Efficacy and Safety of Selective JAK 1 Inhibitor Filgotinib in Active Rheumatoid Arthritis Patients With Inadequate Response to Methotrexate

Study Overview
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Brief Summary
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The administration of Janus kinase (JAK) inhibitors as well as biological disease-modifying anti-rheumatic drugs has dramatically improved even the clinical outcomes in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX). The dysregulation of JAK-signal transducer and activator of transcription (STAT) pathways via overproduction of cytokines, such as interleukin-6 (IL-6) is involved in the pathogenesis of RA. Filgotinib is a selective JAK1 inhibitor to be approved for use in RA. Filgotinib is effective in suppressing disease activity and preventing the progression of joint destruction due to inhibition of the JAK-STAT pathway. IL-6 inhibitors such as tocilizumab also inhibit the JAK-STAT pathways due to inhibition of IL-6 signaling. We will evaluate whether the effectiveness and safety of filgotinib monotherapy is non-inferior to those of tocilizumab monotherapy in RA patients with inadequate response to MTX.

Official Title
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Efficacy and Safety of Selective JAK 1 Inhibitor Filgotinib in Active Rheumatoid Arthritis Patients With Inadequate Response to Methotrexate: Comparative Study With Filgotinib and Tocilizumab Examined by Clinical Index as Well as Musculoskeletal Ultrasound Assessment

Conditions
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Rheumatoid Arthritis, JAK Inhibitor, IL-6 Inhibitor, Musculoskeletal Ultrasound, Biomarker

Intervention / Treatment
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* Drug: filgotinib 200mg/day
* Drug: subcutaneous tocilizumab 162mg/biweekly


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all of the following requirements to be considered for entry into the study: ≥20 years old with the diagnosis of RA based on the ACR/EULAR 2010 RA Classification Criteria with at least moderate disease activity defined as a DAS28-ESR ≥3.2 at the eligibility evaluation treated with MTX for ≥8 weeks prior to the providing consent, including 4 weeks or more at the same doses of 8 to 16 mg per week (stable doses of <8 mg per week are allowed only in the presence of intolerance to higher doses) ability and willingness to provide written informed consent and comply with the requirements of the study protocol Exclusion Criteria: The exclusion criteria are as follows: concurrent use of a corticosteroid equivalent to >5 mg/day of prednisolone applicable an item for the contraindication of filgotinib or tocilizumab a previous use of a JAK inhibitor or IL-6 inhibitor treatment with a corticosteroid and csDMARD and change of dose within 4 weeks prior to the providing consent treatment with a biologic DMARD or a biosimilar DMARD (ie, infliximab, biosimilar of infliximab, adalimumab, biosimilar of adalimumab, golimumab, certolizumab pegol or abatacept) within 8 weeks prior to the providing consent treatment with a TNF inhibitor (ie, etanercept or biosimilar of etanercept) within 4 weeks prior to the providing consent use of a prohibited drug or therapy, other than the agents noted above, within 4 weeks prior to the providing consent a complication causing musculoskeletal disorders other than RA (ie, ankylosing spondyloarthritis, reactive arthritis, psoriatic arthritis, crystal-induced arthritis, systemic lupus erythematosus, systemic scleroderma, inflammatory myopathy, or mixed connective tissue disease) current pregnancy, breastfeeding, or noncompliant with a medically approved contraceptive regimen during and 12 months after the study period inappropriateness for inclusion in this study as determined by the investigator

Ages Eligible for Study
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Minimum Age: 20 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Filgotinib monotherapy<br>The administration of filgotinib 200mg/day switched from MTX ± other csDMARDs throughout the study period. | Drug: filgotinib 200mg/day<br>* Patients will be randomized in a 1:1 ratio to the administration of filgotinib 200mg/day or subcutaneous tocilizumab 162mg/biweekly switched from MTX ± other csDMARDs throughout the study period.<br>|
| Active Comparator: Tocilizumab monotherapy<br>The administration of subcutaneous tocilizumab 162mg/biweekly switched from MTX ± other csDMARDs throughout the study period. | Drug: subcutaneous tocilizumab 162mg/biweekly<br>* Patients will be randomized in a 1:1 ratio to the administration of filgotinib 200mg/day or subcutaneous tocilizumab 162mg/biweekly switched from MTX ± other csDMARDs throughout the study period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the proportion of patients who achieve an American College of Rheumatology (ACR) 50 response |  | at week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the proportion of patients who achieve an ACR20 response |  | at weeks 2, 4, 8, 12, 24, 36 and 52 | 
| the proportion of patients who achieve an ACR50 response |  | at weeks 2, 4, 8, 24, 36 and 52 | 
| the proportion of patients who achieve an ACR70 response |  | at weeks 2, 4, 8, 12, 24, 36 and 52 | 
| changes in the clinical disease activity index (CDAI) value | Higher scores mean a more active of RA. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| changes in the simplified disease activity index (SDAI) value | Higher scores mean a more active RA. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| changes in the Disease Activity Score (DAS)28-ESR value | Higher scores mean a more active RA. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| changes in the DAS28-CRP value | Higher scores mean a more active RA. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| changes in the serum levels of biomarkers | We analyze the serum levels of multiple biomarkers such as cytokines and chemokines. | from baseline to weeks 2, 4, 12, 24, 36, and 52 | 
| changes in the total power Doppler (PD) score | Higher scores mean a more active RA. | from baseline to weeks 4, 12, 24, 36, and 52 | 
| changes in the total grayscale (GS) score | Higher scores mean a more active RA. | from baseline to weeks 4, 12, 24, 36, and 52 | 
| changes in the combined PD score | Higher scores mean a more active RA. | from baseline to weeks 4, 12, 24, 36, and 52 | 
| change in van der Heijde-modified total Sharp score (vdH-mTSS) | Higher scores mean a more joint destruction and deformity. | from baseline to weeks 24 and 52 | 
| change in the Health Assessment Questionnaire-Disability Index (HAQ-DI) data | Higher scores mean a more active RA. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| change in the EuroQol 5 Dimensions 5-Level (EQ-5D-5L) data | Higher scores mean a worse QOL. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| change in the Functional Assessment of Chronic Illness-Fatigue (FACIT-F) data | Higher scores mean a worse fatigue. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| changes in the morning stiffness duration | Higher scores mean a more active RA. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 | 
| changes in the morning stiffness activity | We analyze the visual analog scale of morning stiffness activity. Higher scores mean a more active RA. | from baseline to weeks 2, 4, 8, 12, 24, 36, and 52 |