Brain Volume Loss, Cognition
Conditions
Keywords
RRMS,, Cognition,, brain,, Fingolimod,, Multiple Sclerosis,, neurodegeneration,, Brain atrophy,, gray matter atrophy,, thalamic atrophy,, biomarkers,, BICAMS Battery,
Brief summary
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.
Interventions
DRUG0,5 mg Fingolimod
0.5 mg p.o fingolimod daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Diagnosed with RRMS as described in 2010 McDonald criteria (36) 2. Provided written informed consent prior to any intervention 3. 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) 4. 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: 1. Corticosteroids or adrenocorticotropic hormone (ACTH) during the last 1 month 2. Immunosuppressive medications such as azathioprine or methotrexate etc. 3. Immunoglobulin treatment during the last 3 months 4. Cladribine, cyclophosphamide, mitoxantrone, natalizumab at any time
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 12 Months | baseline , month 12. | 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). |
| Change From Baseline in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Battery Test at 24 Months | baseline and month 24 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Brain Gray Matter Atrophy and Thalamic Atrophy | baseline, month 6, month 12, month 18 and month 24 | 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. |
| Change From Baseline in PASAT Test | baseline ,months 6, month 12 and month 24 | 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. |
| the Correlation Between Effect of Fingolimod on Cognitive Performances and Brain Atrophy (Gray Matter Atrophy and Thalamic Atrophy) by Comparing Baseline and Month 24. | baseline, month 24 | Correlation between effect of fingolimod on cognitive performances based on cognitive tests and brain atrophy based on MRI assessments will be explored. |
| Change From Baseline in Serum Levels of 24S-hydroxycholesterol (24OHC) , Osteopontin and Matrix Metalloproteinases (and Also MMPI's) | baseline, month 6, month , month 12 and month 24 | 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). |
| Change From Baseline in Stroop Test | baseline, month 6, month 12 and month 24 | The Stroop Color and Word Test assesses cognitive processing and provides valuable diagnostic information on brain dysfunction, cognition, and psychopathology |
Countries
Turkey (Türkiye)
Participant flow
Recruitment details
It was planned to recruit 80 patients. By the end of the first year, 4 patients have been recruited and the study was stopped due to low enrollment and study results were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod Arm 0.5 mg p.o fingolimod daily | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 4 |
Baseline characteristics
| Characteristic | Fingolimod Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Race/Ethnicity, Customized | 4 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 1 / 4 |
| serious Total, serious adverse events | 0 / 4 |
Outcome results
Primary
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).
Time frame: baseline , month 12.
Population: The trial terminated early because there were only 4 patients who enrolled and only baseline visit was conducted.
Primary
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).
Time frame: baseline and month 24
Population: The trial terminated early because there were only 4 patients who enrolled and only baseline visit was conducted.
Secondary
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.
Time frame: baseline, month 6, month 12, month 18 and month 24
Population: The trial terminated early because there were only 4 patients who enrolled and only baseline visit was conducted.
Secondary
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.
Time frame: baseline ,months 6, month 12 and month 24
Population: The trial terminated early because there were only 4 patients who enrolled and only baseline visit was conducted.
Secondary
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).
Time frame: baseline, month 6, month , month 12 and month 24
Population: The trial terminated early because there were only 4 patients who enrolled and only baseline visit was conducted.
Secondary
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
Time frame: baseline, month 6, month 12 and month 24
Population: The trial terminated early because there were only 4 patients who enrolled and only baseline visit was conducted.
Secondary
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.
Time frame: baseline, month 24
Population: The trial terminated early because there were only 4 patients who enrolled and only baseline visit was conducted.