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

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

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

Study Overview

• Status: Completed
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: Tacrolimus; Drug: MTX

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Feiying Wang; Phone Number: 0086-0531-82169654; Email: 375286453@qq.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250012
      • Qilu hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients diagnosed based on 1987 ACR classification criteria for rheumatoid arthritis;
2. Age ≥18 years;
3. 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;
4. Medium or high disease activity (DAS28≥3.2);
5. Extra-articular manifestations (such as pulmonary fibrosis, proteinuria, leukopenia and peripheral neuropathy ) of RA patients are stable or no significant progress;
6. Dose of prednisone and NSAIDs remain stable for at least one month.

Exclusion Criteria:

1. Patients with acute or chronic infections such as active bacterial, viral, fungal, tuberculosis infection or active hepatitis B;
2. Platelet counts(PLT) <80 x 10^9 / L, or white blood cell (WBC) <3 x 10^9 / L;
3. Propionate acid aminotransferase (ALT) or aspartate aminotransferase (AST) is two times higher than the upper limit of normal;
4. Renal insufficiency: serum Cr ≥ 176 umol / L;
5. Pregnant or nursing women (breastfeeding) ；
6. Patients has a history of malignancy (cure time in less than 5 years);
7. Patients with severe or poorly controlled hypertension, diabetes or cardiac dysfunction;
8. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tacrolimus group; RA patients treated with tacrolimus, without MTX	Drug: Tacrolimus; 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.; Other Names: FK506
Active Comparator: Tacrolimus + MTX group; RA patients treated with tacrolimus and MTX	Drug: Tacrolimus; 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.; Other Names: FK506; Drug: MTX; MTX：5mg to 15mg, po, once per week (Qw) until the endpoint or adjusted due to unacceptable toxicity develops.; Other Names: methotrexate

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Qiang Shu
• Investigators: Principal Investigator: Qiang Shu, Dr., Qilu Hospital of Shandong University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): September 30, 2022
• Study Completion (Actual): December 30, 2022

Study Registration Dates

• First Submitted: July 13, 2016
• First Submitted That Met QC Criteria: July 15, 2016
• First Posted (Estimated): July 20, 2016

Study Record Updates

• Last Update Posted (Actual): November 18, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Safety; Tacrolimus; Treatment outcome; Arthritis, Rheumatoid
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Methotrexate; Tacrolimus
• Other Study ID Numbers: Tacrolimus RA QiluH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available within 12 months of study completion.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No