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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Participants Who Complete the Study Protocol
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18-60 inclusive (at time of screening).
- •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]
- •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. [EBNA: Epstein-Barr nuclear antigen]
- •No prior MS disease-modifying therapy or a 12-week washout period for participants 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 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.
- •Not actively participating in another interventional MS clinical trial (participation in other observational research studies is allowable).
排除标准
- •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 of 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 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]
- •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, and 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 Common Variable Immunodeficiency (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<
- •[INR: international normalized ratio, WBC: White Blood cell, CD4: cluster of differentiation 4, eGFR: epidermal growth factor receptor]
- •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.
- •Unable or unwilling to comply with study protocol requirements.
研究组 & 干预措施
Interventional FMT Treatment Arm
After providing written informed consent, participants will undergo screening and baseline assessments of stool and blood sampling, questionnaires, physical examination, MS rating scales, and MRI. Participants 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, participants will undergo the FMT procedure by an experienced gastroenterologist. Participants 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 off 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).
干预措施: Fecal Microbiota Transplantation (FMT) of FMP30 Donor Stool (Procedure)
Interventional FMT Treatment Arm
After providing written informed consent, participants will undergo screening and baseline assessments of stool and blood sampling, questionnaires, physical examination, MS rating scales, and MRI. Participants 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, participants will undergo the FMT procedure by an experienced gastroenterologist. Participants 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 off 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).
干预措施: FMP30 Donor Stool (Drug)
Observational Control Arm
Participants, 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, participants 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, participants 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.
干预措施: Observational Control (Other)
结局指标
主要结局
Participants Who Complete the Study Protocol
时间窗: Baseline through week 48
This includes the proportion of participants who completed the study protocol, including the completion of the study visits at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, and a safety follow-up through week 48.
Change in Fecal Microbiota
时间窗: 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 by 16S ribosomal RNA amplicon sequencing (as a measure of the diversity of fecal microbiota by detecting sequence variations). Comment on unit of measure: The Shannon Index is used to assess changes in fecal microbiota diversity, with higher values indicating greater microbial diversity. Changes in the Shannon index over time will reflect the impact of the intervention on gut microbial composition.
Number of Treatment-Emergent Serious Adverse Events [Safety and Tolerability]
时间窗: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks.
Treatment-emergent serious adverse events from baseline through week 12. The proportion of participants who develop an adverse event (AE) of severity grade 2 or more by NIH CTCAE criteria V4.0 is considered serious. NIH CTCAE is a standardized classification and severity grading scale for adverse events used in clinical trials. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE. Grade 1 is considered mild, Grade 2 as moderate, Grade 3 as severe or medically significant, Grade 4 as life-threatening, and Grade 5 as death related to AE.
Number of Treatment-Emergent Non-Serious Adverse Events [Safety and Tolerability]
时间窗: Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks.
Treatment-emergent non-serious adverse events from baseline through week 12. The proportion of participants who develop an adverse event (AE) of severity grade 2 or more by NIH CTCAE criteria V4.0 is considered serious. NIH CTCAE is a standardized classification and severity grading scale for adverse events used in clinical trials. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE. Grade 1 is considered mild, Grade 2 as moderate, Grade 3 as severe or medically significant, Grade 4 as life-threatening, and Grade 5 as death related to AE.
次要结局
- Change in Plasma CD19+ B Cells in Interventional Arm [CD19: Cluster of Differentiation Antigen 19](Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks.)
- Change in Plasma CD19+ B Cells in Observational Arm(Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks.)
- Change in Serum IgA Immunoglobulin Levels in Interventional Arm [IgA: Immunoglobulin A](Baseline Visit, 2 weeks, 4 weeks, 8 weeks, and 12 weeks.)
- Change in Serum IgA Immunoglobulin Levels in Observational Arm(Baseline Visit, 2 weeks, 4 weeks, and 12 weeks.)
- Change in Serum IgM Immunoglobulin Levels in Interventional Arm [IgM: Immunoglobulin M](Baseline Visit, 2 weeks, 4 weeks, 8 weeks and 12 weeks.)
- Change in Serum IgM Immunoglobulin Levels in Observational Arm(Baseline Visit, 2 weeks, 4 weeks, 8 weeks and 12 weeks.)
- Change in Serum IgG Immunoglobulin Levels in Interventional Arm [IgG: Immunoglobulin G](Baseline Visit, 2 weeks, 4 weeks, 8 weeks and 12 weeks)
- Change in Serum IgG Immunoglobulin Levels in Observational Arm(Baseline Visit, 2 weeks, 4 weeks, 8 weeks and 12 weeks)
- Incidence of New T2/FLAIR Lesions(At pre-treatment visit and week 12.)
- Treatment-emergent Gadolinium Enhancing Lesions(At pre-treatment visit and week 12.)
- Clinical Relapse(From baseline to week 12)
- Percentage of Induced T-regulatory Cells(Pre-screening, Screening, Baseline, Week 2, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48)
研究者
Jeffrey Gelfand
Professor of Clinical Neurology
University of California, San Francisco