RANDOMIZED DOUBLE BLIND CONTROLLED STUDY ASSESSING THE EFFICACY OF FECAL MICROBIOTA TRANSPLANTATION IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS RESISTANT TO CONVENTIONAL TREATMENT
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Increase in gut Metagenome Species Pangenome (MSP) richness in the "intervention" arm.
研究概览
简要总结
Current pharmacological management of inflammatory rheumatism and in particular axial SpA remains imperfect. Only 50% of patients respond to the most effective biotherapies, and many of them are only partially relieved. In addition, these are extremely expensive treatments that expose them to the risk of potentially serious side effects. Compelling evidence indicates that gut dybiosis could be a critical trigger of inflammation in axial SpA and thus correcting dysbiosis represents an attractive way of reversing the pathogenic process.The efficacy of FMT in patients with axial SpA has never been studied. This randomized double-blind study will be the first to assess feasability of FMT in axial SpA, the capacity of this procedure to restore healthy microbiome, its tolerance and its potential efficacy on disease activity. If sucessfull, this trial would set the path to larger-scale clinical trials of FMT to treat axial SpA.
Two-co primary objectives in a hierarchical design:
- to evaluate the capacity of FMT to correct dysbiosis in active axial SpA despite well-conducted phamacological treatment by replacing pre-existing dysbiotic microbiota with healthier microbiota.
- to explore the efficacy of FMT versus placebo on clinical evolution of SpA.
详细描述
Axial spondyloarthritis (SpA) is a chronic inflammatory disease primarily affecting the sacroiliac and spinal joints that usually begins in young adults and is a major cause of chronic pain and disability that profoundly alter the quality of life of patients. Besides non-steroidal anti-inflammatory drugs, the development of anti-tumor necrosis factor-α (TNFα) and anti-interleukin (IL-17) biotherapies and of JAK inhibitors, has improved the management of these patients. However only half of the patients respond to these treatments and many of them are only partially relieved. Remarkably, this disorder frequently combines with overt inflammatory bowel disease (IBD) -i.e. Crohn's disease (CD) or ulcerative colitis (UC)- and even more frequently with subclinical gut inflammation, leading to suspect a role of the gut microbiota as a possible trigger. Consistently, recent studies evidenced an alteration of gut microbiota composition -or dysbiosis- in the course of SpA that appeared all the more pronounced that disease was more active. It was notably shown a restriction of bacterial diversity and an expansion of species considered as potentially pro-inflammatory, including Ruminococcus gnavus. Given its potential involvement in the pathogenesis of SpA, gut microbiota could be considéred as a promising therapeutic target. Fecal microbiota transplantation (FMT) is a technic consisting in thorough replacement of dysbiotic microbiota by healthy dondor's microbiota that has recently been developped to correct dysbiosis. It has been validated for the treatment of intractable colitis due to Clostridium difficile and its efficacy has been reported in CD or UC. The current trial, aims to evaluate efficacy of FMT in drug-resistant axial SpA.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patient (age 18 to 75 years old) with SpA, meeting the ASAS classification criteria for axial SpA, with presence of radiographic sacro-illitis (ankylosing spondylitis) or not.
- •Patient suffering of active SpA, with or without treatment, having a BASDAI score ≥ 4 (0-10) at baseline and a score of back pain ≥ 4 (0-10) despite optimal drug management for at least 6 months including at least 2 different NSAIDs at the maximum tolerated dose for at least 2 months (or less in case of intolerance or contra-indication) and at least a first line of biotherapy (anti-TNFα or anti-IL-17) for at least 4 months (or less in case of intolerance or contra-indication).
- •Subjects are allowed to continue NSAID, sulfasalazin (≤ 3 g/day) and/or methotrextae ( ≤ 25 mg/week) and/or hydroxychloroquine (≤ 400 mg/day) and/or oral corticosteroid (≤ 10 mg/day of prednisone), as long as these treatments have remained at stable dose for 4 weeks prior to baseline.
- •Subjects are allowed to continue anti-TNFα, anti-IL-17 or JAKinhibitor therapies, as long as these treatments have remained at stable dose for 3 months prior to baseline.
- •Women of childbearing potential with efficient contraceptive protection at the inclusion and during at least the interventional phase (D168).
- •Patient with health insurance (AME except).
- •Patient is willing to provide written informed consent prior to enrolment and agrees to follow the protocol.
排除标准
- •Patient under legal protection (guardianship or curatorship)
- •Subject who, in the judgment of the Investigator, is likely to be non-compliant or uncooperative during the study, or unable to cooperate because of a language problem, poor mental development
- •Pregnant or breastfeeding woman
- •Patient with IBD in active state, according to the judgment of the Investigator
- •Corticosteroid injection within 4 weeks before inclusion
- •Active infection according to the judgment of the Investigator
- •Any antibiotic (including Sulfasalazin) or antifungal treatment within 4 weeks before inclusion
- •Probiotics intake within 4 weeks before inclusion
- •Known infection with Clostridoides difficile or Escherichia coli within 10 days before inclusion
- •Patients with unstable severe condition other than axial SpA on that could jeopardize treatment procedure or evaluation according to the investigator's assessment
- •Previous FMT treatment
- •Contra-indication to colon preparation (Moviprep® or Moviprep orange®) according to SmPC
- •Current or past evidence of bowel obstruction
- •Confirmed or suspected intestinal ischemia
- •Confirmed or suspected toxic megacolon or gastrointestinal perforation
- •Extended colectomy (> two-thirds of colon)
- •Any gastro-intestinal bleeding in the past 3 months before inclusion
- •Any history of gastro-intestinal surgery in the past 3 months before inclusion
- •Severe organ dysfunction
- •Any contra-indication to swallow capsules
- •Known allergy or intolerance to IMP and / or excipients according to Investigator's Brochure
- •Lack of access to a refrigerator to store the medication (MaaT033® or MaaT030®)
- •Concomitant participation in another interventional clinical trial
研究组 & 干预措施
Experimental
active FMT
干预措施: active FMT (Drug)
Placebo
placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Increase in gut Metagenome Species Pangenome (MSP) richness in the "intervention" arm.
时间窗: at baseline and D 42
Fecal microbiota composition will be assessed by thorough microbial DNA sequencing (shotgun) at baseline (anytime between D-4 and D-1) and then at D28, D42, D84 and D168. The success will be evaluated by an increase in gut Metagenome Species Pangenome (MSP) richness over the period of study.
The proportion of patients satisfying ASAS 20 improvement criteria by randomization group
时间窗: at D 42
ASAS20 is defined by an improvement of ≥ 20% and of ≥ 10 points on a 0-100 numerical scale of 3 of the 4 following domains: global evaluation by the patient (PGA), pain, Bath Ankylosing Spondylitis Functional Index (BASFI) and inflammation (evaluated by the answer to both last questions of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) as well as an absence of deterioration from baseline by ≥ 20% and by ≥ 10 points in the fourth domain. The comparison of ASAS20 scores at D42 between randomization groups will be an exploratory analysis, considering literature data.
次要结局
- efficacy of FMT(week 6)
- Clinical improvement(at baseline, weeks 3, 6, 12 and 24)
- Change of dysbiotic fecal microbiota(at baseline, at weeks 3, 12 and 24)
- ESR and CRP levels(at weeks 3, 6, 12 and 24)
- CHANGE OF ASDAS_CRP and ASDAS_ESR(at weeks 3, 6, 12 and 24)
- Change in Bath Ankylosing Spondylitis Metrology Index(at weeks 3, 6, 12 and 24)
- non-steroidal anti-inflammatory drugs (NSAID) intake(through study completion, an average of 18 months)