Efficacy and Safety of Fecal Microbiota Transplantation in Patients With Rheumatoid Arthritis Refractory to Methotrexate

Overview

In this 24-week, single center, randomized, double-blind study, the investigators will evaluate the efficacy and safety of fecal microbiota transplantation in patients with active rheumatoid arthritis refractory to methotrexate

Full Title of Study: “Efficacy and Safety of Faecal Microbiota Transplantation in Patients With Rheumatoid Arthritis Refractory to Methotrexate: a 24-week, Double-Blind, Randomised Trial”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Outcomes Assessor)
  • Study Primary Completion Date: March 31, 2020

Detailed Description

Rheumatoid arthritis (RA) is a chronic autoimmune disease, characterized by painful synovium inflammation, bony erosions, immune activation. Gut microbiota plays an important role in pathophysiology of RA. FMT(fecal microbiota transplantation) is the engraftment of microbiota from a healthy donor into a recipient to achieve restoration of the normal gut microbial community structure.This study evaluates the efficacy and safety of FMT with methotrexate in patients with active RA refractory to methotrexate

Objectives:

1. To evaluate the efficacy of FMT with MTX for the treatment of signs and symptoms of RA in patients refractory to MTX.

2. To evaluate the safety of FMT with MTX for the treatment of signs and symptoms of RA in patients refractory to MTX DESIGN

This is a Phase 2, randomized, 24-week, double-blind, parallel group study, and 30 patients with active RA refractory to MTX will be randomized in a 1:1 ratio to one of the following 2 parallel treatment arms:

1. FMT from healthy donor plus methotrexate

2. autologous FMT(from the participant himself/herself) plus methotrexate

Escape:

On week 16, all participants with inadequate response, defined as a <20% improvement of swollen and tender joint counts from baseline can switch type and dose of DMARDs.

Endpoints :

1. Primary endpoint:

ACR20 response rates at 16 weeks.

2. Secondary endpoint: 1)ACR50 and ACR70 response at 16, 24 weeks,ACR20 response at 24 weeks. 2)DAS 28 (CRP) and DAS 28 (ESR) at 16 and 24 weeks. 3) EULAR response rates at 16 and 24 weeks. 4) Health assessment questionnaire (HAQ) at 16 and 24 weeks. 5) Patient assessment of arthritis pain at 16 and 24 weeks. 6) Patient and physician global assessment of arthritis at 16 and 24 weeks

Interventions

  • Procedure: FMT+MTX
    • FMT is performed at the beginning of the study and is repeated after 4 weeks plus MTX in the same dose.

Arms, Groups and Cohorts

  • Experimental: FMT+MTX
    • FMT One FMT is performed at baseline by gastroscopic guidance. The same FMT is repeated 4 weeks later. The transplant consists of 50 g mixed feces obtained from 3-5 non-related healthy donors. The donor feces is suspended into NaCl (0.9%) and glycerol (10%), and will be stored at minus 80 degrees celsius until use. The total volume of the suspension is 150 mL and its temperature will be 37 degrees celsius when infused into ileus of the recipient. Drug: Methotrexate (MTX) Weekly methotrexate
  • Placebo Comparator: autologous FMT+MTX
    • autologous FMT (the feces used in FMT is from participant themselves) One identical FMT is performed at baseline using gastroscopic guidance and is repeated 4 weeks later. The corresponding participant’s feces is suspended into NaCl (0.9%) and glycerol (10%), and will be stored at minus 80 degrees celsius until use. The total volume of the suspension is 150 mL and its temperature will be 37 degrees celsius when infused into ileus of the participant himself or herself. Drug: Methotrexate (MTX) Weekly methotrexate

Clinical Trial Outcome Measures

Primary Measures

  • The American College of Rheumatology 20 (ACR20) response at 16 weeks
    • Time Frame: week 16
    • The difference of ACR20 between Arm 1 (FMT+MTX) and Arm 2 (autologous FMT+MTX)

Secondary Measures

  • The American College of Rheumatology 50/70 (ACR50/ACR70) response at 16 weeks
    • Time Frame: week 16
    • The difference of ACR50/70 between Arm 1 (FMT+MTX) and Arm 2 (autologous FMT+MTX)
  • The American College of Rheumatology 20/50/70 (ACR20/ACR50/ACR70) response at 24 weeks
    • Time Frame: week 24
    • The difference of ACR20, ACR50 and ACR70 between Arm 1 (FMT+MTX) and Arm 2(autologous FMT+MTX) at week 24
  • The Disease Activity Score-28 (DAS28) response at 16 weeks
    • Time Frame: week 16
    • The change in DAS28 score from baseline to week 16 between Arm 1 (FMT+MTX) and Arm 2(autologous FMT+MTX). DAS28 = 0.56*SQRT(TJC28) + 0.28*SQRT(SJC28) + 0.36*ln(CRP + 1) + 0.014*GH + 0.96 TJC28: The number of tender joints (0-28). SJC28: The number of swollen joints (0-28). CRP: The C-Reactive Protein level (in mg/l). GH: The patient global health assessment (from 0=best to 100=worst). The 28 joint: shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints and the knees.
  • The Disease Activity Score-28 (DAS28) response at 24 weeks
    • Time Frame: week 24
    • The change in DAS28 score from baseline to week 24 between Arm 1 (FMT+MTX) and Arm 2(autologous FMT+MTX). DAS28 = 0.56*SQRT(TJC28) + 0.28*SQRT(SJC28) + 0.36*ln(CRP + 1) + 0.014*GH + 0.96 TJC28: The number of tender joints (0-28). SJC28: The number of swollen joints (0-28). CRP: The C-Reactive Protein level (in mg/l). GH: The patient global health assessment (from 0=best to 100=worst). The 28 joint: shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints and the knees.
  • The European League Against Rheumatism (EULAR) response at 16 weeks
    • Time Frame: week 16
    • The difference of proportions of patients meeting EULAR response between Arm 1(FMT+MTX) and Arm 2 (autologous FMT+MTX) at week 16
  • Health Assessment Questionnaire without Didability Index (HAQ-DI) at 16 weeks
    • Time Frame: week 16
    • The change in HAQ-DI score from baseline to week 16 between Arm 1(FMT+MTX) and Arm 2 (autologous FMT+MTX). HAQ-DI is an index measuring the quality of life related to health, which includes 20 questions in terms of three categories: from 0 to 1: mild difficulties to moderate disability, from 1 to 2: disability moderate to severe, from 2 to 3: severe to very severe disability. The mean score is recorded as the result.
  • Incidence of adverse events and sever adverse events (SAE) during the study
    • Time Frame: week 24
    • Safety profile

Participating in This Clinical Trial

Inclusion Criteria

  • Age 18-65 years with informed consent
  • Fulfill the 2010 ACR/EULAR classification criteria for rheumatoid arthritis
  • Positive RF or anti-CCP antibody on screening
  • Have active RA shown by swollen joint count(SJC)≥4 and tender joint count(TJC)≥4 and ESR >28 mm/hr or C-reactive protein > 1.5 ULN
  • Have received methotrexate for 3 months or longer and at a stable dose of 7.5 to 25 mg/week (extremes included) for at least four weeks prior to screening and willing to continue on this regimen for the duration of the study.
  • Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA
  • If taking oral steroids, these should be at a dose ≤10 mg/day of prednisone or prednisone equivalent and stable for at least four weeks prior to screening;
  • If taking non-steroidal anti-inflammatory drugs (NSAIDs), these must be at a stable dose for at least two weeks prior to screening;
  • 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);
  • Women of childbearing potential must use a medically acceptable means of birth control and agree to continue its use during the study and for at least four weeks after the last dose of study drug. Sexually active men must agree to use a medically acceptable form of contraception during the study and continue its use for at least 3 months after the last dose of study drug; and
  • Willing to suspend the use of other adjuvant treatment for the duration of the study including acupuncture, massage, etc.

Exclusion Criteria

  • Pregnant, lactating or further fertility requirements
  • History of any inflammatory rheumatological disorders other than RA;
  • Previously received any biologic agents.
  • Treatment with disease-modifying antirheumatic drugs (DMARDs), other than background methotrexate;
  • Receipt of an intra-articular or parenteral corticosteroid injection within four weeks prior to screening;
  • Active or chronic infection, including HIV, HCV, HBV, tuberculosis.
  • Malignancy or history of malignancy.
  • Severe, progressive, or uncontrolled cardiac, pulmonary, renal, hepatic, gastrointestinal, hematologic, metabolic, endocrine or neurologic disease
  • unable to undergo colonoscopy.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Peking Union Medical College Hospital
  • Provider of Information About this Clinical Study
    • Principal Investigator: Xuan Zhang, Professor – Peking Union Medical College Hospital
  • Overall Official(s)
    • Xuan Zhang, MD, Principal Investigator, Peking Union Medical College Hospital
  • Overall Contact(s)
    • Yue Li, MD, +8618601309256, yuelee76@gmail.com

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