A prospective, observational, multi-centre study investigating alterations of gut microbiome with its subsequent interaction on the brain-immune-intestine axis in patients with active relapsing remitting Multiple Sclerosis who start with oral treatment.

Environmental factors are known to be important in the pathogenesis of Multiple
Sclerosis. Recent findings show that the intestinal microbiota and gut
microbiome in MS patients is different from controls and is different between
patients with and without relapses.
Connection between microbiota, treatment and changes in immunity has not been
examined well yet. The question is whether the effect of oral treatment is due
to modulation of the gut microbiota with its subsequent change in the
immunological system due to downregulation of the pro-inflammatory change.

For the purpose of this investigation, the population of study subjects has
been limited to MS patients receiving oral Cladribine (Mavenclad ®) according
to standard of care. With Cladribine it is known that after 2 years
approximately 50% of the patients do not have relapses, show no disease
progression and do not have active disease on MRI. This response rate is
relatively high compared to other oral MS treatment currently available and
will result in an approximately equal number of responders and non-responders.
The choice for oral treatment is based on the assumption that this type of
treatment is more likely to have direct effect on the gut microbiome.
Cladribine is also used for treatment of coeliac disease, a condition in which
there is inflammation of the small intestine due to exposure to gluten. It is
proven that Cladribine has a positive effect on the gut immunological system.
.

Primary Objective: To determine if the (change in) gut and oral microbiome at
baseline or in the first 3 months after start of Cladribine is a predictor for
treatment response in subjects with active relapsing remitting MS.

The secondary objectives are to determine:
1. What is the difference between the gut and oral microbiome in patients who
experience disease activity (relapse, radiological activity or disability
progression) in comparison to patients without disease activity at baseline,
3, 12 and 24 months?
2. What is the difference between the immune profile in patients who experience
disease activity in comparison to patients without disease activity at
baseline, 3, 12 and 24 months?
3. Will cladribine treatment result in a more balanced microbial profile and a
less inflammatory immune profile at 3, 12 and 24 months?
4. What is the difference between the immune profile, the gut and oral
microbiome at baseline, 3, 12 and 24 months inbetween patients who experience
disease activity (relapse, radiological activity or disability progression) at
month 36 and month 48 and patients who do not experience disease activity?

This is a prospective, observational, multi-centre study. Patients with active
relapsing remitting multiple sclerosis who start with oral Cladribine,
according to standard of care, will be asked to participate in this study.
Subjects will be examined clinically at baseline, after 3, 12 and 24 months.
This observational study includes several invasive measurements: Laboratory
tests will be performed and oral swabs will be taken at baseline, after 3, 12
and 24 months and a MRI is performed (T1-weighted and T2-weighted and
T1-weighted imaging with gadolinium) after 2 years. These MRIs will be assessed
by a central reader.

Several non-invasive measures are also performed: at baseline, months 3, 12 and
24 a stool sample is collected. Subjects will also be asked to register their
food and drink intake for a short period of time.

After 36 and 48 months we register data which are assessed as regular care
(neurological examination, reports of standard MRI's and relapses).

The interventions in this study consist of additional blood sampling,
collection of stool samples, one additional MRI (including MRI contrast agent)
and food intake registration for a limited period of time.

For each subject this study covers for a period of approximately 24 months.
During this period subjects will routinely visit the hospital approximately
every 3 months, as indicated by their treating physician. During 4 of these
routine visits and one additional visit, several study specific assessments
will be performed. Study specific assessments include blood sampling,
collecting stool samples, collecting oral swabs, quantitative assessment of
disease activity (EDSS), one additional MRI and subjects are requested to
register their food intake 4 times for 7 consecutive days.
These additional assessments will take approximately 15-20 minutes per visit.
The MRI takes about 20-30 minutes. Food intake registration will take
approximately 5 minutes per day.
Risks associated with invasive measurements and assessments are considered
minimal as these are routine activities.

If a patient gives informed consent for the extension of the follow-up, only
data which are part of standard care will be registered as study data.