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Fecal Microbiota Transplantation (FMT) of FMP30 in Relapsing-Remitting Multiple Sclerosis (MS-BIOME)

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ClinicalTrials.gov Identifier: NCT03594487
Recruitment Status : Recruiting
First Posted : July 20, 2018
Last Update Posted : December 5, 2018
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
In this Phase 1b open-label prospective clinical trial, patients with relapsing-remitting MS will undergo FMT of FMP30 (donor stool) via colonoscopy and immunological efficacy endpoints will be assessed at various time points. The active phase of the study will continue for 12 weeks post-FMT with safety and biomarker (engraftment) follow-up for 48 weeks. A parallel observational control arm of MS patients who otherwise satisfy study inclusion criteria based on their MS phenotype, demographics, disease duration and prior use of allowable MS therapies, will be recruited as a comparison observational group to measure stability of stool and serum immunological measures. The study duration for the Observational Control Arm is 12 weeks.

Condition or disease Intervention/treatment Phase
Relapsing Remitting Multiple Sclerosis Drug: FMP30 Donor Stool Procedure: Fecal Microbiota Transplantation (FMT) of FMP30 Donor Stool Other: Observational Control Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Fecal Microbiota Transplantation (FMT) of FMP30 in Relapsing-Remitting Multiple Sclerosis: A Phase 1b Clinical Trial to Evaluate Feasibility, Safety, Tolerability and Effects on Immune Function
Actual Study Start Date : November 16, 2018
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Interventional FMT Treatment Arm

After providing written informed consent, subjects will undergo screening and baseline assessments of stool and blood sampling, questionnaires, physical examination, MS rating scales, and MRI. Subjects will then initiate an oral antibiotic regimen for 5 days to precondition the gut for the Fecal Microbiota Transplantation (FMT) of FMP30 donor stool and optimize engraftment of the FMP30 donor stool microbiome. Following standard bowel preparation for colonoscopy, subjects will undergo the FMT procedure by an experienced gastroenterologist. Subjects will return for scheduled assessments and follow-up MRI for 12 weeks, with additional safety and biomarker follow-up for 36 weeks.

The active study time is designed to be short (12 weeks active phase) to minimize time not on other MS disease modifying therapy (DMT). This arm of the study will last for approximately 52 weeks total (4 weeks of screening + 12 weeks active treatment phase + 36 weeks of safety follow up).

Drug: FMP30 Donor Stool
FMP30 is manufactured by the non-profit stool bank Openbiome. Each FMP30 filtered donor stool engraftment has approximately 12.5g of stool per 30mL of normal saline. It is homogenized in sterile normal saline.

Procedure: Fecal Microbiota Transplantation (FMT) of FMP30 Donor Stool
Three doses of filtered donor stool engraftments homogenized in sterile normal saline (FMP30), obtained from the non-profit stool bank OpenBiome, will be administered via colonoscopy in patients with Relapsing-Remitting Multiple Sclerosis. FMT dosage via colonoscopy may include a lower amount of transplanted stool at the discretion of the study gastroenterologist if there are any peri-procedural safety or technical considerations. Total FMT dose (in milliliters) will be documented.

Active Comparator: Observational Control Arm

Subjects, who otherwise satisfy study inclusion criteria based on their MS phenotype, demographics, disease duration and prior use of allowable MS therapies, will be recruited as a comparison observational group to measure stability of stool and serum immunological measures.

After providing written informed consent, subjects will undergo screening and baseline assessments, including collection of blood and stool samples, demographic data collection, concomitant medication review, and an MS Relapse assessment. At week 2, subjects will mail in stool samples with a prepaid air bill and packaging. Weeks 4, 8, and 12 assessments will include concomitant medication review, relapse assessment, and blood and stool collection.

The duration of the study for the observational control arm will last for 12 weeks. All study procedures will be performed at the University of California, San Francisco.

Other: Observational Control
Subjects, who otherwise satisfy study inclusion criteria based on their MS phenotype, demographics, disease duration and prior use of allowable MS therapies, will be recruited as a comparison observational group to measure stability of stool and serum immunological measures.




Primary Outcome Measures :
  1. Subjects who complete the study protocol [ Time Frame: 1 year ]
    Proportion of subjects who complete the study protocol

  2. Change in fecal microbiota [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. ]
    Engraftment: Change in fecal microbiota community structure at Baseline Visit, 2 weeks, 4 weeks, 8 weeks, 12 weeks.

  3. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. ]
    Treatment-emergent adverse events including treatment-emergent serious and non-serious adverse events through week 12 defined as proportion of subjects who develop an adverse event of severity grade 2 or more by NIH CTCAE criteria.


Secondary Outcome Measures :
  1. Induction of T regulatory or Th2 cells and/or reduction of Th1 or Th17 cells [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. ]
    Induction of T regulatory or Th2 cells and/or reduction of Th1 or Th17 cells at 0, 2, 4, 8 and 12 weeks.

  2. Plasma CD19+ B cell count percentages [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. ]
    Plasma CD19+ B cell count will be measured as percentages at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks.

  3. Plasma CD20+ B cell count percentages [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. ]
    Plasma CD20+ B cell count will be measured as percentages at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks.

  4. Plasma CD19+ B cell absolute count [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. ]
    Plasma CD19+ B cells will be measured as an absolute count in uL at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks.

  5. Plasma CD20+ B cell absolute count [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. ]
    Plasma CD20+ B cells will be measured as an absolute count in uL at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks.

  6. Measurement of Serum Immunoglobulin Levels [ Time Frame: Baseline Visit, 2 weeks, 4 weeks, and 12 weeks. ]
    Serum Immunoglobulin levels of IgA, IgG, and IgM will be measured in mg/dL at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks.

  7. Incidence of new T2/FLAIR lesions [ Time Frame: At baseline visit and week 12. ]
    The number of new or enlarging T2/FLAIR lesions will be counted at baseline and week 12.

  8. Measurement of T2/FLAIR lesion volume [ Time Frame: At baseline visit and week 12. ]
    T2/FLAIR lesion volume will be measured in milliliters at baseline and week 12.

  9. Number of T2/FLAIR lesions [ Time Frame: At baseline visit and week 12. ]
    The number of T2/FLAIR lesions will be counted at baseline and week 12.

  10. Total Gadolinium Enhancing Lesions [ Time Frame: At baseline visit and week 12. ]
    New gadolinium enhancing lesions, total gadolinium enhancing lesions at baseline and week 12.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18-60 inclusive (at time of screening).
  2. Diagnosis of relapsing-remitting multiple sclerosis (MS) by International Panel McDonald Criteria (2010)(1) incorporating 2017 revisions which reclassify select high-risk Clinically Isolated Syndromes under 2010 criteria as RRMS under 2017 criteria, and Lublin criteria (2014)(2).
  3. Recent documented MS disease activity, defined as at least 1 clinical relapse within the past 1 year prior to baseline OR 2 clinical relapses in the past 2 years prior to baseline OR at least 1 new T2/FLAIR lesion on brain or spine MRI OR at least 1 gadolinium enhancing lesion on brain or spine MRI in the past 1 year prior to baseline.
  4. Expanded Disability Status Scale (EDSS) less than or equal to 6.0; EDSS 5.5 or less if MS disease duration is greater than 15 years (no other disease duration restriction).
  5. Must have positive serology for Epstein-Barr Virus (EBV) (IgG anti-EBNA positive) at screening, indicating prior exposure.
  6. No prior MS disease modifying therapy or a 12 week washout period for subjects on glatiramer acetate or interferon-beta therapy.
  7. At least 4 weeks from baseline since last use of IV or oral glucocorticoids Protocol: MS-BIOME Study.
  8. Agree to maintain a stable diet during the course of the study (over the counter probiotics are allowable).
  9. Premenopausal women and women <12 months after the onset of menopause must have a negative serum pregnancy test unless they have undergone surgical sterilization.
  10. Female subjects of childbearing potential who are sexually active with a non-sterilized male partner must agree to use a highly effective method of contraception; non-sterilized male subjects who are sexually active with a female partner of childbearing potential must agree to use a highly effective method of contraception.
  11. Not actively participating in another interventional MS clinical trial (participation in other observational research studies is allowable).

Exclusion Criteria:

  1. Prior use of fingolimod, dimethyl fumarate, teriflunomide, natalizumab, alemtuzumab, mitoxantrone, cyclophosphamide, rituximab, ocrelizumab, daclizumab, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, leflunomide or induction chemotherapy.
  2. No use of diuretics like furosemide (Lasix) 1 week before the first dose oral antibiotics. The use of hydrochlorothiazide (HCTZ) for hypertension at a dose < 50 mg/day is allowable.
  3. Progressive MS by Lublin criteria (2014).
  4. No oral or IV antibiotics within 8 weeks of screening and 12 weeks of scheduled of the planned FMT procedure if in the FMT arm or first stool collection if in control arm (note that topical, otic, ocular antibiotics are specifically allowable which is consistent with the IMSMS.org protocol for collaborative gut microbiome research in MS).
  5. Hypersensitivity or allergy to study antibiotics, conscious sedation medications or bowel preparation.
  6. Contraindication to study procedures including MRI, anesthesia (ASA criteria IV and V), colonoscopy, phlebotomy.
  7. History of inflammatory bowel disease (Crohn's Disease, Ulcerative Colitis) Protocol: MS-BIOME Study.
  8. Active symptomatic C. Difficile infection (colonization is not an exclusion).
  9. 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.
  10. History of malignancy (except excised cutaneous basal cell carcinoma or squamous cell carcinoma which are allowable) including no concurrent induction chemotherapy, radiation therapy or biological treatment for active malignancy.
  11. Pregnant or lactating women or intention of getting pregnant during the trial period.
  12. Active infection including untreated latent or active tuberculosis, HIV, hepatitis, syphilis or other major active infection.
  13. Known immunodeficiency including CVID.
  14. INR>1.5, Platelets<100, Hemoglobin <8.5, WBC<2.0, Absolute lymphocyte count <0.8, Absolute Neutrophil Count <0.5, CD4<200, eGFR<45.
  15. Any condition that in the opinion of the study PI could jeopardize the safety of the subject, would make it unlikely for the subject to complete the study or could confound the results of the study.
  16. Unable or unwilling to comply with study protocol requirements.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03594487


Contacts
Contact: Samuel Friedman 415-502-7206 samuel.friedman@ucsf.edu

Locations
United States, California
UCSF Multiple Sclerosis Center Recruiting
San Francisco, California, United States, 94158
Contact: Samuel Friedman    415-502-7206    samuel.friedman@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Jeffrey Gelfand UCSF Multiple Sclerosis Center

Publications:

Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03594487     History of Changes
Other Study ID Numbers: 17-23827
First Posted: July 20, 2018    Key Record Dates
Last Update Posted: December 5, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Outcome data as well as study data related to diagnosis, disease presentation, and date of birth, along with biological specimens collected as part of the study, may be shared (in coded form) in the future with other qualified researchers on a case by case basis at the discretion of the PI and Co-PIs. Any such investigator will be required to provide appropriate documentation that the research being conducted has been approved by an Institutional Review Board and demonstrate that it will be of value in determining the cause of MS or a related disorder, and as allowed by the UCSF Institutional Review Board.
Supporting Materials: Study Protocol
Time Frame: After initial study results are published and on a case by case basis.
Access Criteria: Limited data to include demographic and clinical information and biological specimens collected as part of the study, may be shared (in coded form) in the future with other qualified researchers on a case by case basis at the discretion of the PI and Co-PIs. Any such investigator will be required to provide appropriate documentation that the research being conducted has been approved by an Institutional Review Board and demonstrate that it will be of value in determining the cause of MS or a related disorder, and as allowed by the UCSF Institutional Review Board.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of California, San Francisco:
Multiple Sclerosis
Relapsing Remitting Multiple Sclerosis
Fecal Microbiota Transplantation

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases