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| Name | Class |
|---|---|
| Shiraz University of Medical Sciences | OTHER |
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This study evaluates the effect of adding fish oil to Fingolimod on some serum cytokines in patients with Relapsing-Remitting Multiple Sclerosis.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Fingolimod and Fish Oil | Experimental | Fingolimod 0.5 mg capsule daily by mouth and Fish Oil 1 g capsule daily by mouth for one year. |
|
| Fingolimod and Placebo | Active Comparator | Fingolimod 0.5 mg capsule daily by mouth and Placebo capsule daily by mouth for one year. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fingolimod | Drug | Produced by Osveh ® Pharm Company in Iran |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline |
| 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. | Baseline |
| 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. | Baseline |
| 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. | Baseline |
| Serum Level of TNF-α |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Shaygannejad Shaygannejad, M.D. | Isfahan University of Medical Sciences | Study Chair |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20551946 | Background | Aktas O, Kury P, Kieseier B, Hartung HP. Fingolimod is a potential novel therapy for multiple sclerosis. Nat Rev Neurol. 2010 Jul;6(7):373-82. doi: 10.1038/nrneurol.2010.76. Epub 2010 Jun 15. | |
| 21031003 | Background | Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010 Nov;9(11):883-97. doi: 10.1038/nrd3248. Epub 2010 Oct 29. |
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The investigators may make individual participant data available regarding drug side effects or other factors that need to be described individually however the primary outcome will be published as group result and not individual results.
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After recruitment, no medication was prescribed for the patients for two months as the wash-out period. Then patients were assigned to study groups.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
We used a per-protocol analysis approach.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Fingolimod and Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Per-protocol analysis | Posted | Mean | Standard Deviation | Pg/ml | Baseline |
|
Patients were evaluated in the study for one year and were observed for adverse events during this period.
Adverse events were collected through follow up phone calls and visits.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypotension and bradycardia | Cardiac disorders | Serious | Systematic Assessment | Adverse effects stopped after medication discontinuation in all cases. |
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Small sample size and trial duration; Not giving patients specific nutritional diets; Receiving tocopherol in the placebo capsules which may confound our findings considering the antioxidant nature of tocopherol; Lower doses of fish oil prescribed.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Vahid Shaygannejad | Isfahan University of Medical Sciences | +98 913 313 3550 | shaygannejad@med.mui.ac.ir |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| D000068876 | Fingolimod Hydrochloride |
| D005395 | Fish Oils |
| ID | Term |
|---|---|
| D013110 | Sphingosine |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 | Organic Chemicals |
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| Fish Oil | Dietary Supplement | produced by Zahravi ® Pharm Company in Iran |
|
|
| Placebo (for Fish Oil) | Drug | placebo capsules to mimic Fish Oil 1 g capsules |
|
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. |
| 6 months after intervention |
| 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. | 1 year after intervention |
| 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. | 6 months after intervention |
| 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. | 1 year after intervention |
| 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. | 6 months after intervention |
| 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. | 1 year after intervention |
| 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. | 6 months after intervention |
| 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. | 1 year after intervention |
| 7860710 | Background | Gallai V, Sarchielli P, Trequattrini A, Franceschini M, Floridi A, Firenze C, Alberti A, Di Benedetto D, Stragliotto E. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol. 1995 Feb;56(2):143-53. doi: 10.1016/0165-5728(94)00140-j. |
| 20089952 | Background | Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P; FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):387-401. doi: 10.1056/NEJMoa0909494. Epub 2010 Jan 20. |
| 10987373 | Background | Nordvik I, Myhr KM, Nyland H, Bjerve KS. Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol Scand. 2000 Sep;102(3):143-9. doi: 10.1034/j.1600-0404.2000.102003143.x. |
| 23861993 | Background | Ramirez-Ramirez V, Macias-Islas MA, Ortiz GG, Pacheco-Moises F, Torres-Sanchez ED, Sorto-Gomez TE, Cruz-Ramos JA, Orozco-Avina G, Celis de la Rosa AJ. Efficacy of fish oil on serum of TNF alpha , IL-1 beta , and IL-6 oxidative stress markers in multiple sclerosis treated with interferon beta-1b. Oxid Med Cell Longev. 2013;2013:709493. doi: 10.1155/2013/709493. Epub 2013 Jun 18. |
| 22507886 | Background | Torkildsen O, Wergeland S, Bakke S, Beiske AG, Bjerve KS, Hovdal H, Midgard R, Lilleas F, Pedersen T, Bjornara B, Dalene F, Kleveland G, Schepel J, Olsen IC, Myhr KM. omega-3 fatty acid treatment in multiple sclerosis (OFAMS Study): a randomized, double-blind, placebo-controlled trial. Arch Neurol. 2012 Aug;69(8):1044-51. doi: 10.1001/archneurol.2012.283. |
| Protocol Violation |
|
| Withdrawal by Subject |
|
| relapse during the study |
|
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 |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
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| Dietary habits, Categorical (seafood meals per month) | Count of Participants | Participants |
|
| EDSS | Expanded disability status scale (EDSS) is a measure of disability for patients. The score ranges from 0-10, with 0 showing normal neurological exam and 10 showing death due to the disabling disease. Thus, higher scores represent more profound levels of disability. | Mean | Standard Deviation | units on a scale |
|
| OG001 |
| 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 |
|
|
| 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. | Posted | Mean | Standard Deviation | Pg/ml | Baseline |
|
|
|
| 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. | Posted | Mean | Standard Deviation | Pg/ml | Baseline |
|
|
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | Baseline |
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|
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 6 months after intervention |
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|
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 1 year after intervention |
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 6 months after intervention |
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 1 year after intervention |
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 6 months after intervention |
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|
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 1 year after intervention |
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 6 months after intervention |
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| 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. | Posted | Mean | Standard Deviation | Pg/ml | 1 year after intervention |
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|
|
| 0 |
| 25 |
| 2 |
| 25 |
| 0 |
| 25 |
| EG001 | 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 | 0 | 25 | 2 | 25 | 0 | 25 |
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| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D011409 |
| Propylene Glycols |
| D006018 | Glycols |
| D000588 | Amines |
| D009821 | Oils |
| D008055 | Lipids |
| >4 meals per month |
|