The Efficacy of Fecal Microbiota Transplatation on Axial Spondyloarthritis Patients Resistant to Conventional Treatment

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Efficacy of Fecal Microbiota Transplatation in Patients With Axial Spondyloarthritis Resistant to Conventional Treatment

Conditions
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Axial Spondyloarthritis

Intervention / Treatment
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* Drug: active FMT
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patient (age 18 to 90 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. Exclusion Criteria: Patient under guardianship Refusal to participate to the study or to sign the informed consent 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 Women of childbearing potential without efficient contraceptive protection Pregnant or breastfeeding woman Patient with active IBD Corticosteroid injection within 4 weeks before inclusion Active uncontrolled infection according to the attending physician Antibiotic or antifungic treatment within 4 weeks before inclusion Probiotics intake within 4 weeks before inclusion Confirmed positive result to SARS-CoV-2 test at screening Infection with Clostridium difficile within 10 days before inclusion Patients with unstable severe condition other than axial SpA on that could jeopardize treatment procedure or evaluation No affiliation to a social security scheme Previous FMT treatment Contra-indication to colon preparation (Moviprep®) Confirmed or suspected intestinal ischemia Confirmed or suspected toxic megacolon or gastrointestinal perforation Any gastro-intestinal bleeding in the past 3 months Any history of gastro-intestinal surgery in the past 3 months Severe organ dysfunction Any contra-indication to swallow capsules Known allergy or intolerance to trehalose, maltodextrin or PEG Patients with EBV-negative serology

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental<br>active FMT | Drug: active FMT<br>* MaaT033®, a lyophilized full-ecosystem intestinal microbiota delayed release oral capsule containing native, donor-derived (pooled from 4-6 donors) microbiome product manufactured by MaaT Pharma® will be delivered orally. Patients will receive 20 Maat033 capsules, each containing approximatively 0.42 g of microbiome product at once at day 0, then 3 capsules/day from day 1 through day 20.<br>|
| Placebo Comparator: Placebo<br>placebo | Drug: Placebo<br>* Patients will receive 20 capsules placebo, each containing placebo at once at day 0, then 3 capsules/day from day 1 through day 20.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The correction of dysbiosis at 6 weeks | Fecal microbiota composition will be assessed by thorough microbial DNA sequencing (shotgun) at baseline (anytime between day -5 and day -1) and then at weeks 3, 6, 12 and 24. The success will be analyzed by the variation in gut Metagenome Species Pangenome (MSP) richness over the period of study. The primary endpoint will be a correction of dysbiosis at 6 weeks. | at baseline, weeks 3, 6, 12 and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| efficacy of FMT | Superior efficacy of FMT over placebo defined by an increase in MSP richness at week 6 in the FMT group, superior to variation in the placebo group | week 6 | 
| Change of dysbiotic fecal microbiota | To correct dysbiotic fecal microbiota at weeks 3, 12 and 24 in FMT-treated group, by comparison with baseline. Fecal microbiota composition will be assessed by thorough microbial DNA sequencing (shotgun), in a way similar to week 6 in FMT and placebo groups and the variation between baseline and different end-points (weeks 3, 12, 24) will be compared between both arms. | at baseline, at weeks 3, 12 and 24 | 
| Clinical improvement | Clinical improvement during the 24 weeks follow-up after FMT or sham-FMT. We will compare between both arms the proportion of patients satisfying ASAS20 improvement criteria at weeks 3, 6, 12 and 24 as compared to baseline (week 0). [ASAS20 is defined by an improvement of at least 20% and of at least 10 points on a 0-100 scale in ≥ 3 of the following 4 domains: global assessment by the patient (PGA), back 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) and absence of deterioration in the potential remaing domain, where deterioration is defined as a change for the worse of ≥ 20% and net worsening of ≥ 10 points (on a scale of 0-100) | at baseline, weeks 3, 6, 12 and 24 | 
| ESR and CRP levels | Improvement of biological inflammation by ESR and CRP levels variation | at weeks 3, 6, 12 and 24 | 
| CHANGE OF ASDAS_CRP and ASDAS_ESR | Improvement of ASDAS_CRP and ASDAS_ESR at weeks 3, 6, 12 and 24 | at weeks 3, 6, 12 and 24 | 
| Change in Bath Ankylosing Spondylitis Metrology Index | Improvement of Bath Ankylosing Spondylitis Metrology Index (BASMI) at weeks 3, 6, 12 and 24 | at weeks 3, 6, 12 and 24 | 
| non-steroidal anti-inflammatory drugs (NSAID) intake | Decrease of non-steroidal anti-inflammatory drugs (NSAID) intake score. | through study completion, an average of 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Axial Spondyloarthritis, dysbiotic microbiota, Fecal microbiota transplantation, eubiotic microbiota