Clinical trial NCT05654753: The Efficacy of Fecal Microbiota Transplatation on Axial Spondyloarthritis Patients Resistant to Conventional Treatment
Official title: RANDOMIZED DOUBLE BLIND CONTROLLED STUDY ASSESSING THE EFFICACY OF FECAL MICROBIOTA TRANSPLANTATION IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS RESISTANT TO CONVENTIONAL TREATMENT
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Axial Spondyloarthritis
Keywords: Axial Spondyloarthritis
dysbiotic microbiota
Fecal microbiota transplantation
eubiotic microbiota
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Fondation Arthritis & Clarins Worldwide 2016
First posted: 2022-12-16
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

1. Patient under legal protection (guardianship or curatorship)
2. 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
3. Pregnant or breastfeeding woman
4. Patient with IBD in active state, according to the judgment of the Investigator
5. Corticosteroid injection within 4 weeks before inclusion
6. Active infection according to the judgment of the Investigator
7. Any antibiotic (including Sulfasalazin) or antifungal treatment within 4 weeks before inclusion
8. Probiotics intake within 4 weeks before inclusion
9. Known infection with Clostridoides difficile or Escherichia coli within 10 days before inclusion
10. Patients with unstable severe condition other than axial SpA on that could jeopardize treatment procedure or evaluation according to the investigator's assessment
11. Previous FMT treatment
12. Contra-indication to colon preparation (Moviprep® or Moviprep orange®) according to SmPC
13. Current or past evidence of bowel obstruction
14. Confirmed or suspected intestinal ischemia
15. Confirmed or suspected toxic megacolon or gastrointestinal perforation
16. Extended colectomy (\> two-thirds of colon)
17. Any gastro-intestinal bleeding in the past 3 months before inclusion
18. Any history of gastro-intestinal surgery in the past 3 months before inclusion
19. Severe organ dysfunction
20. Any contra-indication to swallow capsules
21. Known allergy or intolerance to IMP and / or excipients according to Investigator's Brochure
22. Lack of access to a refrigerator to store the medication (MaaT033® or MaaT030®)
23. Concomitant participation in another interventional clinical trial

Primary outcomes:
measure: Increase in gut Metagenome Species Pangenome (MSP) richness in the "intervention" arm.
timeFrame: at baseline and D 42
measure: The proportion of patients satisfying ASAS 20 improvement criteria by randomization group
timeFrame: at D 42
Secondary outcomes:
measure: efficacy of FMT
timeFrame: week 6
measure: Change of dysbiotic fecal microbiota
timeFrame: at baseline, at weeks 3, 12 and 24
measure: Clinical improvement
timeFrame: at baseline, weeks 3, 6, 12 and 24
measure: ESR and CRP levels
timeFrame: at weeks 3, 6, 12 and 24
measure: CHANGE OF ASDAS_CRP and ASDAS_ESR
timeFrame: at weeks 3, 6, 12 and 24
measure: Change in Bath Ankylosing Spondylitis Metrology Index
timeFrame: at weeks 3, 6, 12 and 24
measure: non-steroidal anti-inflammatory drugs (NSAID) intake
timeFrame: through study completion, an average of 18 months
Other outcomes:
Locations:
city: Boulogne-Billancourt
country: France
facility: Rheumatology Department, Ambroise Paré hospital - APHP
Study officials:
affiliation: Rheumatology Department - Ambroise Paré hospital - APHP
name: Maxime Breban, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: