The Efficacy and Safety of Tacrolimus in Refractory Rheumatoid Arthritis Patients for 6 Months and Long-term Treatment

Study Overview
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Brief Summary
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This study is designed to observed prospectively the efficacy and safety of 6 months and long-term treatment of Tacrolimus alone or with methotrexate (MTX) in moderate and severe Chinese RA patients who shown insufficiency response or intolerance to DMARDs

Detailed Description
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This study will enroll 150 cases of refractory rheumatoid arthritis (RA) patients in Chinese，who are in moderate or severe disease activity and insufficiency response or intolerance to DMARDs. The participants plan to be treated with Tacrolimus alone, or along with methotrexate (MTX) if participants were tolerant to MTX. The efficacy and safety of 6 month Tacrolimus treatment in RA patients will be evaluated with DAS28 and other disease activity indices.

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

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: MTX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed based on 1987 ACR classification criteria for rheumatoid arthritis; Age ≥18 years; Patients have a history of DMARDs including csDMARDs（methotrexate，leflunomide, hydroxychloroquine, iguratimod, sulfasalazine) or any biologic DMARDs（TNFi，tocilizumab or Tofacitinib），prednisone or Chinese traditional Medicine（tripterygium Glycosides，Sinomenine）for 3 months, but couldn't achieve clinical remission， or couldn't tolerate one or more DMARDs; Medium or high disease activity (DAS28≥3.2); Extra-articular manifestations (such as pulmonary fibrosis, proteinuria, leukopenia and peripheral neuropathy ) of RA patients are stable or no significant progress; Dose of prednisone and NSAIDs remain stable for at least one month. Exclusion Criteria: Patients with acute or chronic infections such as active bacterial, viral, fungal, tuberculosis infection or active hepatitis B; Platelet counts(PLT) <80 x 10^9 / L, or white blood cell (WBC) <3 x 10^9 / L; Propionate acid aminotransferase (ALT) or aspartate aminotransferase (AST) is two times higher than the upper limit of normal; Renal insufficiency: serum Cr ≥ 176 umol / L; Pregnant or nursing women (breastfeeding) ； Patients has a history of malignancy (cure time in less than 5 years); Patients with severe or poorly controlled hypertension, diabetes or cardiac dysfunction; Other comorbidities that cannot be treated with immune suppressants. In addition, once patients experience severe adverse drug reactions、ineffective treatment or rapid progression of rheumatoid arthritis, then quit this research.

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: Tacrolimus group<br>RA patients treated with tacrolimus, without MTX | Drug: Tacrolimus<br>* Tacrolimus capsule: 0.5mg to 1mg, po, twice per day (Bid)，adjusted by its concentration in blood or due to patient response. Then may titer down until the endpoint.<br>* Other names: FK506;|
| Active Comparator: Tacrolimus + MTX group<br>RA patients treated with tacrolimus and MTX | Drug: Tacrolimus<br>* Tacrolimus capsule: 0.5mg to 1mg, po, twice per day (Bid)，adjusted by its concentration in blood or due to patient response. Then may titer down until the endpoint.<br>* Other names: FK506;Drug: MTX<br>* MTX：5mg to 15mg, po, once per week (Qw) until the endpoint or adjusted due to unacceptable toxicity develops.<br>* Other names: methotrexate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline Disease Activity Score 28 (DAS28-ESR) at 24 and longer weeks. | Change from baseline Disease Activity Score 28 (DAS28) erythrocyte sedimentation rate (ESR) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline ACR20 response rate at 24 and longer weeks. | Change from baseline ACR20 response rate at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| The clinical remission rate at 24 and longer weeks. | The percentage of patients who achieve clinical remission patients at the endpoint or withdraw timepoint. High disease activity: DAS28 score exceeding 5.1, Moderate disease activity: DAS28 score of exceeding 3.2 to 5.1, Low disease activity (LDA): DAS28 score of less than or equal to 3.2, Remission: DAS28 score is less than 2.6. clinical remission means Low disease activity or remission. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Clinical response was analyzed using the European League Against Rheumatism (EULAR) improvement criteria. | Good response: ΔDAS28 > 1.2 and DAS28 ≤3.2； Moderate response: 1.2 ≥ΔDAS28 > 0.6 and 3.2<DAS28 ≤5.1； or ΔDAS28 > 1.2 and still DAS28>3.2； No response:ΔDAS28≤0.6； or 1.2≥ΔDAS28 > 0.6 and DAS28>5.1。 | 12 week,3 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline Simplified Disease Activity Index (SDAI) at 24 and longer weeks. | Change from baseline Simplified Disease Activity Index (SDAI) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline Clinical disease activity index (CDAI) at 24 and longer weeks. | Change from baseline Clinical disease activity index (CDAI) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline Erythrocyte Sedimentation Rate (ESR) at 24 and longer weeks. | Change from baseline Erythrocyte Sedimentation Rate (ESR) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline C-Reactive Protein (CRP) at 24 and longer weeks. | Change from baseline C-Reactive Protein (CRP) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline swollen joint number (SW28) at 24 and longer weeks. | Change from baseline swollen joint number (SW28) at 24 and longer weeks. SW28 means the number of joints with swelling counted in 28 synovial joints, including proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2) bilateral. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline tenderness joint number (T28) at 24 and longer weeks. | Change from baseline tenderness joint number (T28) at 24 and longer weeks. T28 means the number of joints with tenderness upon touching counted in 28 synovial joints, including proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2) and knees (2) bilateral. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline patient global assessment(PGA) at 24 and longer weeks. | Change from baseline patient global assessment(PGA) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline physician global assessment(PHGA) at 24 and longer weeks. | Change from baseline physician global assessment(PHGA) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Change from baseline Health Assessment Questionnaire (HAQ) at 24 and longer weeks. | Change from baseline Health Assessment Questionnaire (HAQ) at 24 and longer weeks. | 12 week, 24week,36 week,48 week,72 week,96 week,120 week,144 week | 
| Safety assessed by Adverse 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product | Up to 144 weeks | 
| Safety assessed by incidence of serious adverse events (SAE) | Adverse Event is considered serious if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event. | Up to 144 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arthritis, Rheumatoid, Tacrolimus, Treatment outcome, Safety