The Clinical Efficacy of Immunomodulators in RA Patients

The Clinical Study to Observe the Efficacy and Safety of Immunomodulators in Rheumatoid Arthritis Patients for 6 Months Treatment in China

This study includes naive patients and csDMARDs-IR RA patients, treated with different regimens such as Iguratimod combination of different csDMARDs, or csDMARD with TNF inhibitors for 24 weeks. The disease activity and drug response will be observed. The immune disorder and synovial function will be evaluated at the same time.

Study Overview

• Status: Recruiting
• Conditions: Arthritis, Rheumatoid
• Intervention / Treatment: Drug: Iguratimod; Drug: Methotrexate; Drug: Adalimumab Injection; Drug: Leflunomide; Drug: Hydroxychloroquine

Detailed Description

In this study cohorts, naïve or csDMARDs-IR patients are treated with different csDMARDs combination or TNF inhibitors for 24 weeks to get remission in clinical. The biomarkers in their plasma and synovial fluid and tissue specimens from RA patients are screened to predict the efficacy of specific treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Bingbing Ren; Phone Number: 0086-18765361979; Email: sdrenbingbing@163.com

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250012
      • Recruiting
      • Qilu hospital
      • Contact: Xiaoyun Yang, Dr.; Phone Number: 0086-0531-82169166; Email: qlyykyc@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

-

1.Patients with RA who meet ACR 1987 rheumatoid arthritis classification criteria or ACR/EULAR 2010 rheumatoid arthritis Classification Criteria and have knee dysfunction.

1. ACR 1987 rheumatoid arthritis classification criteria

   1. morning stiffness lasting at least 1 hour (≥6w)
   2. there are 3 or more joint areas swollen (≥6w)
   3. swelling of the wrist, metacarpophalangeal, and proximal phalangeal joint areas (≥6w)
   4. symmetrical arthrogryposis (≥6w)
   5. hand x-ray changes (at least osteoporosis and joint space narrowing)
   6. positive rheumatoid factor (titer > 1:32) RA can be diagnosed by meeting 4 of the above 7 items

2. ACR/EULAR 2010 rheumatoid arthritis Classification Criteria

   1. Involved joints

      - 1 large joint (0 points)

      • 2-10 large joints (1 point)
      • 1-3 small joints (with or without large joints) (2 points)
      • 4-10 small joints (with or without large joints) (3 points)
      • more than 10 small joints (at least one small joint) (5 points)

   2. Serological indicators

      • RF and ACPA negative (0 points)
      • RF and ACPA, at least one of which is low titer positive. (2 points)
      • RF and ACPA with at least one high titer positive (3 points)

   3. Acute chronotropic reactants

      • Both CRP and ESR normal (0 points)
      • Abnormal CRP or ESR (1 point)

   4. Duration of synovitis

      • <6 weeks (0 points)

      • ≥6 weeks (1 point)

        2.Patients with OA who meet the 1995 Classification Criteria for OA and have knee dysfunction 1995 Classification Criteria for Osteoarthritis of the Knee Clinical criteria

        a. Knee pain most of the time in the last 1 month b. Bone rubbing sound c, morning stiffness ≤ 30 minutes d, age ≥ 38 years e, with bony enlargement Knee OA can be diagnosed if a+b+c+d or a+b+e is met

        3.Age-sex matched healthy volunteers who checked in our hospital.

        4.Age > 18 years old;

        5.Voluntarily participate in this study and sign an informed consent form

Exclusion Criteria:

1. Patients with combined active hepatitis
2. Patients with active tuberculosis
3. Patients withinfection and malignancy

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methotrexate(MTX)+Iguratimod(IGU); Drug: Iguratimod（IGU），25mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Drug: Methotrexate(MTX)，10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. For RA patients with naive or csDMARDs-IR	Drug: Iguratimod; 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.; Other Names: IGU; T-614; Drug: Methotrexate; Methotrexate，10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.; Other Names: MTX
Experimental: Adalimumab+Methotrexate(MTX); Drug: Adalimumab，40mg, iH,q2w, once two weeks (q2w) prescribed at the beginning and adjusted due to patient response. Drug: Methotrexate(MTX)，7-10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. For RA patients with csDMARDs-IR	Drug: Methotrexate; Methotrexate，10mg, po, quaque week (qw) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.; Other Names: MTX; Drug: Adalimumab Injection; Adalimumab Injection，40mg，iH，every two weeks (q2w) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.; Other Names: adalimu
Experimental: Iguratimod(IGU)+Leflunomide(LEF)+Hydroxychloroquine(HCQ); Drug: Iguratimod（IGU），25mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. Drug: Leflunomide(LEF)，20mg, po, quaque day (qd) prescribed at the beginning and adjusted due to patient response. Drug: Hydroxychloroquine(HCQ)，200mg, po, twice per day (Bid) prescribed at the beginning and adjusted due to patient response. For RA patients with csDMARDs-IR	Drug: Iguratimod; 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.; Other Names: IGU; T-614; Drug: Leflunomide; Leflunomide，20mg, po, quaque day (qd) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.; Other Names: LEF; Drug: Hydroxychloroquine; Hydroxychloroquine，200mg, po, twice per day (bid) prescribed at the beginning and adjusted due to patient response. Then may titer down until the endpoint.; Other Names: HCQ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of patients who achieve clinical remission 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 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percentage of patients who achieve clinical remission using DAS28-ESR.	The percentage of patients whose DAS28 achieve remission（DAS28-ESR≤ 2.6）and Low Disease Activity (DAS28-ESR ≤ 3.2) .	week 12
Percentage of Disease Activity Score 28 (DAS28) -ESR Criteria Responders	△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.	baseline,week 12,week 24
Percentage of participants achieving ACR/EULAR remission	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 12,week 24
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 24
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 24
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 24
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 24
Change from baseline Health Assessment Questionnaire Disability Index (HAQ-DI)	hange 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 24
Percentage of American College of Rheumatology [ACR] 20、 [ACR]50、 [ACR]70 Criteria Responders every time	Percentage of American College of Rheumatology [ACR] 20、 [ACR]50、 [ACR]70 Criteria Responders every time.	up to week 24
Incidence of participant withdrawal	Percentage of participants who withdraw from this study.	up to week 24
Number of participants with"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. Number of participants with"adverse 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 24

Collaborators and Investigators

• Sponsor: Qilu Hospital of Shandong University
• Investigators: Study Director: Xiaoyun Yang, Qilu Hospital of Shandong University

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2021
• Primary Completion (Anticipated): June 30, 2025
• Study Completion (Anticipated): December 31, 2026

Study Registration Dates

• First Submitted: November 15, 2022
• First Submitted That Met QC Criteria: November 15, 2022
• First Posted (Actual): November 23, 2022

Study Record Updates

• Last Update Posted (Actual): November 29, 2022
• Last Update Submitted That Met QC Criteria: November 28, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: csDMARDs; TNFi
• 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; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Adalimumab; Methotrexate; Leflunomide; Hydroxychloroquine
• Other Study ID Numbers: Response of DMARDs in RA QiluH

Drug and device information, study documents

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