Pharmacogenetics of Liver Toxicity in Patients With Multiple Sclerosis Treated With Fingolimod

Study Overview
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Brief Summary
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To investigate whether polymorphic differences can be identified between Multiple Sclerosis patients developing elevated liver enzymes (defined as ALT, AST, GGT or bilirubinemia levels five above the upper normal limit on at least one) compared to those not developing elevated liver enzymes after exposure to fingolimod for multiple sclerosis.

Detailed Description
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PURPOSE: To investigate whether polymorphic differences can be identified between Multiple sclerosis (MS) patients treated by fingolimod who had liver enzymes elevation compared to those who do not. OBJECTIVE: To determine whether elevated liver enzyme tests (ALT, AST, GGT or bilirubinemia above the upper limit of normal) in MS patients treated with fingolimod is associated with genetic polymorphisms. METHOD OF RECRUITMENT: Patients will be identified through a clinic database and chart reviews. A phone call will be made to determine interest. Upon a follow-up neurological consultation, consent into study will be sought. PROCEDURES: Blood samples will be collected for genetic analyses, fingolimod and fingolimod-phosphate quantification and a questionnaire will be administered

Official Title
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Pharmacogenetic Investigation of Susceptibility to Liver Toxicity in Patients With Multiple Sclerosis Treated With Fingolimod

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Genetic: Genetic polymorphism
* Diagnostic Test: Measurement of fingolimod and fingolimod-phosphate concentrations


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (> 18 years) Have a definite Multiple Sclerosis with a relapsing-remitting course (McDonald criteria) Treated with fingolimod Have given consent and signed an informed consent form Exclusion Criteria: an elevated liver test result on baseline before starting fingolimod treatment presence of a viral, hereditary or auto-immune liver pathology Time of fingolimod exposure lower than three months Woman currently pregnant or breastfeeding

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 |
| --- | --- |
| Case<br>MS patients treated with fingolimod who experienced liver enzymes elevation | Genetic: Genetic polymorphism<br>* One blood tube will be taken for genetic testing<br>Diagnostic Test: Measurement of fingolimod and fingolimod-phosphate concentrations<br>* Measurement of fingolimod and fingolimod-phosphate concentrations before usual drug administration time<br>|
| Control<br>MS patients treated with fingolimod not experiencing elevated liver enzymes | Genetic: Genetic polymorphism<br>* One blood tube will be taken for genetic testing<br>Diagnostic Test: Measurement of fingolimod and fingolimod-phosphate concentrations<br>* Measurement of fingolimod and fingolimod-phosphate concentrations before usual drug administration time<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CYP4F2 polymorphism frequency in case and control groups | Proportion of CYP4F2 polymorphism in case and control groups | At inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fingolimod concentrations in case and control groups | Trough concentration of fingolimod in blood samples determined by liquid chromatography-tandem mass spectrometry (LC-MS) | At inclusion | 
| Fingolimod-phosphate concentrations in case and control groups | Trough concentration of fingolimod-phosphate in blood samples determined by liquid chromatography-tandem mass spectrometry (LC-MS) | At inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fingolimod, hepatic adverse events, polymorphism