Multiple Sclerosis, Relapsing-Remitting Clinical Trial
— Calorie-MSOfficial title:
Calorie Restriction as a Novel Therapeutic Tool to Manipulate Immunity and Improve Therapeutic Potential of First Line Drug Treatments During Relapsing Remitting Multiple Sclerosis
There is a strong relationship between metabolic state and immune tolerance through a direct control exerted on immune cells by specific intracellular nutrient-energy sensors. An increased "metabolic work load" represents a novel issue linking metabolism with loss of self-immune tolerance. Several disease-modifying drugs have been approved for Relapsing-remitting Multiple Sclerosis (RR-MS) treatments and have shown to reduce relapse rates by modulating immune responses; however, their impact on long-term disease progression and accrual of irreversible neurological disability remains largely unclear, underlining the need for novel therapeutic strategies. In this context, both acute fasting (AF) and chronic caloric restriction (CR) have been shown to improve experimental autoimmune encephalomyelitis (EAE). Despite this evidence, no specific studies have been performed to dissect at the cellular level the mechanism of action of CR in the context of autoimmunity and MS. This study aims at investigating this specific point in order to pave the way for a wider utilization of a nutritional approach to alter MS progression and activity. The aim of this study is to improve the outcome of RR-MS and the efficacy of first line drug treatments (ie. Copaxone or Tecfidera) by altering the metabolic state of the host via calorie restriction with the aim to re-equilibrate immune/inflammatory responses of patients.
Status | Recruiting |
Enrollment | 120 |
Est. completion date | September 2023 |
Est. primary completion date | September 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 60 Years |
Eligibility | Inclusion Criteria: - Subjects with early diagnosis (no more than 2 years) of RR-MS according to the revised McDonald (2017) criteria; - Subjects naïve-to-treatment; - Subjects with EDSS between 0-5.5; - No use of oral or systemic corticosteroids or adrenocorticotropic hormone (ACTH) within 30 days prior to screening visit; - Subjects with BMI > 22 kg/m2 and BMI < 28 kg/m2; - Willing to collect a food diary for one week and to donate a blood and stool samples; - No antibiotic treatment within 3 months of enrolment; - No immunosuppressive therapy; - Signed informed consent. Exclusion Criteria: - Pregnancy and breast-feeding; - History of alcohol or drug abuse; - Serious psychiatric disorders; - Any major medical problem that in the opinion of the investigator could bias the results (e.g. HIV infection) or affect adherence to the protocol; - Subjects with inadequate haematological function (defined by leukocyte = 2,0 x 109; platelets <100 x 109; haemoglobin <12 g/dl for female and <13 g/dl for male), liver function (defined by aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase > 2.0 times upper limit of normal), thyroid function (according to physician's discretion); - Known hypersensitivity to gadolinium; - Any other condition that would prevent the subject from undergoing a contrast-enhanced MRI scan; - Any contra-indication according to the specific first line treatment for MS. |
Country | Name | City | State |
---|---|---|---|
Italy | Neuromed - Istituto Neurologico Mediterraneo Pozzilli | Pozzilli | IS |
Lead Sponsor | Collaborator |
---|---|
Federico II University | Fondazione Italiana Sclerosi Multipla |
Italy,
De Rosa V, La Cava A, Matarese G. Metabolic pressure and the breach of immunological self-tolerance. Nat Immunol. 2017 Oct 18;18(11):1190-1196. doi: 10.1038/ni.3851. — View Citation
De Rosa V, Procaccini C, La Cava A, Chieffi P, Nicoletti GF, Fontana S, Zappacosta S, Matarese G. Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis. J Clin Invest. 2006 Feb;116(2):447-55. Epub 2006 Jan — View Citation
Matarese G, Carrieri PB, La Cava A, Perna F, Sanna V, De Rosa V, Aufiero D, Fontana S, Zappacosta S. Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells. Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5150- — View Citation
Sanna V, Di Giacomo A, La Cava A, Lechler RI, Fontana S, Zappacosta S, Matarese G. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest. 2003 Jan;111(2):241-50. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change of the "no evident disease activity" (NEDA) from baseline clinical status of MS patients at 6, 12, and 24 months | Evaluation of the "no evident disease activity" (NEDA) defined thanks to the evaluation of three components: (i) absence of confirmed disability progression (CDP), (ii) absence of relapses and (iii) absence of radiological activity before and after starting caloric restricted diet. | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention | |
Secondary | Percentage of different immune cells populations (circulating immune cells, regulatory T cells, conventional T cells, etc.) | Evaluation of the percentage of different subclasses of circulating immune cells in the blood of patients | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention | |
Secondary | Mitotic cell divisions of conventional T cells | Evaluation of the amount of conventional T cell divisions in the presence or absence of regulatory T cells through evaluation of 3H-thymidine incorporation into new strands of chromosomal DNA | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention | |
Secondary | Glycolytic metabolism of T cells (mpH/min) | Evaluation of Glycolysis (mpH/min) through measurement of Extracellular Acidification Rate (ECAR) of circulating T cell populations | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention | |
Secondary | Oxidative metabolism of T cells (pMol/min) | Evaluation of oxidative phosphorylation (pMol/min) through measurement of Oxygen Consumption Rate (OCR) of circulating T cell populations | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention | |
Secondary | Circulating adipokines (pg/ml) | Evaluation of the serum/plasma concentration (pg/ml) of circulating adipokines (Leptin, adiponectin, etc...) | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention | |
Secondary | Change in the expression level of molecules involved in the signalling pathway of T-cell receptor (TCR) | Analysis of molecules involved in the signalling pathway after T-cell receptor (TCR) stimulation (ERK-mTOR-p27kip1 etc); | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention | |
Secondary | Change in the composition of the gut microbiota | Evaluation of the components of the gut microbiota before and after starting caloric restricted diet. | T0: before intervention, T1: after 6 months of intervention, T2: after 12 months of intervention, T3: after 24 months of intervention |
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