Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis, Fingolimod, Fish Oil
Brief summary
This study evaluates the effect of adding fish oil to Fingolimod on some serum cytokines in patients with Relapsing-Remitting Multiple Sclerosis.
Detailed description
Multiple Sclerosis (MS) is a chronic autoimmune disease characterized by inflammatory demyelinative lesions in central nervous system. Relapsing-Remitting MS is the most common form of the disease observed in 85% of patients. This form presents with acute or sub-acute onset of neurological symptoms and patients may fully or partially recover and relapses may occur from time to time. Regarding MS pathogenesis, the findings suggest the role of environmental factors in triggering the innate immune system and activating T cells and the onset of a chronic inflammatory response against myelin antigens in the central nervous system in people who are genetically prone to the disease. Among immune cells, T helper 17 (Th17) plays an important role in autoimmune response and are shown to be involved in clinical course of Relapsing-Remitting MS. Th17 cell differentiation is controlled by several cytokines, including interleukin-6 (IL-6), interleukin-1b (IL-1b) and interleukin-10 (IL-10). Also, IL 6 have an inhibitory effect on Th17 cell differentiation through increased production of interferon-gamma (IFN-gamma) and IL 10. Currently, immunomodulatory drugs are considered as the first line treatment in MS. Fingolimod is the first oral immunomodulatory medication used for Relapsing-Remitting MS. It is phosphorylated by crossing the blood-brain barrier and is converted to its active metabolite, Fingolimod-P. This metabolite acts as a Sphingosine-1-phosphate receptor (S1PR1) on oligodendrocytes, microglias, astrocytes, and neurons and inhibits the entry of lymphocytes into the central nervous system. Therefore, it reduces demyelination and may also lead to remyelination. Nutrition is known as a possible environmental factor in pathogenesis of MS. Positive clinical and biological effects of dietary supplements containing polyunsaturated fatty acids omega -3 (PUFA) in the course of autoimmune diseases such as MS have been studied. High levels of PUFA is found in fish oil which is also known as an antioxidant, anti-inflammatory and immunomodulatory agent. Several studies have evaluated the effect of fish oil as a dietary supplement in the treatment of MS however, conflicting findings are reported. In this study, the investigators aim to evaluate the effect of Fingolimod with Fish oil compared to Fingolimod with placebo on TNF-α, IL1b, IL6, and IFN-gamma in patients with Relapsing-Remitting Multiple sclerosis.
Interventions
DRUGFingolimod
Produced by Osveh ® Pharm Company in Iran
DIETARY_SUPPLEMENTFish Oil
produced by Zahravi ® Pharm Company in Iran
DRUGPlacebo (for Fish Oil)
placebo capsules to mimic Fish Oil 1 g capsules
Sponsors
Shiraz University of Medical Sciences
Isfahan University of Medical Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Patients with relapsing-remitting multiple sclerosis according to McDonald's criteria (2010) * Age between 18 and 45 years * Expanded Disability Status Scale (EDSS) between 0-5 * History of at least one relapse during the last year * Intolerance or serious complications when receiving interferons * Not receiving interferons in the last two months * Not having relapse in the last 30 days * Negative pregnancy test * History of varicella or varicella vaccination, or positive test for anti-varicella antibodies * Not to take any medication or dietary complement without permission of the physician * Filling informed consent
Exclusion criteria
* Having chronic and infectious diseases * History of cardiovascular diseases * Taking corticosteroids in the last 30 days * Taking chemotherapy agents such as Cyclophosphamide * Patients who have taken fingolimod before * Patients who experience relapse during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Level of TNF-α | Baseline | 5 cc of venous blood is taken from patients and are kept in test tubes without ethylenediaminetetraacetic acid (EDTA). Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions. |
| Serum Level of IL1b | Baseline | 5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions. |
| Serum Level of IL6 | Baseline | 5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions. |
| Serum Level of IFN-gamma | Baseline | 5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions. |
Participant flow
Recruitment details
The recruitment period started on April 2015. 74 patients were screened initially and 50 of them were recruited. All the patients were recruited from the neurology department of Kashani hospital, Isfahan, iran. They were patients referred to the neurology department (multiple sclerosis clinic) for evaluation and treatment.
Pre-assignment details
After recruitment, no medication was prescribed for the patients for two months as the wash-out period. Then patients were assigned to study groups.
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod and Fish Oil Fingolimod 0.5 mg capsule daily by mouth and Fish Oil 1 g capsule daily by mouth for one year.
Fingolimod: Produced by Osveh ® Pharm Company in Iran
Fish Oil: produced by Zahravi ® Pharm Company in Iran | 21 |
| Fingolimod and Placebo Fingolimod 0.5 mg capsule daily by mouth and Placebo capsule daily by mouth for one year.
Fingolimod: Produced by Osveh ® Pharm Company in Iran
Placebo (for Fish Oil): placebo capsules to mimic Fish Oil 1 g capsules | 20 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | relapse during the study | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Fingolimod and Fish Oil | Fingolimod and Placebo | Total |
|---|---|---|---|
| Age, Continuous | 35.19 years STANDARD_DEVIATION 9.97 | 31.40 years STANDARD_DEVIATION 8.41 | 33.34 years STANDARD_DEVIATION 9.21 |
| Dietary habits, Categorical (seafood meals per month) 0-1 meals per month | 19 Participants | 18 Participants | 37 Participants |
| Dietary habits, Categorical (seafood meals per month) 2-4 meals per month | 2 Participants | 2 Participants | 4 Participants |
| Dietary habits, Categorical (seafood meals per month) >4 meals per month | 0 Participants | 0 Participants | 0 Participants |
| EDSS | 3.10 units on a scale STANDARD_DEVIATION 1.28 | 2.55 units on a scale STANDARD_DEVIATION 1.38 | 2.83 units on a scale STANDARD_DEVIATION 1.33 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Iran | 21 participants | 20 participants | 41 participants |
| Sex: Female, Male Female | 13 Participants | 16 Participants | 29 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 0 / 25 | 0 / 25 |
| serious Total, serious adverse events | 2 / 25 | 2 / 25 |
Outcome results
Primary
Serum Level of IFN-gamma
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IFN-gamma | 6.38 Pg/ml | Standard Deviation 1.51 |
| Fingolimod and Placebo | Serum Level of IFN-gamma | 6.98 Pg/ml | Standard Deviation 3.87 |
Primary
Serum Level of IFN-gamma
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 6 months after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IFN-gamma | 5.71 Pg/ml | Standard Deviation 0.57 |
| Fingolimod and Placebo | Serum Level of IFN-gamma | 6.37 Pg/ml | Standard Deviation 1.77 |
Primary
Serum Level of IFN-gamma
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 1 year after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IFN-gamma | 5.92 Pg/ml | Standard Deviation 1.31 |
| Fingolimod and Placebo | Serum Level of IFN-gamma | 5.99 Pg/ml | Standard Deviation 0.84 |
Primary
Serum Level of IL1b
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 6 months after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IL1b | 13.61 Pg/ml | Standard Deviation 0.58 |
| Fingolimod and Placebo | Serum Level of IL1b | 13.47 Pg/ml | Standard Deviation 0.74 |
Primary
Serum Level of IL1b
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IL1b | 13.76 Pg/ml | Standard Deviation 0.74 |
| Fingolimod and Placebo | Serum Level of IL1b | 14 Pg/ml | Standard Deviation 1.03 |
Primary
Serum Level of IL1b
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 1 year after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IL1b | 13.17 Pg/ml | Standard Deviation 0.52 |
| Fingolimod and Placebo | Serum Level of IL1b | 13.15 Pg/ml | Standard Deviation 0.61 |
Primary
Serum Level of IL6
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IL6 | 6.19 Pg/ml | Standard Deviation 0.35 |
| Fingolimod and Placebo | Serum Level of IL6 | 6.33 Pg/ml | Standard Deviation 0.58 |
Primary
Serum Level of IL6
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 6 months after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IL6 | 6.65 Pg/ml | Standard Deviation 2.11 |
| Fingolimod and Placebo | Serum Level of IL6 | 6.17 Pg/ml | Standard Deviation 0.71 |
Primary
Serum Level of IL6
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 1 year after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of IL6 | 6.17 Pg/ml | Standard Deviation 0.76 |
| Fingolimod and Placebo | Serum Level of IL6 | 6.05 Pg/ml | Standard Deviation 0.47 |
Primary
Serum Level of TNF-α
5 cc of venous blood is taken from patients and are kept in test tubes without ethylenediaminetetraacetic acid (EDTA). Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: Baseline
Population: Per-protocol analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of TNF-α | 37.16 Pg/ml | Standard Deviation 92.74 |
| Fingolimod and Placebo | Serum Level of TNF-α | 28.79 Pg/ml | Standard Deviation 47.46 |
Primary
Serum Level of TNF-α
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 6 months after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of TNF-α | 28.03 Pg/ml | Standard Deviation 60.36 |
| Fingolimod and Placebo | Serum Level of TNF-α | 17.18 Pg/ml | Standard Deviation 18.88 |
Primary
Serum Level of TNF-α
5 cc of venous blood is taken from patients and are kept in test tubes without EDTA. Test tubes are kept one hour immobilized so that clotted blood and serum are separated. Then, the serum is divided into four samples of 0.5 cc for immunologic testing of all primary outcomes. Immunologic testing is performed by sandwich ELISA method using Diaclone ® kits (made in France) and according to manufacturer's instructions.
Time frame: 1 year after intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fingolimod and Fish Oil | Serum Level of TNF-α | 21.20 Pg/ml | Standard Deviation 36.45 |
| Fingolimod and Placebo | Serum Level of TNF-α | 16.47 Pg/ml | Standard Deviation 16.64 |