Fecal Microbial Transplantation in Relapsing Multiple Sclerosis Patients

Study Overview
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Brief Summary
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The proposed randomized, open label, with treat as usual control group (standard treatment or any disease modifying drugs), crossover phase II study will be conducted in 40 patients (n=20 per group) with the relapsing forms of multiple sclerosis according to the McDonald 2010 Criteria. Patients will be randomized into 2 intervention groups. One will receive the FMT from month 1 and for the first 6 months (early intervention group). On the other hand, the other group will be a control group during the first 6 months and will receive the FMT for the last 6 months of the study. Patients will be screened for eligibility based on MS diagnosis and EDSS and if eligible then consented. All qualified patients will not be currently or recently treated with high dose steroids.

Detailed Description
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At Visit 1, before FMT(fecal microbial transplantation), patients will be evaluated for their vital signs, medical history and concomitant medications. Also before transplantation, patient's stool will be collected to study their microbial profile, blood collected for analysis to evaluate cytokines levels as well as blood DNA bacteria and finally, urinalysis to assess gut permeability (baseline). Other assessments (prior to the first dose of therapy) include an Expanded Disability Status Scale (EDSS), pregnancy test (if applicable), physical exam and ECG. Blood samples are also taken at month 1 in order to establish a baseline for routine chemistry/hematology. After all these assessments FMT will be performed by a trained nurse via a rectal enema. FMT for the early intervention group will be at V1, 2, 2.1, 2.2, V3 and V4. FMT randomized to late intervention group will be V4, 5, 6, 6.1.6.2, 6.3 and V7 Both groups, at Visit 1, Visit 4 and Visit 7, patients will be instructed to drink lactulose solution and collect the urine throughout the previous night and first thing in the morning. A proper collecting bottle will be provided and will also undergo a contrast-enhanced brain MRI scan at Robarts Institute London Ontario. Those randomized to the Early Intervention group, will return to the clinic for visit 2, 1 month after the first FMT(fecal microbial transplantation). Another stool sample to evaluate the microbial before the second FMT will be collected and peripheral blood samples for cytokines and blood bacterial DNA analysis. Both groups this same routine procedure repeated at visits 2.1, 2.2, 3, 4, 5, 6, 6.1.6.2, 6.3 and visit 7. Another safety assessment 2 weeks after FMT is to review any adverse events that may have occurred. Both groups will have an MRI at M1, M6 and M12.

Official Title
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Fecal Microbial Transplantation in Relapsing Multiple Sclerosis Patients

Conditions
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Autoimmune Diseases, Relapsing Multiple Sclerosis

Intervention / Treatment
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* Drug: Fecal microbiota


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a confirmed diagnosis of relapsing MS defined by the 2010 Revised McDonald Criteria for the Diagnosis of Multiple Sclerosis Any disease duration will be accepted. Have a baseline EDSS of = or <7.0 Older than 18 years of age. Be able to attend all clinic appointments without interruption Patients must be able to understand English sufficiently well to understand and comply with the clinic and medication schedules and procedures. Be willing and able to give written informed consent Negative blood pregnancy test at screening Exclusion Criteria: Not meeting all of the above inclusion criteria Pregnancy or breastfeeding Current or recent [in the last 90 days] exposure to high dose corticosteroids Ongoing use of antibiotics Standard of care exclusions for MRI scans Presence of a chronic intestinal disease e.g. Celiac, malabsorption, colonic tumor Inability to provide informed written consent. Immunosuppression from transplantation, HIV, cancer chemotherapy or ongoing use of any immunosuppressive agents. Concomitant inflammatory diseases Pregnant women Any contra-indications for MRI. Participants are to be screened by a CMRTO (The College of Medical Radiation Technologists of Ontario) certified MRI Technologist in order to determine the MRI compatibility or exclusion of implantable/external devices according to the manufacturer's safety guidelines. The devises include cerebral aneurysm clips, neuro-stimulator, mechanical heart valves, cardiac stents, IUDs(intrauterine device), vena cava filters, shunts, embolization coils, cochlear implants, non-removable prosthesis/artificial limbs. Contraindications are pacemaker of defibrillator, shrapnel/metallic fragments, previous brain surgery, seizure, severe claustrophobia, weight or body index that will prevent a successful MRI study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a prospective, cross-over, open label, randomized 1:1 early versus delayed groups, interventional [FMT] versus no interventional [no FMT] controlled trial to explore the effects of FMT from a healthy donor to RMS patients and investigate whether this can influence disease activity based on a panel of biological markers.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Early Intervention<br>Fecal microbiota via enema at Month 1, 2, 3. 4, 5 and month 6 along with stool, urine and blood collection. At months 7, 8, 9, 10, 11 and 12 only stool, urine and blood collection. | Drug: Fecal microbiota<br>* fecal microbial transplantation<br>* Other names: fecal microbial transplantation;|
| Active Comparator: Late Intervention<br>At months 1, 2, 3, 4, 5 and 6, stool, urine and blood collection. Fecal microbiota via enema at month 6, 7, 8, 9, 10, 11and 12 months along with stool, urine and blood collection. | Drug: Fecal microbiota<br>* fecal microbial transplantation<br>* Other names: fecal microbial transplantation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Fecal Microbial Transplantation in Peripheral Blood Cytokines Within Relapsing Multiple Sclerosis Patients | Luminex test to evaluate the levels of 25 cytokines in peripheral blood pre-fecal transplant and post fecal transplant. Due to early termination of the trial, we didn't meet the number of participants required for statistical analysis; therefore, we analyzed the data pre and post FMT, rather than early and late intervention groups as originally planned. Due to the small sample size there was a large variation between cytokine levels of each participant for pre and post FMT, resulting in large standard deviations. | Within 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate Effect of Fecal Microbial Transplantation in Gut Microbiome | PCR (polymerase chain reaction) to assess blood DNA bacteria | Monthly for 6 months | 
| Evaluate Effect of Fecal Microbial Transplantation in Gut Permeability | Urinalysis to evaluate lactulose and mannitol levels | Baseline, 6 months, 12 months | 
| Evaluate Treatment Clinical Safety: Neurological Exam Using the Expanded Disability Status Scale | Neurological exam using the Expanded Disability Status Scale | Monthly for 6 months | 
| Evaluate Treatment Safety: MRI to Access Subclinical Disease Activity | MRI to access subclinical disease activity | Baseline, 6 months and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gut, microbiome, multiple sclerosis, microbiota