Prebiotic vs Probiotic in Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
This is a randomized crossover-designed study to explore the immunologic effects of Prebiotics, as opposed to direct supplementation with beneficial bacteria (Probiotics) in the immune system of patients with MS and Clinically Isolated Syndrome (CIS). Eligible patients will take 6 weeks of two different supplements - Prebiotics and Probiotics. Participants will be randomly assigned to take either of two agents for 6 weeks as their first supplement. Then, participants enter a 6-week washout period. After the washout period, participants will take the second supplement for 6 weeks. After taking the second supplement, participants will have a 6-week washout period.

Detailed Description
-----------------
Soluble fibers (prebiotics) are fermented by beneficial bacteria (probiotics) in the colon to produce short-chain fatty acids (SCFAs) which are the main source of nutrition for the cells in the gut. It has been reported that the fermentable fiber inulin and SCFAs may exert some beneficial effects including anti-inflammatory effect on the immune system. To date, the effect of supplementation with fermentable dietary fiber, such as prebiotics in patients with Multiple Sclerosis (MS) has not been investigated.

Official Title
-----------------
Prebiotic and Probiotic Treatment Trial in Multiple Sclerosis

Conditions
-----------------
Multiple Sclerosis, Clinically Isolated Syndrome (CIS)

Intervention / Treatment
-----------------
* Dietary Supplement: Prebiotics (Prebiotin Prebiotic Fiber Stick Pac)
* Dietary Supplement: Probiotics (Visbiome®)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult patients (age 18 or older) diagnosed with MS (Relapsing-remitting type) or CIS and recruited within 10 years of symptom onset, and Adult patients receiving anti-CD20 therapy (rituximab or ocrelizumab) who have received at least one cycle at the time of recruitment Exclusion Criteria: Active relapse within 3 months of enrollment Steroid use within 4 weeks of enrollment Antibiotics use within 3 months of enrollment Daily pre or prebiotic use within 3 months of enrollment Diagnosed with any of the autoimmune disorders: Rheumatoid Arthritis, Lupus, Celiac disease, Vitiligo, Psoriasis, Psoriatic Arthritis, Hashimoto's Thyroiditis, Graves' Disease, Sjogren's syndrome, Type 1 Diabetes, Scleroderma, Crohn's Disease, Ulcerative Colitis, Alopecia Areata. Had surgery of the GI tract in the last 5 years (with the exception of cholecystectomy and appendectomy) Had a major bowel resection Prior use of any of the following drugs: Mycophenolate/Cellcept, Cyclophosphamide/Cytoxan, Methotrexate/Novantrone, Azathioprine/Imuran, Cladribine/Leustatin/Mavenclad, Daclizumab/Zenepax, Alemtuzumab/Campath/Lemtrada Have any of the following active uncontrolled gastrointestinal (GI) illnesses: Crohn's disease, ulcerative colitis, indeterminate colitis Irritable bowel syndrome: moderate-severe Persistent or chronic diarrhea of unknown etiology Severe Chronic constipation or difficulties with defecation Persistent, infectious gastroenteritis, colitis or gastritis Clostridium difficile infection (recurrent) Gastric or intestinal ulcerations/GI bleeding Gastrointestinal or colonic malignancy: polyps, masses, dysplasia or cancer Active use of bismuth subsalicylate-containing products Currently pregnant

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a randomized, interventional trial with a crossover design, in which participants will be taking either probiotic (commercially available Visbiome) or prebiotic (prebiotin prebiotic) for 6 weeks as the first agent. Then, participants enter a 6-week washout period. After the washout period, participants take the second agent for 6 weeks. After taking the second agent, participants again have a 6-week wash-out period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Prebiotic/ Probiotic<br>These subjects will be assigned to first receive prebiotics (Prebiotin Prebiotic Fiber Stick Pac) for 6 weeks. Then after a 6 week wash-out period, subjects will take probiotics (Visbiome®) for 6 weeks (followed again by a 6 week washout period). | Dietary Supplement: Prebiotics (Prebiotin Prebiotic Fiber Stick Pac)<br>* Commercially available Prebiotin Prebiotic. 2 packets (Inulin 4000 mg), Twice Daily (Total of 16 g Daily)<br>Dietary Supplement: Probiotics (Visbiome®)<br>* Commercially available Probiotics Visbiome extra strength, which is a combination of live lactic acid bacteria probiotics that have been cultivated, freeze-dried and mixed in very high concentrations. 2 packets (450 billion CFU), Twice Daily (Total of 3,600 billion Daily)<br>|
| Other: Probiotic/ Prebiotic<br>These subjects will be assigned to first receive probiotics (Visbiome®) for 6 weeks. Then after a 6 week wash-out period, subjects will take (Prebiotin Prebiotic Fiber Stick) for 6 weeks (followed again by a 6 week washout period). | Dietary Supplement: Prebiotics (Prebiotin Prebiotic Fiber Stick Pac)<br>* Commercially available Prebiotin Prebiotic. 2 packets (Inulin 4000 mg), Twice Daily (Total of 16 g Daily)<br>Dietary Supplement: Probiotics (Visbiome®)<br>* Commercially available Probiotics Visbiome extra strength, which is a combination of live lactic acid bacteria probiotics that have been cultivated, freeze-dried and mixed in very high concentrations. 2 packets (450 billion CFU), Twice Daily (Total of 3,600 billion Daily)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Peripheral Blood Mononuclear Cells (pBMCs) | Measure the number of differentially expressed probe sets in the pBMCs post-supplementation, as compared to subject baseline. Probe sets will count as differentially expressed based on a threshold of pBH <0.05 and a Fold Change (FC) > ±2. | Up to 24 weeks | 
| Change in Serum Neurofilament Light Concentration | Change in serum neurofilament light concentration post-supplementation as compared to baseline. Serum neurofilament light (NfL) will be measured in terms of pg/ML. | Up to 24 weeks | 
| Change in relative abundance of gut microbiome | Changes in the gut microbiota in stool samples will be assessed as percent relative abundance at the genus level post supplementation as compared to baseline. Gut microbiota will be identified by extracting bacterial DNA from stool samples and performing metagenome shotgun sequencing. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Fatigue Impact Scale | Modified Fatigue Impact Scale assesses fatigue effects in terms of physical, cognitive, and psychosocial functioning. The total core ranges from 0 - 20 (5 item version). Higher scores suggest a greater impact of fatigue on a patient's activities. | Up to 24 weeks | 
| Bowel Control Scale | Bowel Control Scale measures the impact of bowel control on lifestyle. The total score range from 0 - 26 (5 item version). Higher scores indicate greater bowel control issues. | Up to 24 weeks | 
| Patient Determined Disease Steps | Patient Determined Disease Steps assesses disability and walking ability in MS patients. Scores range from 0 (normal) to 8 (bedridden). | Up to 24 weeks | 
| Multiple Sclerosis Rating Scale | Multiple Sclerosis Rating Scale - Revised evaluates functional status to identify disability in domains other than walking. Scores range from 0 (normal status) to 4 (severe disability). | Up to 24 weeks | 
| Patient Health Questionnaire | Patient Health Questionnaire helps identify symptoms that could be related to depression. The total score ranges from 0 (None) to 27 (Severe). | Up to 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prebiotics, Probiotics, Gut microbiome, Multiple Sclerosis