Multiple Sclerosis Clinical Trial
Official title:
A Pilot Study of Adipokines and Calorie Restriction in Multiple Sclerosis Patients
The investigators hypothesize that adipokine (soluble molecules produced by the adipose
tissue) levels are altered in MS compared to control subjects. Additionally, the
investigators hypothesize that calorie restriction (CR) will improve clinical recovery from
an MS relapse, ameliorate the adipokine and metabolic-inflammatory profile in MS, and enhance
immune-regulatory mechanisms.
This is a pilot study to determine the effects of CR in MS patients during an acute MS
relapse (Acute CR phase) and for 6 months afterwards (Chronic CR phase). Calorie restriction
will be achieved by following a regimen of alternate day fasting. The investigators will
evaluate clinical outcomes and blood biomarkers at different time points.
The goal of this study is to determine the effects of CR on blood biomarkers (including serum
levels of adipokines, cytokines, cortisol and T reg numbers) compared to standard therapies
in MS patients during recovery from a relapse. Sixteen MS patients (body mass index-BMI ≥ 23)
having an attack will be enrolled and randomized to either:
1. steroid treatment (10 days) which is standard therapy for MS relapses; or
2. CR plus steroid treatment (10 days). Calorie restriction will be achieved by following a
regimen of alternate day fasting (during the day of fasting the subject will be allowed
to eat two salads with olive oil and lemon juice or vinegar). Briefly, the subjects will
fast on day 1 (first day of steroids) and then continue to fast on alternate days until
day 15, another fasting day. After 15 days of alternate day fasting, both groups will be
offered to enroll in the intermittent fasting regimen for 6 months (with salads allowed
on the fasting day) (chronic CR phase). Specifically, patients with a BMI <28 will
follow a regimen of fasting for two days per week while patients with BMI>28 will follow
a regimen of fasting for three days per week. Blood samples will be obtained and
analyzed at specified points during the study for routine testing (CBC and CMP) and
immune/inflammatory analyses. Specifically, a blood sample will be obtained at baseline
(day 1, before starting steroids) and after 15 days on alternate fasting. For those
patients that will be enrolled in the chronic CR study for six months blood samples will
also be obtained at month 3 and 6. MS subjects will be evaluated on day 15 after
initiation of steroids. Those subjects that will participate in the chronic CR study
will also donate blood at months 3 and 6. If patients are taking an immunomodulatory
medication for MS, they will continue during the entire trial. They will be followed and
assessed during the study by a nutritionist experienced with human CR. Patients will be
seen by the nutritionist at baseline, day 15 for the first portion of the study. At the
baseline visit they will be instructed to fast on day 1 and then every other day. During
the fasting days, patients are allowed to eat a salad with 2 Table spoons of olive oil
or canola oil plus vinegar or lemon juice twice/day. The goal is to eat less than 500
calories on fasting days. The nutritionist will also educate the patient to consume a
nutritionally adequate diet during non-fasting days to avoid "overeating". Patients will
keep a daily food diary and those entering the chronic CR phase will return to the
center to meet with the nutritionist at months 3 and 6 (with telephone contacts in
between).
At the baseline visit, patients will sign the informed consent, and the investigators will
collect medical history, perform physical examination, calculate BMI (defined as weight in Kg
/ height in m2) and waist circumference (index of visceral fat accumulation) and perform
neurological assessments, including the EDSS which is the standard neurologic exam used in MS
trials which assigns a score from 0 (no deficit) to 10 (dead from MS), the multiple sclerosis
functional composite (MSFC), which is a quantitative test of upper and lower limb function
and cognition supplemented with an additional cognitive test called the Symbol Digit Modality
Test (SDMT) and MS quality of life inventory (MSQLI).
Blood will be collected for routine testing (CBC, CMP) and for adipokine/cytokine, cortisol,
and T reg cell analyses performed by the investigators' laboratory. All these assessments and
sample collections will be repeated at day 15 and at month 3 and 6 for patients that will
participate in the chronic CR phase. Neurologic exams will be also performed on day 2, 3
during steroid treatment and day 15. Additional assessments will be performed at month 1, 3
and 6 for those patients entering the chronic CR phase. These assessments will include at
each visit: physical evaluation with neurological assessments (neurologic exam / EDSS, MSFC)
and MSQLI, BMI and waist circumference to reflect the changes in body weight due to CR. Blood
will be acquired on day 1, day 15 and month 3 and 6 for those patients in the CR chronic
phase. This will be 15 ml of blood collected in the morning following an overnight fast. CBC,
CMP and total cortisol testing will be performed by the Barnes Jewish Hospital chemistry
laboratory. The rest of the blood will be processed within one hour in the investigators'
laboratory. Serum will be aliquoted and stored at -80 ⁰C for future analyses (adiponectin,
leptin, resistin, tumor necrosis factor-alpha and IL-6 by ELISA). The investigators will also
investigate the number and function of peripheral T reg cells. T reg number will be evaluated
by flow cytometry after staining fresh blood with the specific markers that identify T regs
(CD4+ cells expressing high levels of CD25) and Foxp3. T reg function will be evaluated in
vitro as described. Briefly, CD4+CD25high and CD4+CD25- cell populations will be isolated
from peripheral blood and co-cultured at different ratios in the presence of anti cluster
differentiation (CD) 3 antibodies which stimulate CD4+CD25- cell proliferation. CD4+CD25-
proliferation is inhibited differentially based on the proportion of T reg cells in culture.
Proliferation of CD4+CD25- cells and cytokine levels in the culture supernatants will reflect
T reg suppressive capacities.
A stool sample will also be collected at baseline, day 15, month 3 and 6. These samples will
be analyzed to study effects of CR on gut microbiota.
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