Therapeutic Monitoring of Drugs Used in the Treatment of Multiple Sclerosis

NCT05112484 | Not Yet Recruiting

• 2 other identifiers: FNO-02/06/2021/2.02021-003195-13
• Study Type: observational
• Target: 600
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Multiple Sclerosis

Keywords

Multiple Sclerosis; Therapeutic Drug Monitoring; Concentrations; Disease-Modifying Drugs

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (2)

• Analysis of the relationship between the measured concentrations of orally used "DMDs" and the concentrations of other biomarkers of MS

  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

  up to 3 years

Study Arms (4)

Gilenya

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; Diagnostic Test: Genetic testing; Diagnostic Test: Parameters for routine use of DMDs; Other: Side effects of orally used DMDs

Tecfidera

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; Diagnostic Test: Genetic testing; Diagnostic Test: Parameters for routine use of DMDs; Other: Side effects of orally used DMDs

Mavenclad

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; Diagnostic Test: Genetic testing; Diagnostic Test: Parameters for routine use of DMDs; Other: Side effects of orally used DMDs

Aubagio

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; Diagnostic Test: Genetic testing; Diagnostic Test: Parameters for routine use of DMDs; Other: Side effects of orally used DMDs

Interventions

Measurement of concentrations of orally-used DMDs DIAGNOSTIC_TEST

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.

Aubagio; Gilenya; Mavenclad; Tecfidera

Genetic testing DIAGNOSTIC_TEST

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.

Aubagio; Gilenya; Mavenclad; Tecfidera

Parameters for routine use of DMDs DIAGNOSTIC_TEST

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).

Aubagio; Gilenya; Mavenclad; Tecfidera

Side effects of orally used DMDs OTHER

For tolerability - possible side effects of orally used "DMDs" will be monitored and the effect of genetic testing of drug transporters will be analyzed.

Aubagio; Gilenya; Mavenclad; Tecfidera

Eligibility Criteria

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

Study Population

The study participants of all four study groups will be both patients with established treatment and patients who will be newly introduced to the "DMDs" medication.

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• University Hospital Ostrava: lead
• University of Ostrava: collaborator

Study Sites (2)

University of Ostrava

Ostrava, Moravian-Silesian Region, 70300, Czechia

Location

University Hospital Ostrava

Ostrava, Moravian-Silesian Region, 70852, Czechia

Location

Related Publications (18)

• Hunter SF. Overview and diagnosis of multiple sclerosis. Am J Manag Care. 2016 Jun;22(6 Suppl):s141-50.

  PMID: 27356023 BACKGROUND

• McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review. JAMA. 2021 Feb 23;325(8):765-779. doi: 10.1001/jama.2020.26858.

  PMID: 33620411 BACKGROUND

• Hocevar K, Ristic S, Peterlin B. Pharmacogenomics of Multiple Sclerosis: A Systematic Review. Front Neurol. 2019 Feb 26;10:134. doi: 10.3389/fneur.2019.00134. eCollection 2019.

  PMID: 30863357 BACKGROUND

• Grossman I, Knappertz V, Laifenfeld D, Ross C, Zeskind B, Kolitz S, Ladkani D, Hayardeny L, Loupe P, Laufer R, Hayden M. Pharmacogenomics strategies to optimize treatments for multiple sclerosis: Insights from clinical research. Prog Neurobiol. 2017 May;152:114-130. doi: 10.1016/j.pneurobio.2016.02.001. Epub 2016 Mar 4.

  PMID: 26952809 BACKGROUND

• Nicholas JA, Edwards NC, Edwards RA, Dellarole A, Grosso M, Phillips AL. Real-world adherence to, and persistence with, once- and twice-daily oral disease-modifying drugs in patients with multiple sclerosis: a systematic review and meta-analysis. BMC Neurol. 2020 Jul 14;20(1):281. doi: 10.1186/s12883-020-01830-0.

  PMID: 32664928 BACKGROUND

• Apostolopoulos V, Matsoukas J. Advances in Multiple Sclerosis Research-Series I. Brain Sci. 2020 Oct 29;10(11):795. doi: 10.3390/brainsci10110795.

  PMID: 33137992 BACKGROUND

• Jalkh G, Abi Nahed R, Macaron G, Rensel M. Safety of Newer Disease Modifying Therapies in Multiple Sclerosis. Vaccines (Basel). 2020 Dec 26;9(1):12. doi: 10.3390/vaccines9010012.

  PMID: 33375365 BACKGROUND

• Madden MC, Vender RL, Friedman M. Effect of hypoxia on prostacyclin production in cultured pulmonary artery endothelium. Prostaglandins. 1986 Jun;31(6):1049-62. doi: 10.1016/0090-6980(86)90208-x.

  PMID: 3094092 BACKGROUND

• Rotstein D, Montalban X. Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis. Nat Rev Neurol. 2019 May;15(5):287-300. doi: 10.1038/s41582-019-0170-8.

  PMID: 30940920 BACKGROUND

• Olsson A, Gustavsen S, Hasselbalch IC, Langkilde AR, Sellebjerg F, Oturai AB, Sondergaard HB. Biomarkers of inflammation and epithelial barrier function in multiple sclerosis. Mult Scler Relat Disord. 2020 Nov;46:102520. doi: 10.1016/j.msard.2020.102520. Epub 2020 Sep 19.

  PMID: 32980645 BACKGROUND

• Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mossner R, Muller MJ, Paulzen M, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G, Baumann P. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018 Jan;51(1-02):e1. doi: 10.1055/s-0037-1600991. Epub 2018 Feb 1. No abstract available.

  PMID: 29390205 BACKGROUND

• Hopkins AM, O'Doherty CE, Foster DJ, Upton RN, Proudman SM, Wiese MD. Individualization of leflunomide dosing in rheumatoid arthritis patients. Per Med. 2014 Jun;11(4):449-461. doi: 10.2217/pme.14.23.

  PMID: 29783485 BACKGROUND

• Zarzuelo Romero MJ, Perez Ramirez C, Carrasco Campos MI, Sanchez Martin A, Calleja Hernandez MA, Ramirez Tortosa MC, Jimenez Morales A. Therapeutic Value of Single Nucleotide Polymorphisms on the Efficacy of New Therapies in Patients with Multiple Sclerosis. J Pers Med. 2021 Apr 23;11(5):335. doi: 10.3390/jpm11050335.

  PMID: 33922540 BACKGROUND

• Yao X, Wu Y, Jiang J, Chen X, Liu D, Hu P. A population pharmacokinetic study to accelerate early phase clinical development for a novel drug, teriflunomide sodium, to treat systemic lupus erythematosus. Eur J Pharm Sci. 2019 Aug 1;136:104942. doi: 10.1016/j.ejps.2019.05.020. Epub 2019 May 30.

  PMID: 31154006 BACKGROUND

• Fewings NL, Gatt PN, McKay FC, Parnell GP, Schibeci SD, Edwards J, Basuki MA, Goldinger A, Fabis-Pedrini MJ, Kermode AG, Manrique CP, McCauley JL, Nickles D, Baranzini SE, Burke T, Vucic S, Stewart GJ, Booth DR. The autoimmune risk gene ZMIZ1 is a vitamin D responsive marker of a molecular phenotype of multiple sclerosis. J Autoimmun. 2017 Mar;78:57-69. doi: 10.1016/j.jaut.2016.12.006. Epub 2017 Jan 4.

  PMID: 28063629 BACKGROUND

• Carlstrom KE, Ewing E, Granqvist M, Gyllenberg A, Aeinehband S, Enoksson SL, Checa A, Badam TVS, Huang J, Gomez-Cabrero D, Gustafsson M, Al Nimer F, Wheelock CE, Kockum I, Olsson T, Jagodic M, Piehl F. Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes. Nat Commun. 2019 Jul 12;10(1):3081. doi: 10.1038/s41467-019-11139-3.

  PMID: 31300673 BACKGROUND

• Hermann R, Karlsson MO, Novakovic AM, Terranova N, Fluck M, Munafo A. The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis. Clin Pharmacokinet. 2019 Mar;58(3):283-297. doi: 10.1007/s40262-018-0695-9.

  PMID: 29987837 BACKGROUND

• Abdelhak A, Huss A, Stahmann A, Senel M, Krumbholz M, Kowarik MC, Havla J, Kumpfel T, Kleiter I, Wustinger I, Zettl UK, Schwartz M, Roesler R, Friede T, Ludolph AC, Ziemann U, Tumani H. Explorative study of emerging blood biomarkers in progressive multiple sclerosis (EmBioProMS): Design of a prospective observational multicentre pilot study. Contemp Clin Trials Commun. 2020 May 19;18:100574. doi: 10.1016/j.conctc.2020.100574. eCollection 2020 Jun.

  PMID: 32478196 BACKGROUND

Related Links

• The Atlas of Multiple Sclerosis

Biospecimen

Retention: SAMPLES WITH DNA

The only difference will be the collection of 2 extra tubes for each standard and routine collection from one pre-drug injection and 1 additional tube 2-3 hours after drug administration, either from a new injection or with an established cannula, for a maximum of 3 years (depending on the time of entry into the research project). 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.

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Genetic Testing

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Ivana Kacířová, Assoc. Prof.,MD,PhD

  University Hospital Ostrava

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jiří Hynčica

CONTACT

0042059737; jiri.hyncica@fno.cz

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2021
• First Posted: November 9, 2021
• Study Start: June 1, 2024
• Primary Completion: November 1, 2025
• Study Completion: May 1, 2026
• Last Updated: January 18, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

CZ (2)