Iguratimod Combined With Tofacitinib in the Treatment of Rheumatoid Arthritis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy and safety of Iguratimod combined with Tofacitinib in the treatment of csDMARD-IR patients with active moderate-to-severe rheumatoid arthritis

Detailed Description
-----------------
After being informed about the study and potential risks, all patients giving written informed consent will undergo a 1-week screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in a double-blind manner (participant and investigator) in a 1:1 ratio to Iguratimod (25mg, twice daily) combined with Tofacitinib (5mg, twice daily) or placebo (25mg, twice daily) combined with Tofacitinib (5mg, twice daily).

Official Title
-----------------
Efficacy and Safety of Iguratimod Combined With Tofacitinib in the Treatment of csDMARD-IR Patients With Active Moderate-to-severe Rheumatoid Arthritis： a Prospective, Randomized, Controlled, Multicenter Study

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: Iguratimod combined with Tofacitinib;


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients who meet the following inclusion criteria will be eligible to participate in the study: Male or female aged 18-65 years old; Weight not less than 40kg; Since the diagnosis of RA, the course of disease was ≥6 months; Patients who meet RA standards in 1987 and 2010 ; RA patients with moderate to high disease activity (DAS28 > 3.2) at the time of screening; Active RA (≥6 joints swelling [66 joints count]; ≥Tenderness of 6 joints [68 joint counts]; ESR>28 mm/h or C-reactive protein (CRP) >1.0 mg/dL); Poor response or intolerance to at least one DMARD, including csDMARDs, bDMARDs, but not tsDMARDs; Previous use of any JAK inhibitor was discontinued for six months before enrollment; For patients who have used DMARDs, the washout criteria must be met; Written informed consent; Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study: Pregnant or lactating women; Platelet count < 10^9/L, or white blood cell < 3*10^9/L, or absolute neutrophil count < 1.2*10^9/L, or Hemoglobin < 9 g/dL or hematocrit <30%; According to Cockcroft-Gault, the glomerular filtration rate was ≤40 ml/min. ALT>1.5×ULN, AST>1.5×ULN, Cr>135umol/L; Subjects with serious cardiovascular, renal, hematologic or endocrine diseases; A history of autoimmune rheumatic diseases other than Sjogren's syndrome; Subjects with uncontrolled infection; Subjects receiving live vaccines within 6 weeks prior to study entry; history of alcohol or drug abuse and abstinence for less than 6 months prior to the first use of the study drug; Subjects participating in other clinical study within 3 months prior to study entry; Have a history of malignant tumor; History of recurrent herpes zoster, diffuse herpes zoster; People who are allergic to any of the study drugs; Other conditions in which the investigator deemed the patient inappropriate for trial entry;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: prospective, randomized, controlled, multicenter study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Double-Blind Iguratimod<br>Iguratimod (25mg twice daily) combined with Tofacitinib (5mg twice daily) for 24 weeks (6 months) | Drug: Iguratimod combined with Tofacitinib;<br>* Iguratimod (taken orally, 25mg, bid, daily) combined with Tofacitinib (taken orally, 5mg, bid, daily); Placebo of Iguratimod (taken orally, 25mg, bid, daily) combined with Tofacitinib (taken orally, 5mg, bid, daily)<br>* Other names: Placebo of Iguratimod combined with Tofacitinib;|
| Placebo Comparator: Double-Blind Placebo<br>Placebo (25mg twice daily) combined with Tofacitinib (5mg twice daily) for 24 weeks (6 months) | Drug: Iguratimod combined with Tofacitinib;<br>* Iguratimod (taken orally, 25mg, bid, daily) combined with Tofacitinib (taken orally, 5mg, bid, daily); Placebo of Iguratimod (taken orally, 25mg, bid, daily) combined with Tofacitinib (taken orally, 5mg, bid, daily)<br>* Other names: Placebo of Iguratimod combined with Tofacitinib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The percentage of patients who achieve clinical remission at week 24 using European League Against Rheumatism (EULAR) response criteria DAS28 | The proportion of patients with DAS28-CRP<2.6 at the end of 24 weeks was compared between the two groups. 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 C reactive protein (CRP, mg/L) and to make a patient assessment of disease activity. | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of American College of Rheumatology [ACR] 20 Criteria Responders at the end of 24 weeks was compared between the two groups. | Percentage of American College of Rheumatology [ACR] 20 Criteria Responders at the end of 24 weeks was compared between the two groups. | week 24 | 
| Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at the end of 24 weeks was compared between the two groups. | Percentage of American College of Rheumatology [ACR] 50 Criteria Responders at the end of 24 weeks was compared between the two groups. | week 24 | 
| Percentage of American College of Rheumatology [ACR] 70 Criteria Responders at the end of 24 weeks was compared between the two groups. | Percentage of American College of Rheumatology [ACR] 70 Criteria Responders at the end of 24 weeks was compared between the two groups. | week 24 | 
| The change of DAS28 score between the two groups at the end of 24 weeks was compared with the baseline value (week 0) | The change of DAS28 score between the two groups at the end of 24 weeks was compared with the baseline value (week 0) | up to week 24 | 
| The change of Clinical Disease Activity Index (CDAI) score between the two groups at the end of 24 weeks was compared with the baseline value (week 0) | The 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 | 
| The change of Simplified Disease Activity Index (SDAI) score between the two groups at the end of 24 weeks was compared with the baseline value (week 0) | 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 | 
| The percentage of patients who achieve clinical remission at week 12 using European League Against Rheumatism (EULAR) response criteria DAS28 | The proportion of patients with DAS28-CRP<2.6 at the end of 12 weeks was compared between the two groups. 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 C reactive protein (CRP, mg/L) and to make a patient assessment of disease activity. | week 12 | 
| The proportion of patients with SDAI≤3.3 at the end of 24 weeks was compared between the two groups. | The proportion of patients with SDAI≤3.3 at the end of 24 weeks was compared between the two groups. | week 24 | 
| The proportion of patients with CDAI≤2.8 at the end of 24 weeks was compared between the two groups. | The proportion of patients with CDAI≤2.8 at the end of 24 weeks was compared between the two groups. | week 24 | 
| The changes of ACPA, RF, serum immunoglobulin (IgG, IgA, IgM) levels between the two groups at the end of 24 weeks were compared with the baseline values (week 0). | The changes of ACPA, RF, serum immunoglobulin (IgG, IgA, IgM) levels between the two groups at the end of 24 weeks were compared with the baseline values (week 0). | up to week 24 | 
| The drug retention rate was compared between the two groups at the end of 12 and 24 weeks. | The drug retention rate was compared between the two groups at the end of 12 | week 12 and 24 | 
| The proportion of patients with minimal clinically important difference (MCID) of 0.22 on the Health Assessment Questionnaire Disability Index (HAQ-DI) was compared between the two groups at the end of 24 weeks. | The proportion of patients with minimal clinically important difference (MCID) of 0.22 on the Health Assessment Questionnaire Disability Index (HAQ-DI) was compared between the two groups at the end of 24 weeks. | week 24 |