Therapeutic Monitoring of Drugs Used in the Treatment of Multiple Sclerosis

Study Overview
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Brief Summary
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The main goal of multiple sclerosis (MS) treatment is to prevent further relapses of the disease and the progression of neurological deficit. Although MS cannot yet be cured, early control of symptoms and reduction of disease progression is associated with a longer time to disability and improve long-term treatment outcomes. Currently, MS is treated using a multidisciplinary approach, which consists of treatment with so-called disease-modifying drugs (DMDs), symptomatic therapy of individual symptoms, lifestyle adjustments, psychological support, and rehabilitation interventions. According to the latest results, treatment with DMDs can reduce the annual incidence of relapses by 29-68% compared to placebo or an active comparator. Thus, as can be seen, even this group of modern drugs does not completely compensate for MS in many patients. For this reason, there is a need to use certain parameters to best assess the effectiveness of individual treatments in specific patients with MS in routine clinical practice. Therapeutic drug monitoring (TDM) is a specific method of clinical pharmacology that has long been used to monitor therapy for a variety of diseases by measuring drug concentrations in body fluids (plasma, serum, whole blood, cerebrospinal fluid, breast milk) with subsequent interpretation by clinical pharmacologist and acceptance by the clinician. The groups of drugs for which TDM is routinely performed include selected groups of antibiotics (aminoglycosides, vancomycin, beta-lactams), immunosuppressants, digoxin, and especially drugs used in neurology and psychiatry (antiepileptics and psychotropic drugs). As far as DMDs is concerned, the first data on the possibility of using TDM in the therapy of MS have already appeared in the professional literature, but these are so far rare and completely insufficient. In addition, individual drugs differ not only in efficacy but also in dose, dosing schedule, and safety profile. The development of new analytical methods to determine serum or whole blood DMDs concentrations, together with the objectification of the relationship between measured concentrations to the patient's clinical condition and the possibility of objectifying patient adherence to treatment, could therefore significantly help individualize the dosage of DMDs in each individual patient.

Detailed Description
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The study group will consist of individuals with MS who will be indicated for some of the orally used disease-modifying drugs (DMDs) - fingolimod, dimethyl fumarate, cladribine, or teriflunomide, both patients with established treatment and patients who will have this medication newly used. All medical care will be performed according to the habits and decisions of the attending physician depending on the clinical condition of the patient, in addition, only 3 blood tubes will be taken on the day of scheduled standard collection and 1 blood tube for the entire duration of the study for genetic testing. Of these, 2 tubes will be collected as part of a standard fasting sample from fasting before drug administration with other routinely collected blood samples (including one tube for the duration of the genetic testing study) and 1 tube will be collected 2-3 hours after drug administration. to determine the maximum drug concentration. For the patient, all the load will mean only one extra collection, ie a collection after taking the drug, either from a new injection or with an inserted cannula. Blood samples obtained from 2 tubes taken on an empty stomach will be used to determine the concentration of DMDs of the drug before use and to analyze other biomarkers that could be used to evaluate the patient's clinical condition, such as signs of axonal damage (plasma neuro-filament light chain - pNfL). ), Glial damage (so-called chitinase 3-like 1 - CHI3L1 ), concentrations of selected cytokines or concentrations of CD4 + and CD8 + T cells. One tube of blood taken also on an empty stomach, once for the duration of the study, will be used for genetic testing of drug transporters such as P-gp (ABCB1) or BCRP (ABCG2). At the same time, the patient will perform the usual clinical examinations (physical assessment of the clinical condition, evaluation of the EDSS scale, monitoring of possible side effects of the medication used and the MSQOL-54 quality of life questionnaire) and once a year routine magnetic resonance imaging of the brain. The information thus obtained will be correlated with the achieved concentration of DMDs used to determine whether this group of drugs would be suitable for routine therapeutic monitoring, similar to antiepileptics, for which TDM has been part of routine clinical practice to optimize since the 1970s. pharmacotherapy in individual patients to compensate for the clinical condition with minimal side effects. The investigators would also try to establish a reference range of individual DMDs, which would be defined as the concentration of drug in serum or whole blood at which most patients are expected to achieve an optimal clinical response. However, since some patients may (similarly to antiepileptics) require a concentration outside this reference range, the investigators would try to determine the so-called individual therapeutic concentration in these cases, i.e. the concentration at which MS without an MS attack with good tolerability of medication would be achieved, possibly as the best compromise between improving MS control and concentration-dependent side effects. For the patient, all loading will mean only one extra collection, i.e. a post-drug collection, which can be done either from a new injection or with an inserted cannula. This collection may involve common risks, such as bleeding from an injection site due to insufficient compression of the injection site, the development of a hematoma, or a drop in blood pressure. By obtaining the valuable parameters mentioned above, not only others, resp. future patients with MS, but due to the short duration of the study and at the same time the lifelong influence of the patient with multiple sclerosis, these results may help to optimize the pharmacotherapy of DMDs also in a specific individual patient - study participant. However, because long-term patient adherence to treatment is equally important for MS compensation, the introduction of TDM DMDs for attending physicians could help not only to optimize the pharmacotherapy of MS but also to control the patient's adherence to treatment.

Official Title
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Importance of Therapeutic Monitoring of Orally Administered Disease-modifying Drugs Used in the Treatment of Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Diagnostic Test: Measurement of concentrations of orally-used DMDs
* Diagnostic Test: Genetic testing
* Diagnostic Test: Parameters for routine use of DMDs
* Other: Side effects of orally used DMDs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients diagnosed with MS of all forms using any of the oral DMDs men and women older than 18 years signature of the Informed Consent to Participate in the Study Exclusion Criteria: minor patients (below 18 years of age) refusal to sign the Informed Consent to Participate in the Study refusal of blood samples taken beyond standard examinations Criteria for exclusion from the study non-compliance with the treatment regimen according to the decision of the attending physician non-participation in blood samples taken as part of standard examinations

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Gilenya<br>Gilenya (fingolimod) - first registration 17 March 2011, last renewal 16 November 2020, selective immunosuppressant (ATC code L04AA27), sphingosine-1-phosphate receptor modulator | Diagnostic Test: Measurement of concentrations of orally-used DMDs<br>* For effectiveness - the measured concentrations of orally used DMDs will be correlated with the clinical condition of patients with MS (usual clinical examinations such as physical assessment of clinical condition, evaluation of EDSS scale, MSQOL-54 quality of life questionnaire, and routine magnetic resonance imaging of the brain once a year). At the same time, the relationship between the measured concentrations of orally used DMDs and the concentrations of other biomarkers of MS, such as signs of axonal (so-called plasma neurofilament light chain - pNfL) and glial (so-called chitinase 3-like 1 - CHI3L1) damage, will be analyzed. concentrations of selected cytokines, concentrations of CD4 + and CD8 + T-lymphocytes, and the results of a genetic examination of drug transporters, again with an effect on the clinical condition of the patient.<br>Diagnostic Test: Genetic testing<br>* One blood tube will be taken for genetic testing for the duration of the study, again with standard and routine single injections before taking the drug.<br>Diagnostic Test: Parameters for routine use of DMDs<br>* For safety - the usual parameters for routine use of DMDs will be monitored (blood count, liver tests, renal function, etc. according to the specifics of individual drugs).<br>Other: Side effects of orally used DMDs<br>* For tolerability - possible side effects of orally used DMDs will be monitored and the effect of genetic testing of drug transporters will be analyzed.<br>|
| Tecfidera<br>Tecfidera (dimethyl fumarate) - first registration 30 January 2014, last renewal 20 September 2018, cytostatic and immunomodulatory drug (ATC code L04AX07), an activator of the transcription pathway of nuclear factor Nrf2 | Diagnostic Test: Measurement of concentrations of orally-used DMDs<br>* For effectiveness - the measured concentrations of orally used DMDs will be correlated with the clinical condition of patients with MS (usual clinical examinations such as physical assessment of clinical condition, evaluation of EDSS scale, MSQOL-54 quality of life questionnaire, and routine magnetic resonance imaging of the brain once a year). At the same time, the relationship between the measured concentrations of orally used DMDs and the concentrations of other biomarkers of MS, such as signs of axonal (so-called plasma neurofilament light chain - pNfL) and glial (so-called chitinase 3-like 1 - CHI3L1) damage, will be analyzed. concentrations of selected cytokines, concentrations of CD4 + and CD8 + T-lymphocytes, and the results of a genetic examination of drug transporters, again with an effect on the clinical condition of the patient.<br>Diagnostic Test: Genetic testing<br>* One blood tube will be taken for genetic testing for the duration of the study, again with standard and routine single injections before taking the drug.<br>Diagnostic Test: Parameters for routine use of DMDs<br>* For safety - the usual parameters for routine use of DMDs will be monitored (blood count, liver tests, renal function, etc. according to the specifics of individual drugs).<br>Other: Side effects of orally used DMDs<br>* For tolerability - possible side effects of orally used DMDs will be monitored and the effect of genetic testing of drug transporters will be analyzed.<br>|
| Mavenclad<br>Mavenclad (cladribine) - first registration 22/08/2017, selective immunosuppressant (ATC code L04AA40), nucleoside analogue of deoxyadenosine | Diagnostic Test: Measurement of concentrations of orally-used DMDs<br>* For effectiveness - the measured concentrations of orally used DMDs will be correlated with the clinical condition of patients with MS (usual clinical examinations such as physical assessment of clinical condition, evaluation of EDSS scale, MSQOL-54 quality of life questionnaire, and routine magnetic resonance imaging of the brain once a year). At the same time, the relationship between the measured concentrations of orally used DMDs and the concentrations of other biomarkers of MS, such as signs of axonal (so-called plasma neurofilament light chain - pNfL) and glial (so-called chitinase 3-like 1 - CHI3L1) damage, will be analyzed. concentrations of selected cytokines, concentrations of CD4 + and CD8 + T-lymphocytes, and the results of a genetic examination of drug transporters, again with an effect on the clinical condition of the patient.<br>Diagnostic Test: Genetic testing<br>* One blood tube will be taken for genetic testing for the duration of the study, again with standard and routine single injections before taking the drug.<br>Diagnostic Test: Parameters for routine use of DMDs<br>* For safety - the usual parameters for routine use of DMDs will be monitored (blood count, liver tests, renal function, etc. according to the specifics of individual drugs).<br>Other: Side effects of orally used DMDs<br>* For tolerability - possible side effects of orally used DMDs will be monitored and the effect of genetic testing of drug transporters will be analyzed.<br>|
| Aubagio<br>Aubagio (teriflunomide) - first registration on 26 August 2013, last renewal on 28 May 2018, selective immunosuppressant (ATC code L04AA31), an inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase | Diagnostic Test: Measurement of concentrations of orally-used DMDs<br>* For effectiveness - the measured concentrations of orally used DMDs will be correlated with the clinical condition of patients with MS (usual clinical examinations such as physical assessment of clinical condition, evaluation of EDSS scale, MSQOL-54 quality of life questionnaire, and routine magnetic resonance imaging of the brain once a year). At the same time, the relationship between the measured concentrations of orally used DMDs and the concentrations of other biomarkers of MS, such as signs of axonal (so-called plasma neurofilament light chain - pNfL) and glial (so-called chitinase 3-like 1 - CHI3L1) damage, will be analyzed. concentrations of selected cytokines, concentrations of CD4 + and CD8 + T-lymphocytes, and the results of a genetic examination of drug transporters, again with an effect on the clinical condition of the patient.<br>Diagnostic Test: Genetic testing<br>* One blood tube will be taken for genetic testing for the duration of the study, again with standard and routine single injections before taking the drug.<br>Diagnostic Test: Parameters for routine use of DMDs<br>* For safety - the usual parameters for routine use of DMDs will be monitored (blood count, liver tests, renal function, etc. according to the specifics of individual drugs).<br>Other: Side effects of orally used DMDs<br>* For tolerability - possible side effects of orally used DMDs will be monitored and the effect of genetic testing of drug transporters will be analyzed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of measured concentrations of orally used DMDs with the clinical condition of patients with MS | Correlation of measured concentrations of orally used DMDs with the clinical condition of patients with MS will be observed. | up to 3 years | 
| Objectification of adherence to treatment in individual DMDs | Objectification of adherence to treatment in individual DMDs will be observed. | up to 3 years | 
| The percentage of patients with DMDs in whom therapeutic monitoring is used | The percentage of patients with DMDs in whom therapeutic monitoring is used will be observed. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of the relationship between the measured concentrations of orally used DMDs and the concentrations of other biomarkers of MS | Analysis of the relationship between the measured concentrations of orally used DMDs and the concentrations of other biomarkers of MS, such as signs of axonal (so-called plasma neurofilament light chain - pNfL) and glial (so-called chitinase 3-like 1 - CHI3L1) damage, concentrations of selected cytokines, concentrations of CD4 + and CD8 + T-lymphocytes | up to 3 years | 
| Analysis of the relationship between the measured concentrations of orally used DMDs with the results of genetic examination of drug transporters of the P-gp (ABCB1) and BCRP (ABCG2) type | analysis of the relationship between the measured concentrations of orally used DMDs with the results of genetic examination of drug transporters of the P-gp (ABCB1) and BCRP (ABCG2) type | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Therapeutic Drug Monitoring, Concentrations, Disease-Modifying Drugs