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

Relapsing Remitting Multiple Sclerosis Clinical Trial

— MS-BIOME  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03594487
• Other study ID #: 17-23827
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: November 16, 2018
• Est. completion date: August 1, 2024

Study information

• Verified date: June 2024
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 30
• Est. completion date: August 1, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

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.

Locations

Country	Name	City	State
United States	UCSF Multiple Sclerosis Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Jeffrey Gelfand

Country where clinical trial is conducted

United States, 

References & Publications (10)

Bafeta A, Yavchitz A, Riveros C, Batista R, Ravaud P. Methods and Reporting Studies Assessing Fecal Microbiota Transplantation: A Systematic Review. Ann Intern Med. 2017 Jul 4;167(1):34-39. doi: 10.7326/M16-2810. Epub 2017 May 23. — View Citation

Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, Kheradman R, Heuman D, Wang J, Gurry T, Williams R, Sikaroodi M, Fuchs M, Alm E, John B, Thacker LR, Riva A, Smith M, Taylor-Robinson SD, Gillevet PM. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology. 2017 Dec;66(6):1727-1738. doi: 10.1002/hep.29306. Epub 2017 Oct 30. — 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

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, Topcuolu BD, Holden J, Kivisakk 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

Lee CH, Steiner T, Petrof EO, Smieja M, Roscoe D, Nematallah A, Weese JS, Collins S, Moayyedi P, Crowther M, Ropeleski MJ, Jayaratne P, Higgins D, Li Y, Rau NV, Kim PT. Frozen vs Fresh Fecal Microbiota Transplantation and Clinical Resolution of Diarrhea in Patients With Recurrent Clostridium difficile Infection: A Randomized Clinical Trial. JAMA. 2016 Jan 12;315(2):142-9. doi: 10.1001/jama.2015.18098. — View Citation

Morris MS, Graham LA, Chu DI, Cannon JA, Hawn MT. Oral Antibiotic Bowel Preparation Significantly Reduces Surgical Site Infection Rates and Readmission Rates in Elective Colorectal Surgery. Ann Surg. 2015 Jun;261(6):1034-40. doi: 10.1097/SLA.0000000000001125. — View Citation

Ochoa-Reparaz 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

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. — 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

Uygun A, Ozturk K, Demirci H, Oger C, Avci IY, Turker T, Gulsen M. Fecal microbiota transplantation is a rescue treatment modality for refractory ulcerative colitis. Medicine (Baltimore). 2017 Apr;96(16):e6479. doi: 10.1097/MD.0000000000006479. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Subjects who complete the study protocol	Proportion of subjects who complete the study protocol	1 year
Primary	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.
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	Total Gadolinium Enhancing Lesions	New gadolinium enhancing lesions, total gadolinium enhancing lesions at baseline and week 12.	At baseline visit and week 12.