Fecal Microbiota Transplantation (FMT) in Multiple Sclerosis

Study Overview
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Brief Summary
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Multiple sclerosis (MS) is a chronic immune central nervous system (CNS) disease of unknown cause. Recent studies suggest that gut microbiota could be a trigger for the neuro-inflammation in MS and abnormal gut microbiota composition has been reported in MS patients. These data provided scientific rationale for microbiota-directed intervention, like stool transplant, for the treatment of MS.

Detailed Description
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A subject (n-of-1) clinically diagnosed with Relapsing Remitting Multiple Sclerosis (RRMS), by Rush University Neurologists, volunteered and provided written informed consent to participate in this study conducted by Rush University Medical Center's department of Digestive Diseases and Nutrition. The RRMS subject underwent a fecal microbiota transplantation (FMT) administered outside the United States, at Taymount Clinic in the Bahamas, for the treatment of their MS. Being one of the investigators' patients, the subject volunteered to donate their stool samples to the Rush University Medical Center Gastrointestinal (GI) tissue repository for microbiota interrogation at the following time points: before FMT (baseline), 3, 13, 26, 39, 52 weeks (1 year) after FMT, to determine the impact on their microbiota composition and sustainability of the change. The subject also agreed to donate their blood during the above stated time points to see if FMT affected markers of bacteria translocation and systemic inflammation. The subject also agreed to have their GI symptoms, diet, sleep, and MS related symptoms (rating scales or questionnaires), MRI (brain & spine), as well as their gait metric activity objectively assessed to see if the FMT affects these symptoms and whether any observed improvement is sustained, in this proof-of-concept study. Based on this research, the investigators hypothesize that the FMT will significantly altered the overall microbial community structure to promote the growth of short chain fatty acid (SCFA)-producing beneficial bacteria, which in turn could potentially improve the MS subject's health outcomes, neurological symptoms, and walking metrics over time. More clinical trials (larger sample size) will be needed to study the potential of FMT for the treatment of MS and to examine the long term effects. FMT is an emerging treatment approach for MS. The donor selection, the separation of fecal bacteria, the frequency of FMT, the way of infusion, the long-term safety, and efficacy are still uncertain and need to be examined.

Official Title
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Single-Arm, Non-Randomized, Time Series, Single-Subject Study: Fecal Microbiota Transplantation (FMT) in Multiple Sclerosis

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Other: Fecal Microbiota Transplantation (FMT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Older than 18 years of age. Diagnosis of relapsing-remitting multiple sclerosis (RRMS) by neurology(primary specialist). Presence of active lesions on brain or spinal cord MRI, in the past 1 year prior to baseline. MS disease duration greater than 1 year. Symptomatic (Active RRMS). On MS therapy/medication greater than 4 weeks. Exclusion Criteria: Newly diagnosed multiple sclerosis. Inactive relapsing-remitting multiple sclerosis (RRMS). Unstable or no MS therapy/medication use. Presence of symptomatically active gastrointestinal diseases such as inflammatory bowel disease or celiac disease (except for hemorrhoids, hiatal hernia, or occasional (˂3 times a week) heartburn)). Pre-existent organ failure or co-morbidities as these may change GI flora: a) liver disease (cirrhosis or persistently abnormal AST or ALT that are 2X˃ normal); b) kidney disease (creatinine ˃ 2.0mg/dL); c) uncontrolled psychiatric illness; d) clinically active lung disease or decompensated heart failure; e) known HIV infection; f) alcoholism; g) transplant recipients (other than FMT); h) diabetes Severe malnutrition or obesity with BMI ˃ 40. Antibiotic and probiotic use (except yogurt) within 4 weeks of enrollment. Chronic use of NSAIDS. A washout period of 3 weeks is needed before the subject could be enrolled into the study. Low dose aspirin is allowed. Pregnant or lactating women or intention of getting pregnant during the trial period. Active infection including untreated latent or active tuberculosis, HIV, hepatitis, syphilis or other major active infection. Active symptomatic C. Difficile infection (colonization is not an exclusion). Active gastrointestinal condition being investigated (i.e. GI bleeding, colon cancer, active GI workup); history of known or suspected toxic megacolon and/or known small bowel ileus, major gastrointestinal surgery (e.g. significant bowel resection) within 3 months before enrollment (note that this does not include appendectomy or cholecystectomy); or history of total colectomy or bariatric surgery.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| N=1 MS patient<br>Single-Arm, Non-Randomized, Time Series, Single-Subject Study. Observational study of the FMT intervention. Single subject studies are based on repeated observations within an individual over time and are acknowledged as an important research method for generating scientific evidence about the health or behavior of an individual. This design is desirable when the available patient pool is limited and thus it is not optimal to randomize participants to a control arm. The subject serves as his/her own control, rather than using another individual/group.These designs are used primarily to evaluate the effect of a variety of interventions in early stage clinical research development. | Other: Fecal Microbiota Transplantation (FMT)<br>* Longitudinal FMT study: Baseline, 3 week, 13 week, 26 week, 39 week, 52 week<br>* Other names: Taymount Clinic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal microbial community structure and functional changes over six time frames for phylum, genus and species taxonomic level bacteria, virus, fungi, and archaea. | Shotgun Metagenomics | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Walking and balance changes over four time frames for stride time (seconds). | Orthopedic gait task, side gaze gait, and alternating gaze gait metrics. | Baseline, 3 week, 13 week, 52 week | 
| Walking and balance changes over four time frames for stride distance (meters). | Orthopedic gait task, side gaze gait, and alternating gaze gait metrics. | Baseline, 3 week, 13 week, 52 week | 
| Walking and balance changes over four time frames for cadence (total number of steps per minute). | Orthopedic gait task, side gaze gait, and alternating gaze gait metrics. | Baseline, 3 week, 13 week, 52 week | 
| Walking and balance changes over four time frames for step width (meters). | Orthopedic gait task, side gaze gait, and alternating gaze gait metrics. | Baseline, 3 week, 13 week, 52 week | 
| Walking and balance changes over four time frames for average pelvis forward velocity (meters per second). | Orthopedic gait task, side gaze gait, and alternating gaze gait metrics. | Baseline, 3 week, 13 week, 52 week | 
| Walking and balance changes over four time frames for pelvis smoothness (pelvis horizontal speed). | Orthopedic gait task, side gaze gait, and alternating gaze gait metrics. | Baseline, 3 week, 13 week, 52 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal targeted short-chain-fatty-acid metabolomics concentration changes over six time frames for acetate (mM/kg), propionate (mM/kg), butyrate (mM/kg), and total SCFA (mM/kg). | Targeted metabolomics of short-chain-fatty-acids (SCFA). | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Measurement of blood serum biomarker brain-derived neurotrophic factor (BDNF) (ng/ml) changes over six time frames. | ELISA (enzyme-linked immunosorbent assay) | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Sleep changes over six time frames. | Munich ChronoType Questionnaire (MCTQ). Questions about work day and free day sleep schedules, work details, and lifestyle provide data to aid in the understanding of how biological clocks work in social life, such as Roenneberg's conclusions of social jetlag. The MCTQ categorizes each participant into one of seven chronotype groups, and utilizes data on participants' midsleep phase and sleep debt to survey what type of sleeper each person is. | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Food timing changes over six time frames. | Food Timing Screener (FTS) questionnaire. A structured food demographics questionnaire was therefore developed to access food timing. The questionnaire consists of eight questions asking subjects' eating habits on work days and non-work days. Questions include the time of the main meal during work and non-work days, time of last meal before bed, consistency of dinner within work and non-work days, and consistency of breakfast, lunch, and dinner between work and non-work days. | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Gastrointestinal symptoms changes over six time frames (t-scores, mean, standard deviations). | Patient-Reported Outcomes Measurements Information System (PROMIS) gastrointestinal questionnaire for Belly Pain (6 questions), Bowel Incontinence (4 questions), Constipation (9 questions), and Gas & Bloating (12 questions). Higher score denoted more GI symptoms. Lower score denotes less GI symptoms. Scores range from 20 (low) to 80 (high). A score of 50 is denoted as the general population. | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Walking changes over six time frames. | Multiple sclerosis walking scale questionnaire. Higher scores indicate a greater impact from MS on walking than lower scores. Scale range from 1 (no impact) to 5 (high impact). 12 questions in total. | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Lesions changes over three time frames. | MRI of brain and spine | Baseline, 26 week and 52 week | 
| Food and frequency of consumption changes over six time frames. | Food Time Questionnaire (FTQ) consists of a list of foods and the frequency in which these foods are consumed in at each time frame. | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Single day food recall changes over six time frames. | Automated Self-Administered 24-Hour Recall (ASA24) Dietary Assessment. Total nutrients from all supplements reported in a given day. | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Diet changes over six time frames. | Vioscreen Food Frequency Questionnaire (FFQ). Total of 19 measured food components collected for each time frame. Vioscreen captures comprehensive dietary behaviors in just 30 minutes. VioScreen is a unique online dietary questionnaire, management and analysis system that efficiently gathers and manages data, that immediately identify dietary habits and counsel for lifestyle changes. | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Measurement of blood serum biomarker Interleukin-6 (IL-6) (pg/ml) changes over six time frames. | ELISA (enzyme-linked immunosorbent assay) | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Measurement of blood serum biomarker Interleukin-* (IL-8) (pg/ml) changes over six time frames. | ELISA (enzyme-linked immunosorbent assay) | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 
| Measurement of blood serum biomarker Tumor necrosis factor alpha (TNFα) (pg/ml) changes over six time frames. | ELISA (enzyme-linked immunosorbent assay) | Baseline, 3 week, 13 week, 26 week, 39 week, 52 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FMT, Microbiome, Gait, Longitudinal, Multiple Sclerosis