Fecal Microbiota Transplantation (FMT) in Multiple Sclerosis

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03975413
• Other study ID #: 18082009
• Status: Completed
• Start date: September 25, 2018
• Est. completion date: May 1, 2020

Study information

• Verified date: October 2020
• Source: Rush University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1
• Est. completion date: May 1, 2020
• Est. primary completion date: April 1, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Older than 18 years of age.

2. Diagnosis of relapsing-remitting multiple sclerosis (RRMS) by neurology(primary specialist).

3. Presence of active lesions on brain or spinal cord MRI, in the past 1 year prior to baseline.

4. MS disease duration greater than 1 year.

5. Symptomatic (Active RRMS).

6. On MS therapy/medication greater than 4 weeks.

Exclusion Criteria:

1. Newly diagnosed multiple sclerosis.

2. Inactive relapsing-remitting multiple sclerosis (RRMS).

3. Unstable or no MS therapy/medication use.

4. 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)).

5. 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

6. Severe malnutrition or obesity with BMI ? 40.

7. Antibiotic and probiotic use (except yogurt) within 4 weeks of enrollment.

8. 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.

9. Pregnant or lactating women or intention of getting pregnant during the trial period.

10. Active infection including untreated latent or active tuberculosis, HIV, hepatitis, syphilis or other major active infection.

11. Active symptomatic C. Difficile infection (colonization is not an exclusion).

12. 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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Other:
• Fecal Microbiota Transplantation (FMT)
Longitudinal FMT study: Baseline, 3 week, 13 week, 26 week, 39 week, 52 week

Locations

Country	Name	City	State
United States	Rush University Medical Center	Chicago	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Rush University Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (15)

Adamczyk-Sowa M, Medrek A, Madej P, Michlicka W, Dobrakowski P. Does the Gut Microbiota Influence Immunity and Inflammation in Multiple Sclerosis Pathophysiology? J Immunol Res. 2017;2017:7904821. doi: 10.1155/2017/7904821. Epub 2017 Feb 20. Review. — View Citation

Berer K, Gerdes LA, Cekanaviciute E, Jia X, Xiao L, Xia Z, Liu C, Klotz L, Stauffer U, Baranzini SE, Kümpfel T, Hohlfeld R, Krishnamoorthy G, Wekerle H. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10719-10724. doi: 10.1073/pnas.1711233114. Epub 2017 Sep 11. — View Citation

Berer K, Mues M, Koutrolos M, Rasbi ZA, Boziki M, Johner C, Wekerle H, Krishnamoorthy G. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011 Oct 26;479(7374):538-41. doi: 10.1038/nature10554. — View Citation

Camara-Lemarroy CR, Metz LM, Yong VW. Focus on the gut-brain axis: Multiple sclerosis, the intestinal barrier and the microbiome. World J Gastroenterol. 2018 Oct 7;24(37):4217-4223. doi: 10.3748/wjg.v24.i37.4217. — View Citation

Cekanaviciute E, Yoo BB, Runia TF, Debelius JW, Singh S, Nelson CA, Kanner R, Bencosme Y, Lee YK, Hauser SL, Crabtree-Hartman E, Sand IK, Gacias M, Zhu Y, Casaccia P, Cree BAC, Knight R, Mazmanian SK, Baranzini SE. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10713-10718. doi: 10.1073/pnas.1711235114. Epub 2017 Sep 11. Erratum in: Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):E8943. — View Citation

Chu F, Shi M, Lang Y, Shen D, Jin T, Zhu J, Cui L. Gut Microbiota in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis: Current Applications and Future Perspectives. Mediators Inflamm. 2018 Apr 2;2018:8168717. doi: 10.1155/2018/8168717. eCollection 2018. Review. — View Citation

Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012 Jun 8;336(6086):1268-73. doi: 10.1126/science.1223490. Epub 2012 Jun 6. Review. — View Citation

Jangi S, Gandhi R, Cox LM, Li N, von Glehn F, Yan R, Patel B, Mazzola MA, Liu S, Glanz BL, Cook S, Tankou S, Stuart F, Melo K, Nejad P, Smith K, Topçuolu BD, Holden J, Kivisäkk P, Chitnis T, De Jager PL, Quintana FJ, Gerber GK, Bry L, Weiner HL. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016 Jun 28;7:12015. doi: 10.1038/ncomms12015. — View Citation

Kaskow BJ, Baecher-Allan C. Effector T Cells in Multiple Sclerosis. Cold Spring Harb Perspect Med. 2018 Apr 2;8(4). pii: a029025. doi: 10.1101/cshperspect.a029025. Review. — View Citation

Kirby TO, Ochoa-Repáraz J. The Gut Microbiome in Multiple Sclerosis: A Potential Therapeutic Avenue. Med Sci (Basel). 2018 Aug 24;6(3). pii: E69. doi: 10.3390/medsci6030069. Review. — View Citation

Makkawi S, Camara-Lemarroy C, Metz L. Fecal microbiota transplantation associated with 10 years of stability in a patient with SPMS. Neurol Neuroimmunol Neuroinflamm. 2018 Apr 3;5(4):e459. doi: 10.1212/NXI.0000000000000459. eCollection 2018 Jul. — View Citation

Ochoa-Repáraz J, Magori K, Kasper LH. The chicken or the egg dilemma: intestinal dysbiosis in multiple sclerosis. Ann Transl Med. 2017 Mar;5(6):145. doi: 10.21037/atm.2017.01.18. — View Citation

Quintana FJ, Prinz M. A gut feeling about multiple sclerosis. Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10528-10529. doi: 10.1073/pnas.1714260114. Epub 2017 Sep 25. — View Citation

Smits LP, Bouter KE, de Vos WM, Borody TJ, Nieuwdorp M. Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013 Nov;145(5):946-53. doi: 10.1053/j.gastro.2013.08.058. Epub 2013 Sep 7. Review. — View Citation

Tremlett H, Fadrosh DW, Faruqi AA, Hart J, Roalstad S, Graves J, Lynch S, Waubant E; US Network of Pediatric MS Centers. Gut microbiota composition and relapse risk in pediatric MS: A pilot study. J Neurol Sci. 2016 Apr 15;363:153-7. doi: 10.1016/j.jns.2016.02.042. Epub 2016 Feb 20. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Lesions changes over three time frames.	MRI of brain and spine	Baseline, 26 week and 52 week
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Measurement of blood serum biomarker Tumor necrosis factor alpha (TNFa) (pg/ml) changes over six time frames.	ELISA (enzyme-linked immunosorbent assay)	Baseline, 3 week, 13 week, 26 week, 39 week, 52 week