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

Study Overview
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Brief Summary
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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
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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: FMT will be safe and tolerable in patients with MS. FMT preceded by antibiotic preconditioning will lead to a change in fecal microbiota community structure Secondary hypotheses are that: FMT preceded by antibiotic preconditioning will induce a favorable shift from pro-inflammatory to immunomodulatory T cell profiles in patients with relapsing-remitting MS That engraftment will not appreciably decay over time That FMT will favorably change humoral function 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.

Official Title
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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

Conditions
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Relapsing Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: FMP30 Donor Stool
* Procedure: Fecal Microbiota Transplantation (FMT) of FMP30 Donor Stool
* Other: Observational Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-60 inclusive (at time of screening). 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). 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. 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). Must have positive serology for Epstein-Barr Virus (EBV) (IgG anti-EBNA positive) at screening, indicating prior exposure. No prior MS disease modifying therapy or a 12 week washout period for subjects on glatiramer acetate or interferon-beta therapy. At least 4 weeks from baseline since last use of IV or oral glucocorticoids Protocol: MS-BIOME Study. Agree to maintain a stable diet during the course of the study (over the counter probiotics are allowable). Premenopausal women and women <12 months after the onset of menopause must have a negative serum pregnancy test unless they have undergone surgical sterilization. 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. Not actively participating in another interventional MS clinical trial (participation in other observational research studies is allowable). Exclusion Criteria: Prior use of fingolimod, dimethyl fumarate, teriflunomide, natalizumab, alemtuzumab, mitoxantrone, cyclophosphamide, rituximab, ocrelizumab, daclizumab, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, leflunomide or induction chemotherapy. 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. Progressive MS by Lublin criteria (2014). 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). Hypersensitivity or allergy to study antibiotics, conscious sedation medications or bowel preparation. Contraindication to study procedures including MRI, anesthesia (ASA criteria IV and V), colonoscopy, phlebotomy. History of inflammatory bowel disease (Crohn's Disease, Ulcerative Colitis) Protocol: MS-BIOME Study. 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. 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. 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. Known immunodeficiency including CVID. 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. 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. Unable or unwilling to comply with study protocol requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional FMT Treatment Arm<br>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<br>* 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.<br>Procedure: Fecal Microbiota Transplantation (FMT) of FMP30 Donor Stool<br>* 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.<br>|
| Active Comparator: Observational Control Arm<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects who complete the study protocol | Proportion of subjects who complete the study protocol | 1 year | 
| Change in fecal microbiota | Engraftment: Change in fecal microbiota community structure at Baseline Visit, 2 weeks, 4 weeks, 8 weeks, 12 weeks. | Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | 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. | Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction of T regulatory or Th2 cells and/or reduction of Th1 or Th17 cells | Induction of T regulatory or Th2 cells and/or reduction of Th1 or Th17 cells at 0, 2, 4, 8 and 12 weeks. | Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. | 
| Plasma CD19+ B cell count percentages | Plasma CD19+ B cell count will be measured as percentages at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks. | Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. | 
| Plasma CD20+ B cell count percentages | Plasma CD20+ B cell count will be measured as percentages at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks. | Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. | 
| Plasma CD19+ B cell absolute count | Plasma CD19+ B cells will be measured as an absolute count in uL at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks. | Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. | 
| Plasma CD20+ B cell absolute count | Plasma CD20+ B cells will be measured as an absolute count in uL at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks. | Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. | 
| Measurement of Serum Immunoglobulin Levels | Serum Immunoglobulin levels of IgA, IgG, and IgM will be measured in mg/dL at Baseline Visit, 2 weeks, 4 weeks, and 12 weeks. | Baseline Visit, 2 weeks, 4 weeks, and 12 weeks. | 
| Incidence of new T2/FLAIR lesions | The number of new or enlarging T2/FLAIR lesions will be counted at baseline and week 12. | At baseline visit and week 12. | 
| Measurement of T2/FLAIR lesion volume | T2/FLAIR lesion volume will be measured in milliliters at baseline and week 12. | At baseline visit and week 12. | 
| Number of T2/FLAIR lesions | The number of T2/FLAIR lesions will be counted at baseline and week 12. | At baseline visit and week 12. | 
| Total Gadolinium Enhancing Lesions | New gadolinium enhancing lesions, total gadolinium enhancing lesions at baseline and week 12. | At baseline visit and week 12. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Relapsing Remitting Multiple Sclerosis, Fecal Microbiota Transplantation