Ignite Creation Date:
2024-05-06 @ 1:48 PM
Last Modification Date:
2024-10-26 @ 1:19 PM
Study NCT ID:
NCT04121065
Status:
RECRUITING
Last Update Posted:
2024-03-29
First Post:
2019-09-26
Brief Title:
Role of ADA SNPs in Subjects With Relapsing Multiple Sclerosis RMS
Sponsor:
Neuromed IRCCS
Organization:
Neuromed IRCCS
Study Overview
Official Title:
Interventional Not Pharmacological Study to Investigate the Role of ADA in Multiple Sclerosis PatientsTreated With an Immune-Reconstitution Therapy 2-CdA
Status:
RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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
Detailed Description:
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 httpbiogpsgnforg 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 35mgkg of oral 2-CdA developed transient Grade 3-4 lymphopenia The rate of patients who discontinued the treatment for lymphopenia was highest 124 in the group that received the greatest cumulative dose of 2-CdA CC 875 mgkg 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 5NT 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-riskrisk allele TC 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 CTCC patients show higher values of EDSS than TT patients p0016
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 sensitivityresistance 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-riskrisk allele TC 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 005 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 httpbiogpsgnforg 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 35mgkg of oral 2-CdA developed transient Grade 3-4 lymphopenia The rate of patients who discontinued the treatment for lymphopenia was highest 124 in the group that received the greatest cumulative dose of 2-CdA CC 875 mgkg 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 5NT 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-riskrisk allele TC 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 CTCC patients show higher values of EDSS than TT patients p0016
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 sensitivityresistance 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-riskrisk allele TC 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 005 will be statistically significant
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None