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

Primary Purpose

Arthritis, Rheumatoid

Status
Unknown status
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Tacrolimus
MTX
Sponsored by
Qiang Shu
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Arthritis, Rheumatoid focused on measuring Arthritis, Rheumatoid, Tacrolimus, Treatment outcome, Safety

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Qilu HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tacrolimus group

Tacrolimus + MTX group

Arm Description

RA patients treated with tacrolimus, without MTX

RA patients treated with tacrolimus and MTX

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Change from baseline ACR20 response rate at 24 and longer weeks.
Change from baseline ACR20 response rate at 24 and longer weeks.
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.
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。
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.
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.
Change from baseline Erythrocyte Sedimentation Rate (ESR) at 24 and longer weeks.
Change from baseline Erythrocyte Sedimentation Rate (ESR) at 24 and longer weeks.
Change from baseline C-Reactive Protein (CRP) at 24 and longer weeks.
Change from baseline C-Reactive Protein (CRP) at 24 and longer weeks.
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.
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.
Change from baseline patient global assessment(PGA) at 24 and longer weeks.
Change from baseline patient global assessment(PGA) at 24 and longer weeks.
Change from baseline physician global assessment(PHGA) at 24 and longer weeks.
Change from baseline physician global assessment(PHGA) at 24 and longer weeks.
Change from baseline Health Assessment Questionnaire (HAQ) at 24 and longer weeks.
Change from baseline Health Assessment Questionnaire (HAQ) at 24 and longer weeks.
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
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.

Full Information

First Posted
July 13, 2016
Last Updated
October 7, 2020
Sponsor
Qiang Shu
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1. Study Identification

Unique Protocol Identification Number
NCT02837978
Brief Title
The Efficacy and Safety of Tacrolimus in Refractory Rheumatoid Arthritis Patients for 6 Months and Long-term Treatment
Official Title
Prospective Clinical Study to Observe the Efficacy and Safety of Tacrolimus in Refractory Rheumatoid Arthritis Patients for 6 Months Treatment in China
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Unknown status
Study Start Date
January 2015 (Actual)
Primary Completion Date
October 30, 2020 (Anticipated)
Study Completion Date
January 30, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Qiang Shu

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arthritis, Rheumatoid
Keywords
Arthritis, Rheumatoid, Tacrolimus, Treatment outcome, Safety

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Tacrolimus group
Arm Type
Experimental
Arm Description
RA patients treated with tacrolimus, without MTX
Arm Title
Tacrolimus + MTX group
Arm Type
Active Comparator
Arm Description
RA patients treated with tacrolimus and MTX
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK506
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
MTX
Other Intervention Name(s)
methotrexate
Intervention Description
MTX：5mg to 15mg, po, once per week (Qw) until the endpoint or adjusted due to unacceptable toxicity develops.
Primary Outcome Measure Information:
Title
Change from baseline Disease Activity Score 28 (DAS28-ESR) at 24 and longer weeks.
Description
Change from baseline Disease Activity Score 28 (DAS28) erythrocyte sedimentation rate (ESR) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Secondary Outcome Measure Information:
Title
Change from baseline ACR20 response rate at 24 and longer weeks.
Description
Change from baseline ACR20 response rate at 24 and longer weeks.
Time Frame
Baseline,12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
The clinical remission rate at 24 and longer weeks.
Description
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.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Clinical response was analyzed using the European League Against Rheumatism (EULAR) improvement criteria.
Description
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。
Time Frame
12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline Simplified Disease Activity Index (SDAI) at 24 and longer weeks.
Description
Change from baseline Simplified Disease Activity Index (SDAI) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline Clinical disease activity index (CDAI) at 24 and longer weeks.
Description
Change from baseline Clinical disease activity index (CDAI) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline Erythrocyte Sedimentation Rate (ESR) at 24 and longer weeks.
Description
Change from baseline Erythrocyte Sedimentation Rate (ESR) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline C-Reactive Protein (CRP) at 24 and longer weeks.
Description
Change from baseline C-Reactive Protein (CRP) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline swollen joint number (SW28) at 24 and longer weeks.
Description
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.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline tenderness joint number (T28) at 24 and longer weeks.
Description
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.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline patient global assessment(PGA) at 24 and longer weeks.
Description
Change from baseline patient global assessment(PGA) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline physician global assessment(PHGA) at 24 and longer weeks.
Description
Change from baseline physician global assessment(PHGA) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Change from baseline Health Assessment Questionnaire (HAQ) at 24 and longer weeks.
Description
Change from baseline Health Assessment Questionnaire (HAQ) at 24 and longer weeks.
Time Frame
Baseline, 12 weeks, 24wks,36 wks,48 wks,72 wks,96 wks,120 wks,144 wks
Title
Safety assessed by Adverse Events (AEs)
Description
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
Time Frame
Up to 144wks
Title
Safety assessed by incidence of serious adverse events (SAE)
Description
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.
Time Frame
Up to 144wks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Qiang Shu, Dr.
Phone
0086-0531-82169654
Email
shuqiang@sdu.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Feiying Wang
Phone
0086-0531-82169654
Email
375286453@qq.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Qiang Shu, Dr.
Organizational Affiliation
Qilu Hospital of Shandong University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Qilu Hospital
City
Jinan
State/Province
Shandong
ZIP/Postal Code
250012
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ming Lv, Prof.
Phone
0086-0531-82169166
Email
qlyykyc@163.com

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
De-identified individual participant data for all primary and secondary outcome measures will be made available within 12 months of study completion.

Learn more about this trial

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

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