A Pilot Study of Intermittent Calorie Restriction in Multiple Sclerosis

Study Overview
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Brief Summary
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Experimental studies of the experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, indicate that the number of calories fed to mice prevent EAE and are also associated with less severe disease in mice who do develop the disease. Currently, whether these results translate favorably in humans is unknown. This is a pilot trial of testing two caloric restriction (CR) diets versus a control diet in multiple sclerosis (MS) patients: one continuous caloric restriction (CR) diet where a small number of calories will be restricted every day or another intermittent CR diet where a caloric intake will be restricted more severely 2 days per week. Participants are randomized to one of the diets, and for the first 8 weeks, will receive standardized, prepared meals tailored to the specific diet. At the conclusion of the controlled feeding study, all participants will transition to an unblinded phase for an additional 40 weeks where they are provided with instructions to follow an intermittent CR diet.

Official Title
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A Pilot Study of Intermittent Calorie Restriction in Multiple Sclerosis

Conditions
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Relapsing Remitting Multiple Sclerosis

Intervention / Treatment
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* Other: Diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-50 Capable of storing food safely, willing to follow diet/eat provided food, and able to receive shipments at home or work Meets 2010 criteria for McDonald MS; Relapse or new lesion in previous 2 years Expanded disability status score (EDSS) < 6 Disease duration ≤15 years Untreated or on stable on first-line MS therapy [injectable] for at least 6 months, with no anticipated changes in the next 10 weeks Unchanged vitamin D dose or thyroid replacement dose (for those on it) with no anticipated changes or in supplement use for the next 10 weeks. Non-regular smoker (average no more than 1 cigarette/day) for at least 2 months Stable weight, by self report, for past 3 months (± 8 lbs) Body mass index (BMI) > 23 kg/m2 Exclusion Criteria: Pregnant or nursing, or unwilling to prevent pregnancy (if of childbearing to potential) History of gastrointestinal disease causing malabsorption History of diabetes requiring medication History of stage IV/V chronic kidney disease or vascular disease History of major surgery in past 3 months Current use of warfarin History of eating disorder Currently on a special diet for MS/other diet (provided diet will be pork free) Chemotherapy within the past year

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Continuous calorie restriction<br>Participants will be provided with a diet that includes approximately 78% of calories each day that would be needed to maintain current BMI. | Other: Diet<br>* Diet, standardized to the 50th percentile for macronutrients, will be provided at varied calorie levels as described.<br>|
| Experimental: Intermittent calorie restriction<br>Participants will be provided a diet that with a daily calorie intake required to maintain current BMI, except only 25% of this calorie intake will be provided for 2 days a week. | Other: Diet<br>* Diet, standardized to the 50th percentile for macronutrients, will be provided at varied calorie levels as described.<br>|
| Placebo Comparator: Control calorie intake<br>Participants will be assigned to consume enough calories each day required to maintain current BMI | Other: Diet<br>* Diet, standardized to the 50th percentile for macronutrients, will be provided at varied calorie levels as described.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Adverse events will be categorized by organ system and by the blinded neurologist's assessment of the relation to the diet. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adherence to Calories Assigned | Adherence will be assessed by comparing the total caloric intake provided to the patients through the assigned diet to the total energy intake determined by the research dieticians. | 8 weeks | 
| Adherence to Calories Assigned | Adherence during the advice-only phase will be compared to adherence in each diet group during the first 8 weeks using paired t-tests, where the grouping is done naturally by subject. | 48 weeks | 
| Adverse Events | Adverse events will be categorized by organ system and by the blinded neurologist's assessment of the relation to the diet. | 48 weeks | 
| Quality of Life Questionnaire | Functional Assessment in MS results will be assessed during the study | 48 weeks | 
| NIH Patient-Reported-Outcomes Measurement Information System (PROMIS )Fatigue Questionnaire | PROMIS Fatigue results will be assessed during the study | 48 weeks | 
| Change in metabolite ratios | The impact of each calorie restriction diet versus control diet on the metabolomics profile will be assessed. | 8 weeks | 
| Immune cell subsets/cytokines | The impact of each calorie restriction diet versus control diet on ratios of immune cell subsets (e.g. T-helper (TH)17, TH1, TH2, T regulatory) and related cytokines will be assessed. | 8 weeks | 
| Change in concentration of measures of metabolism | The impact of each calorie restriction diet versus control diet on fasting glucose, insulin, leptin, ghrelin, C-reactive protein, lipids, and long-chain ceramides will be assessed. | 8 weeks | 
| Change in serum lipid concentration | The impact of each calorie restriction diet versus control diet on fasting lipids and long-chain ceramides will be assessed. | 8 weeks | 
| Change in serum brain-derived neurotrophic factor concentration (BDNF) | The impact of each calorie restriction diet versus control diet on fasting BDNF will be assessed. | 8 weeks | 
| Change in levels of oxidative stress biomarkers | The impact of each calorie restriction diet versus control diet on protein carbonyls, 8-isoprostane, nitrotyrosine, and 4-hydroxynonenal adducts will be assessed. | 8 weeks |