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

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

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.

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, Massachusetts; OpenBiome.org), an established nonprofit stool bank with stringent safety protocols and quality control. Donor stool will be obtained from donors without Multiple Sclerosis (MS) and without other known autoimmune diseases and will be screened for transmissible pathogens. In collaboration with OpenBiome, University of California, San Francisco (UCSF) will additionally screen donor stool using in vitro assays for immunological properties thought to be favorable in Multiple Sclerosis (MS), including decreasing T helper 17 cells (TH17) and increasing T regulatory cells, in order to select the final donor stool to be used in this study for FMT. UCSF will obtain an investigational new drug (IND) from the FDA for FMT of FMP30 donor stool in MS.

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

Participants 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. Participants 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, participants 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 participants 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, participants will then undergo colonoscopy with FMT of FMP30 by an experienced gastroenterologist. Participants will return for scheduled assessments of stool and blood sampling, questionnaires, physical examination, 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 participant wish to go on a MS disease-modifying therapy).

Participants 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, participants will provide blood and stool samples for research along with other study activities, according to the study visit schedule. Participants will mail in a stool sample at week 2 and come in for follow-up visits at weeks 4, 8, and 12.

Inclusion Criteria:

1. Age 18-60 inclusive (at time of screening).
2. Diagnosis of relapsing-remitting multiple sclerosis (MS) by the 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). [RRMS: relapsing remitting multiple sclerosis]
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. [EBNA: Epstein-Barr nuclear antigen]
6. No prior MS disease-modifying therapy or a 12-week washout period for participants 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 participants 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 participants 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 of 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 are allowed within 8 weeks prior to screening and within 12 weeks prior to the planned FMT procedure (for participants in the FMT arm) or prior to the first stool collection (for participants in the 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). [IMSMS: International MS Microbiome Study]
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, and 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 Common Variable Immunodeficiency (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. [INR: international normalized ratio, WBC: White Blood cell, CD4: cluster of differentiation 4, eGFR: epidermal growth factor receptor]
15. Any condition that in the opinion of the study PI could jeopardize the safety of the participant, would make it unlikely for the participant to complete the study or could confound the results of the study.
16. Unable or unwilling to comply with study protocol requirements.