASE2
RRMS: Disease PROgression and Myeloid Profiling After Bone Marrow TRANSPLANTation and Second Line Therapies
NCT06267781
RECRUITING
COMparison Between All immunoTherapies for Multiple Sclerosis.
NCT03193866
COMPLETED
Study Assessing Cognition in Relapsing Remitting Multiple Sclerosis (RRMS) Patients Treated With BG00012
NCT02579681
COMPLETED
PHASE3
Simvastatin as an Add-on Treatment to Interferon-beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis
NCT00492765
COMPLETED
PHASE4
Neural Stem Cell Transplantation in Multiple Sclerosis Patients
NCT03269071
COMPLETED
PHASE1
Special Drug-use Surveillance for Kesimpta for s.c. Injection 20 mg Pen
NCT04940065
COMPLETED
A Canadian Study Assessing the Utility of the Treatment Optimization Recommendations in Multiple Sclerosis
NCT01142583
COMPLETED
Simvastatin as an add-on Treatment to Copaxone for the Treatment of Relapsing Multiple Sclerosis
NCT00429442
WITHDRAWN
PHASE3