The Clinical Efficacy of Immunomodulators in RA Patients

Study Overview
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Brief Summary
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This study includes naive patients and csDMARDs-IR RA patients, treated with different regimens such as Iguratimod combination of different csDMARDs, or csDMARD with TNF inhibitors for 24 weeks. The disease activity and drug response will be observed. The immune disorder and synovial function will be evaluated at the same time.

Detailed Description
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In this study cohorts, naïve or csDMARDs-IR patients are treated with different csDMARDs combination or TNF inhibitors for 24 weeks to get remission in clinical. The biomarkers in their plasma and synovial fluid and tissue specimens from RA patients are screened to predict the efficacy of specific treatment.

Official Title
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The Clinical Study to Observe the Efficacy and Safety of Immunomodulators in Rheumatoid Arthritis Patients for 6 Months Treatment in China

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Iguratimod
* Drug: Methotrexate
* Drug: Adalimumab Injection
* Drug: Leflunomide
* Drug: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - 1.Patients with RA who meet ACR 1987 rheumatoid arthritis classification criteria or ACR/EULAR 2010 rheumatoid arthritis Classification Criteria and have knee dysfunction. ACR 1987 rheumatoid arthritis classification criteria morning stiffness lasting at least 1 hour (≥6w) there are 3 or more joint areas swollen (≥6w) swelling of the wrist, metacarpophalangeal, and proximal phalangeal joint areas (≥6w) symmetrical arthrogryposis (≥6w) hand x-ray changes (at least osteoporosis and joint space narrowing) positive rheumatoid factor (titer > 1:32) RA can be diagnosed by meeting 4 of the above 7 items ACR/EULAR 2010 rheumatoid arthritis Classification Criteria Involved joints - 1 large joint (0 points) 2-10 large joints (1 point) 1-3 small joints (with or without large joints) (2 points) 4-10 small joints (with or without large joints) (3 points) more than 10 small joints (at least one small joint) (5 points) Serological indicators RF and ACPA negative (0 points) RF and ACPA, at least one of which is low titer positive. (2 points) RF and ACPA with at least one high titer positive (3 points) Acute chronotropic reactants Both CRP and ESR normal (0 points) Abnormal CRP or ESR (1 point) Duration of synovitis <6 weeks (0 points) ≥6 weeks (1 point) 2.Patients with OA who meet the 1995 Classification Criteria for OA and have knee dysfunction 1995 Classification Criteria for Osteoarthritis of the Knee Clinical criteria a. Knee pain most of the time in the last 1 month b. Bone rubbing sound c, morning stiffness ≤ 30 minutes d, age ≥ 38 years e, with bony enlargement Knee OA can be diagnosed if a+b+c+d or a+b+e is met 3.Age-sex matched healthy volunteers who checked in our hospital. 4.Age > 18 years old; 5.Voluntarily participate in this study and sign an informed consent form Exclusion Criteria: Patients with combined active hepatitis Patients with active tuberculosis Patients withinfection and malignancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methotrexate(MTX)+Iguratimod(IGU)<br>Drug: Iguratimod（IGU），25mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Drug: Methotrexate(MTX)，10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. For RA patients with naive or csDMARDs-IR | Drug: Iguratimod<br>* Iguratimod tablet，25mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.<br>* Other names: T-614;Drug: Methotrexate<br>* Methotrexate，10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.<br>* Other names: MTX;|
| Experimental: Adalimumab+Methotrexate(MTX)<br>Drug: Adalimumab，40mg, iH,q2w, once two weeks (q2w) prescribed at the beginning and adjusted due to patient response. Drug: Methotrexate(MTX)，7-10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. For RA patients with csDMARDs-IR | Drug: Methotrexate<br>* Methotrexate，10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.<br>* Other names: MTX;Drug: Adalimumab Injection<br>* Adalimumab Injection，40mg，iH，every two weeks (q2w) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.<br>* Other names: adalimu;|
| Experimental: Iguratimod(IGU)+Leflunomide(LEF)+Hydroxychloroquine(HCQ)<br>Drug: Iguratimod（IGU），25mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Drug: Leflunomide(LEF)，20mg, po, quaque day (qd) prescribed at the beginning and adjusted due to patient response. Drug: Hydroxychloroquine(HCQ)，200mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. For RA patients with csDMARDs-IR | Drug: Iguratimod<br>* Iguratimod tablet，25mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.<br>* Other names: T-614;Drug: Leflunomide<br>* Leflunomide，20mg, po, quaque day (qd) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.<br>* Other names: LEF;Drug: Hydroxychloroquine<br>* Hydroxychloroquine，200mg, po, twice per day (bid) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.<br>* Other names: HCQ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients who achieve clinical remission using European League Against Rheumatism (EULAR) response criteria DAS28. | The percentage of patients whose Disease Activity Score in 28 Joints (DAS28) achieve remission（DAS28-ESR≤ 2.6）and Low Disease Activity (DAS28-ESR ≤ 3.2). The DAS28 is a composite score derived from 4 of these measures，that is the count of tender joint count（TJC, 0-28）and swollen joint count（SJC, 0-28）, measure erythrocyte sedimentation rate (ESR, mm/h) or C reactive protein (CRP, mg/L) and to make a patient assessment of disease activity i.e. 'global assessment of health' (GH) using a 100 mm visual analogue scale (VAS) with 0 = best, 100 = worst. DAS28 values were calculated as follows: DAS28- ESR = 0.56√(TJC) + 0.28√(SJC) + 0.70 ln ESR + 0.014 x GH. High disease activity: DAS28-ESR > 5.1; Moderate disease activity: 5.1≥ DAS28 > 3.2 to 5.1; Low disease activity (LDA) and Remission mean Clinical remission. | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients who achieve clinical remission using DAS28-ESR. | The percentage of patients whose DAS28 achieve remission（DAS28-ESR≤ 2.6）and Low Disease Activity (DAS28-ESR ≤ 3.2) . | week 12 | 
| Percentage of Disease Activity Score 28 (DAS28) -ESR Criteria Responders | △DAS28 indicates the decline of DAS28-ESR from the baseline to week 30. EULAR response states were classified as follows: good responders were patients with an improvement from baseline (△DAS28-ESR) of > 1.2 and a DAS28-ESR at week 30 ≤ 3.2. Moderate responders: △DAS28 > 1.2 and still DAS28 > 3.2 at week 30, or 1.2 ≥△DAS28 > 0.6 and DAS28 ≤ 5.1 at week 30. Nonresponders：△DAS28 ≤0.6 or DAS28 >5.1 at week 30. DAS28-defined remission was classified as a score of <2.6. | baseline,week 12,week 24 | 
| Percentage of participants achieving ACR/EULAR remission | If all of the following 4 parameters are fulfilled, it is defined as remission: TJC ≤ 1, SJC ≤ 1, CRP ≤ 1 mg/dL, Patient global assessment（PGA） ≤ 1 cm (on a visual analog scale ranging from 0-10 cm, with higher scores indicating severe disease). | week 12,week 24 | 
| Change from baseline Simplified Disease Activity Index (SDAI) | The SDAI is a composite score derived from these measures，that is the count of tender joint count（TJC, 0-28）, swollen joint count（SJC, 0-28）, C-reactive protein (CRP, mg/L), Patient global assessment（PGA）and physician global assessment（PHGA）, each of the last two was assessed on a visual analog scale ranging from 0-10 cm, with higher scores indicating severe disease. SDAI score will be calculated with formula SDAI = TJC + SJC + PGA+PHGA+ CRP. SDAI score exceeding 26 is considered high disease activity; 11 <SDAI ≤26，moderate disease activity; 3.3 <SDAI ≤11, low disease activity; remission is SDAI score ≤ 3.3. | up to week 24 | 
| Change from baseline Clinical Disease Activity Index (CDAI) | Change from baseline Clinical Disease Activity Index (CDAI) CDAI is a composite score derived from these measures，that is the count of tender joint count（TJC, 0-28）, swollen joint count（SJC, 0-28）, Patient global assessment（PGA）and physician global assessment（PHGA）, each of the last two was CDAI score will be calculated with formula CDAI = TJC + SJC + PGA + PHGA. CDAI > 22 is considered high disease activity; 10 <CDAI ≤ 22, moderate disease activity; 2.8 <CDAI ≤10, low disease activity; remission is CDAI score ≤2.8. | up to week 24 | 
| Change From Baseline in C-reactive Protein (CRP) | Change from Baseline in C-reactive Protein (CRP), a component index of ACR20 and SDAI, CRP will be measured with blood samples. | up to week 24 | 
| Change From Baseline in Erythrocyte Sedimentation Rate (ESR) | Change from Baseline in ESR, that is a component index of ACR20, DAS28-ESR and SDAI, ESR will be measured with blood samples. | up to week 24 | 
| Change from baseline Health Assessment Questionnaire Disability Index (HAQ-DI) | hange from Baseline in HAQ-DI, a participant assessed measure of health assessment, shaveing eight dimensions of functional activity: pruning, dressing, rising, eating, walking, personal hygiene, reach, grip, and other routine activities. Each item on a single scale has 4 degrees ranging from 0 (no functional difficulty) to 3 (unable to do), with higher scores indicating severe disease. | up to week 24 | 
| Percentage of American College of Rheumatology [ACR] 20、 [ACR]50、 [ACR]70 Criteria Responders every time | Percentage of American College of Rheumatology [ACR] 20、 [ACR]50、 [ACR]70 Criteria Responders every time. | up to week 24 | 
| Incidence of participant withdrawal | Percentage of participants who withdraw from this study. | up to week 24 | 
| Number of participants withadverse events (AEs) | An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Number of participants withadverse events (AEs)i.e. physical exam abnormalities，vital sign abnormalities，laboratory value abnormalities，symptom or disease (new or exacerbated) temporally associated with the use of a medicinal product. | up to week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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csDMARDs, TNFi