The Efficacy and Safety of Tofacitinib (TF) With Iguratimod (IGU) on RA

Study Overview
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Brief Summary
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RA is a common autoimmune disease that causes joint damage.It is necessary to reach the standard as soon as possible and give effective drugs according to the patient's disease activity to avoid disability. Tofacitinib(TF) is a new type of oral tyrosine kinase inhibitor (JAKi) for the treatment of moderate to severe active RA. However, there is alack of Chinese data on the joint scheme, long-term use, maintenance and stop of TF in the real world. We will use the new JAK combination regimen to treat RA patients, and carry out long-term clinical follow-up for 30 weeks.

Detailed Description
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Objective: To observe the clinical efficacy and safety of TF combined with/ without IGU for 30 weeks in patients with moderate to severe active RA with different clinical characteristics and subgroups by using a prospective cohort , and to find the best combination scheme of TF.

Official Title
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Efficacy and Safety of Tofacitinib (TF) Combined With Iguratimod(IGU) in the Treatment of Moderate to Severe Active Rheumatoid Arthritis (RA)

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Iguratimod
* Drug: Tofacitinib
* Drug: Pred


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet the following inclusion criteria will be eligible to participate in the study: Patients who meet RA standards in 1987 and 2010 or ERA standards in 2012; Age > 18 years old; the extrapulmonary manifestations of RA were stable; Patients with NSAIDs tolerance; DAS28-ESR is highergreater than 2.6. Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study: Patients with acute and chronic infection; Platelet count < 80*10^9/L, or white blood cell < 3*10^9/L; ALT or AST is 2 times higher than the upper limit of normal value; Renal insufficiency: serum Cr ≥ 176 umol/L; Pregnant or lactating women (breastfeeding); Have a history of malignant tumor (the cure time is less than 5 years); Patients with severe hypertension and cardiac insufficiency; Other diseases or conditions in which immune suppressants cannot be used; People who are allergic to TF.

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: Tofacitinib (TF)+Iguratimod (IGU)<br>Drug: Iguratimod（IGU），25mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Drug: Tofacitinib（TF），5mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Drug: Prednisone （Pred）： 0-10mg, po, once per day (Qd) prescribed if needed and adjusted due to patient response. | 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: Tofacitinib<br>* Tofacitinib,5mg, 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: TF;Drug: Pred<br>* Pred, 0-10mg, po, once per day (Qd) prescribed if needed and adjusted due to patient response.<br>* Other names: Prednisone;|
| Other: Tofacitinib (TF)<br>Drug: Tofacitinib（TF），5mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Drug: Prednisone （Pred）： 0-10mg, po, once per day (Qd) prescribed if needed and adjusted due to patient response. | Drug: Tofacitinib<br>* Tofacitinib,5mg, 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: TF;Drug: Pred<br>* Pred, 0-10mg, po, once per day (Qd) prescribed if needed and adjusted due to patient response.<br>* Other names: Prednisone;|

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 at week 30 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 30 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients who achieve clinical remission using DAS28-ESR at week 18 | The percentage of patients whose DAS28 achieve remission（DAS28-ESR≤ 2.6）and Low Disease Activity (DAS28-ESR ≤ 3.2) at week 18. | week 18 | 
| The percentage of patients who achieve clinical remission using DAS28-ESR at week 6 | The percentage of patients whose DAS28 achieve remission（DAS28-ESR≤ 2.6）and Low Disease Activity (DAS28-ESR ≤ 3.2) at week 18. | week 6 | 
| Percentage of Disease Activity Score 28 (DAS28) -ESR Criteria Responders at week 30 | △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. | week 30 | 
| Percentage of Disease Activity Score 28 (DAS28) -ESR Criteria Responders at week 18 | EULAR response states were classified as follows: DAS28-ESR Good responders: △DAS28 > 1.2 and DAS28 ≤3.2 at week 18. Moderate responders：△DAS28 > 1.2 and still DAS28 > 3.2 at week 18; or 1.2 ≥△DAS28 > 0.6 and DAS28 ≤ 5.1 at week 18. Nonresponders：△DAS28 ≤0.6，or DAS28 >5.1 at week 18. DAS28-defined remission was classified as a score of <2.6. | week 18 | 
| Percentage of Disease Activity Score 28 (DAS28) -ESR Criteria Responders at week 6 | EULAR response states were classified as follows: DAS28-ESR Good responders: △DAS28 > 1.2 and DAS28 ≤3.2 at week 6. Moderate responders：△DAS28 > 1.2 and still DAS28 > 3.2 at week 6; or 1.2 ≥△DAS28 > 0.6 and DAS28 ≤ 5.1 at week 6. Nonresponders：△DAS28 ≤0.6，or DAS28 >5.1 at week 6. DAS28-defined remission was classified as a score of <2.6. | week 6 | 
| Percentage of participants achieving ACR/EULAR remission at week 30 | 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 30 | 
| Percentage of participants achieving ACR/EULAR remission at week 18 | 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 18 | 
| Percentage of participants achieving ACR/EULAR remission at week 6 | 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 6 | 
| 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 30 | 
| 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 30 | 
| 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 30 | 
| 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 30 | 
| Change from baseline Health Assessment Questionnaire Disability Index (HAQ-DI) | Change 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 30 | 
| Percentage of American College of Rheumatology [ACR] 20 Criteria Responders every time | Percentage of American College of Rheumatology [ACR] 20 Criteria Responders every time | up to week 30 | 
| Incidence of participant withdrawal | Percentage of participants who withdraw from this study. | up to week 30 | 
| 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 30 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tofacitinib, Iguratimod