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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03594487
Recruitment Status : Recruiting
First Posted : July 20, 2018
Last Update Posted : January 13, 2020
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE June 7, 2018
First Posted Date  ICMJE July 20, 2018
Last Update Posted Date January 13, 2020
Actual Study Start Date  ICMJE November 16, 2018
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 18, 2018)
  • Subjects who complete the study protocol [ Time Frame: 1 year ]
    Proportion of subjects who complete the study protocol
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 18, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Fecal Microbiota Transplantation (FMT) of FMP30 in Relapsing-Remitting Multiple Sclerosis
Official Title  ICMJE 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
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.
Detailed Description

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 primary hypotheses are that:

  1. FMT will be safe and tolerable in patients with MS.
  2. FMT preceded by antibiotic preconditioning will lead to a change in fecal microbiota community structure

Secondary hypotheses are that:

  1. FMT preceded by antibiotic preconditioning will induce a favorable shift from pro-inflammatory to immunomodulatory T cell profiles in patients with relapsing-remitting MS
  2. That engraftment will not appreciably decay over time
  3. That FMT will favorably change humoral function
  4. That FMT will favorably influence short-term clinical and radiological endpoints.

FMP30 donor stool will be obtained from OpenBiome (Somerville, MA; OpenBiome.org), an established nonprofit stool bank with stringent safety protocols and quality control. Donor stool will be obtained from donors without MS and without other known autoimmune diseases and will be screened for transmissible pathogens. In collaboration with OpenBiome, UCSF will additionally screen donor stool on in vitro assays for immunological properties thought to be favorable in MS, including decreasing TH17 and increasing T regulatory cells, in order to select the final donor stool for to be used in this study for FMT. UCSF will obtain an IND from the FDA for FMT of FMP30 donor stool in MS.

After providing written informed consent and reviewing inclusion and exclusion criteria, subjects will participate in either the FMT Treatment Arm or the Observational Control Arm.

Subjects in the FMT Treatment Arm will first undergo screening assessments according to the study schedule of activities and provide blood samples for eligibility and research, and stool samples for research. Subjects who pass screening will have their pre-treatment baseline visit with 21 days of their screening visit where they will have an MRI, safety and biomarker research blood sample collection, stool sample collection for research, complete study activities according to the study visit schedule, be given antibiotics, bowel preparation, a medication compliance diary and directions on when and how to start the antibiotics and bowel preparation before their scheduled FMT colonoscopy procedure.

The week before their Baseline FMT visit, subjects will be contacted by study staff to initiate an oral antibiotic regimen for 5 days to precondition the gut for FMT and optimize engraftment of the donor microbiome. Study staff will ensure that the subjects understand how to complete their oral antibiotic regimen, compliance diary, and bowel preparation correctly.

At the study Baseline Visit, following standard bowel preparation for colonoscopy, subjects will then undergo colonoscopy with FMT of FMP30 by an experienced gastroenterologist. Subjects will return for scheduled assessments of stool and blood sampling, questionnaires, physical examination and MS rating scales, and follow-up MRI for 12 weeks, with additional safety and biomarker blood sample collection, and followed at weeks 24, 36 and 48. The active study time of 12 weeks was designed to be short to minimize time off MS disease modifying therapies (should the subject wish to go on a MS disease modifying therapy).

Subjects participating in the Observational Control Arm will not undergo the interventional FMT treatment. Participants in this arm will have a total of 5 visits over the course of 12 weeks. At the Screening/Baseline visit, subjects will provide blood and stool samples for research along with other study activities according to the study visit schedule. Subjects will mail in a stool sample at week 2 and come in for follow-up visits at weeks 4, 8 and 12.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Relapsing Remitting Multiple Sclerosis
Intervention  ICMJE
  • 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.
  • 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.
Study Arms  ICMJE
  • 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).

    Interventions:
    • Drug: FMP30 Donor Stool
    • Procedure: Fecal Microbiota Transplantation (FMT) of FMP30 Donor Stool
  • 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.

    Intervention: Other: Observational Control
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 18, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2020
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Samuel Friedman 415-502-7206 samuel.friedman@ucsf.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03594487
Other Study ID Numbers  ICMJE 17-23827
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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.
Responsible Party University of California, San Francisco
Study Sponsor  ICMJE University of California, San Francisco
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jeffrey Gelfand UCSF Multiple Sclerosis Center
PRS Account University of California, San Francisco
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP