Effect of Fingolimod on Neurodegeneration

Study Overview
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Brief Summary
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This was a 24-month, open-label, multicenter study with a single treatment arm design. Primary objective of this study was: -To investigate the effects of Fingolimod on cognitive performance in highly active relapsing remitting multiple sclerosis patients Secondary objectives of this study were: To investigate the correlation between the effect of fingolimod on cognitive performances and MRI data. To evaluate the effect of fingolimod on biomarkers (24 hydroxy cholesterol, osteopontin and matrix metalloproteinases) related to neurodegeneration To investigate the effect of fingolimod on brain gray matter atrophy and thalamic atrophy. Polulation The hope was to recruit a minimum of 80 relapsing remitting MS (RRMS) patients according to the McDonald criteria.

Official Title
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Effect of Fingolimod on Neurodegeneration, Brain Atrophy and Cognitive Impairment in Relapsing Remitting Multiple Sclerosis Patients

Conditions
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Cognition, Brain Volume Loss

Intervention / Treatment
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* Drug: 0,5 mg Fingolimod


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with RRMS as described in 2010 McDonald criteria (36) Provided written informed consent prior to any intervention Unresponsive to treatment with a beta interferon or glatiramer acetate for a minimum of one year at and at adequate dose and with high disease activity . (Unresponsive patients: patients with no changes in relapses, increased relapses, severer relapses with one-year treatment or those who had had at least one relapse during the past one year under previous treatments and one or multiple contrast enhancing lesions in cranial MRI or increased T2 lesions in successive MRIs) EDSS score below 5.5 at screening Exclusion Criteria: 1. Patients with primary or secondary progressive or progressive relapsing MS. 2. Patients with known contraindications for fingolimod treatment. 3. Other coexistent autoimmune diseases including Hashimoto thyroiditis, systemic lupus erythematosus, rheumatoid anthiritis, psoriasis etc. 4. Patients with any of the following cardiovascular conditions: Resting heart rate < 45 bpm/min Cardiac failure at any time during the first study visit (Class III as per NYHA classification) or significant heart disease as judged by the physician Myocardial infarction during the last 6 months History of Mobitz Type II grade 2 AV block Past or current grade 3 AV block Confirmed history of sick sinus syndrome or sino-atrial heart block arrhythmia requiring current treatment with Class Ia drugs (ajmaline, disopyramid, procainamide, quinidine) hypertension uncontrolled with medication 5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. 6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, detected by urinalysis and confirmed by a positive hCG laboratory test. 7. Negative for varicella-zoster virus IgG antibodies at screening. Patients who have negative results for varicella-zoster virus IgG antibodies can be included in the study after vaccination for varicella-zoster virus. 8. Active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, Hepatitis B, Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests, respectively 9. History of previous fingolimod therapy 10. Patient who received any of the treatments below: Corticosteroids or adrenocorticotropic hormone (ACTH) during the last 1 month Immunosuppressive medications such as azathioprine or methotrexate etc. Immunoglobulin treatment during the last 3 months Cladribine, cyclophosphamide, mitoxantrone, natalizumab at any time

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fingolimod arm<br>0.5 mg p.o fingolimod daily | Drug: 0,5 mg Fingolimod<br>* 0.5 mg p.o fingolimod daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 12 Months | The Brief International Cognitive Assessment for MS ( BICAMS Battery ) includes 3 cognitive tests, 1-Symbol Digit Modalities Test (SDMT, 2-the second edition of the California Verbal Learning Test (CVLT2) and 3-the revised Brief Visuospatial Memory Test (BVMTR). | baseline , month 12. | 
| Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 24 Months | The Brief International Cognitive Assessment for MS (BICAMS Battery) includes 3 cognitive tests, 1-Symbol Digit Modalities Test (SDMT, 2-the second edition of the California Verbal Learning Test (CVLT2) and 3-the revised Brief Visuospatial Memory Test (BVMTR). | baseline and month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in PASAT Test | The Paced Auditory Serial Addition Test (PASAT) has been widely used in MS trials and it is considered to be a measure of sustained attention, divided attention, concentration, and information processing speed. | baseline ,months 6, month 12 and month 24 | 
| Change From Baseline in Stroop Test | The Stroop Color and Word Test assesses cognitive processing and provides valuable diagnostic information on brain dysfunction, cognition, and psychopathology | baseline, month 6, month 12 and month 24 | 
| Change From Baseline in Brain Gray Matter Atrophy and Thalamic Atrophy | MRI scans will be obtained by using 1,5T MRI for measuring gray matter atrophy and thalamic atrophy and a standard scanning protocol will be used for MRI in all centers. | baseline, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in Serum Levels of 24S-hydroxycholesterol (24OHC) , Osteopontin and Matrix Metalloproteinases (and Also MMPI's) | Serum samples will be collected at baseline and at months 6, 12 and 24 from each participant after evaluation for inclusion and exclusion criteria for measurement of 24 hydroxy cholesterol, osteopontin and matrix metalloproteinases (including MMPI's). | baseline, month 6, month , month 12 and month 24 | 
| the Correlation Between Effect of Fingolimod on Cognitive Performances and Brain Atrophy (Gray Matter Atrophy and Thalamic Atrophy) by Comparing Baseline and Month 24. | Correlation between effect of fingolimod on cognitive performances based on cognitive tests and brain atrophy based on MRI assessments will be explored. | baseline, month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RRMS,, Cognition,, brain,, Fingolimod,, Multiple Sclerosis,, neurodegeneration,, Brain atrophy,, gray matter atrophy,, thalamic atrophy,, biomarkers,, BICAMS Battery,