In this 24-week, single center, randomized, double-blind, placebo-controlled study, the efficacy and safety of lyophilised oral fecal microbiota transplantation in patients with active refractory rheumatoid arthritis will be evaluated.

Rheumatoid arthritis (RA) is a chronic autoimmune disease, characterized by synovium inflammation and bone and joint erosions, leading to pain, morbidity and increased motality. Nearly half of RA patients displayed incomplete response or intolerance to the anchor drug-methotrexate. Gut microbiota plays an important role in the pathophysiology of RA and abnormal gut microeology has been documented in RA. FMT(fecal microbiota transplantation) is the engraftment of gut microbiota from healthy donors into a recipient, to ideally restore the normal gut microbial community structure. Hopefully, FMT could act as a promising strategy to improve disease control in refractory RA. Oral lyophilised fecal microbiota capsule provides a readily accessible and non-invasive way for FMT. This study will evaluate the efficacy and safety of lyophilised oral FMT in patients with active RA refractory to conventional synthetic disease modifying antirheumatic drugs (csDMARDs）with or without biological DMARDs (bDMARDs）or targeting-synthetic DMARDs (tsDMARDs）.

Objectives:

To evaluate the efficacy of lyophilised oral FMT capsule in the treatment of active RA patients refractory to csDMARDs with or without bDMARDs or tsDMARDs； To evaluate the safety of lyophilised oral FMT capsule in the treatment of active RA patients refractory to csDMARDs with or without bDMARDs or tsDMARDs；

DESIGN

This is a Phase 2, randomized, 24-week, double-blind, placebo-controlled study, and 40 patients with active RA refractory to csDMARDs will be randomized in a 1:3 ratio to one of the following 2 parallel treatment arms:

Placebo group: taking placebo capsules with no microbiota inside and continue previous csDMARDs regimen simutaneously； FMT group: taking lyophilised oral capsules with faecal microbiota prepared from health donors and continue previous csDMARDs regimen simutaneously；

Placebo capsules were indistinguishable from FMT capsules by appearance and were stored in identical coded package.

Disease activity and safety profile were evaluated at 8 weeks, 16 weeks and 24 weeks.

Escape:

On week 16, all participants with no response, defined as a <20% improvement in TJC (tender joint count), SJC (swollen joint count) and CRP (C-reactive protein) from baseline can withdraw and switch to other treatment like biologics.

Endpoints :

Primary endpoint:

ACR 20/50 response rates at 16 weeks.

Secondary endpoint：

1. ACR70 response at 16 weeks;
2. ACR20/50/70 response at 24 weeks;
3. DAS 28 (CRP) and DAS 28 (ESR) at 16 and 24 weeks;
4. EULAR response rates at 16 and 24 weeks;
5. Health assessment questionnaire (HAQ) at 16 and 24 weeks;
6. Patient assessment of joint pain (visual analogue scale,VAS) at 16 and 24 weeks;
7. Patient and physician global assessment （PtGA and PhGA）at 16 and 24 weeks;

Inclusion Criteria:

1. Age 18-65 years with informed consent;
2. Fulfill the 2010 ACR/EULAR classification criteria for rheumatoid arthritis;
3. Positive RF or anti-CCP antibody on screening;
4. Active disease status with swollen joint count(SJC)≥3 and tender joint count(TJC)≥3 and ESR >25 mm/hr or hypersensitive C-reactive protein > 10 mg/L;
5. Having received csDMARDs including but not limited to methotrexate (at a stable dose of 7.5 - 20 mg/week) for 3 months or longer prior to screening and willing to continue current regimen for the duration of the study;
6. Other csDMARDs (e.g. Leflunomide, Iguratimod, Sulfasalazine, Hydroxychloroquine, Tripterygium Wilfordii, etc.) taking before screening with dosage stablized for 3 months or longer are permitted and should continue during the duration of the study;
7. Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA;
8. If taking non-steroidal anti-inflammatory drugs (NSAIDs), must be at a stable dose for at least two weeks prior to screening;
9. Female subjects must have a negative pregnancy test unless they are surgically sterile or have been post-menopausal for at least one year (12 consecutive months without menses) ;
10. Participants with fertility must use a medically effective form of contraception and agree to continue its use during the study or at least 3 monts after the last dose of study intervention.
11. Willing to suspend the use of other adjuvant treatment for the duration of the study including acupuncture, massage, etc.

Exclusion Criteria:

1. Pregnant, lactating or further fertility requirements
2. History of any inflammatory rheumatological disorders other than RA;
3. Having used biologics or small-molecular targeting agents in 6 months prior to screening;
4. Taking oral glucocorticoid (GC) or get GC injection (intra-articular or parenteral) in one month prior to screening;
5. Severe, progressive, or uncontrolled visceral disease including cardiac, pulmonary, renal, hepatic, gastrointestinal, hematologic, metabolic, endocrine or neurologic disease;
6. Severe enteritis, intestinal obstruction or bleeding, or history of gastrointestinal surgery.
7. Active infection in recent 3 months or persistent chronic infection, including HIV, HCV, HBV, tuberculosis;
8. Malignancy or history of malignancy;

8. Other conditions that investigators consider inappropriate for this study.