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 (TRANSFORM study): study protocol for a randomized, open-label, parallel-group, multicenter, and non-inferiority clinical trial

by Selleckchem | Jun 18 2023

Background: Administration of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs has dramatically improved even the clinical outcomes in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Dysregulation of JAK-STAT pathways via overproduction of cytokines, such as interleukin-6, is involved in the pathogenesis of RA. Filgotinib is a selective JAK1 inhibitor pending approval for use in RA. By inhibition of the JAK-STAT pathway, filgotinib is effective in suppressing disease activity and preventing the progression of joint destruction. Similarly, interleukin-6 inhibitors such as tocilizumab also inhibit the JAK-STAT pathways by inhibition of interleukin-6 signaling. We present the protocol for a study that will evaluate whether the effectiveness of filgotinib monotherapy is non-inferior to that of tocilizumab monotherapy in RA patients with an inadequate response to MTX.

Methods: This study is an interventional, multicenter, randomized, open-label, parallel-group, and non-inferiority clinical trial with a 52-week follow-up. Study participants will be 400 RA patients with at least moderate disease activity during treatment with MTX. Participants will be randomized in a 1:1 ratio to administer filgotinib monotherapy or subcutaneous tocilizumab monotherapy switched from MTX. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who achieve an American College of Rheumatology 50 response at week 12. Secondary endpoints are changes from baseline in the MSUS scores. We will also comprehensively analyze serum levels of multiple biomarkers, such as cytokines and chemokines.

Discussion: The study results are expected to show the non-inferiority of the effectiveness of filgotinib monotherapy to that of tocilizumab monotherapy in RA patients with inadequate response to MTX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices, but also MSUS, which accurately and objectively evaluates disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will evaluate the effectiveness of both drugs by integrating multilateral assessments-clinical disease activity indices, MSUS findings, and serum biomarkers.

Comments:

The study is an interventional clinical trial designed to compare the effectiveness of filgotinib monotherapy with tocilizumab monotherapy in patients with rheumatoid arthritis (RA) who have had an inadequate response to methotrexate (MTX). Both filgotinib and tocilizumab target the dysregulated JAK-STAT pathways involved in the pathogenesis of RA.

The study will enroll 400 RA patients with at least moderate disease activity while on MTX treatment. These participants will be randomly assigned to receive either filgotinib monotherapy or subcutaneous tocilizumab monotherapy after discontinuing MTX. The trial will be open-label, meaning both participants and researchers will be aware of the treatment assignments.

The primary endpoint of the study is the proportion of patients who achieve an American College of Rheumatology 50 (ACR50) response at week 12. ACR50 is a measure of treatment response in RA, indicating a 50% improvement in disease activity. The secondary endpoints include changes from baseline in musculoskeletal ultrasound (MSUS) scores, which will evaluate disease activity at the joint level. Additionally, the study will analyze serum levels of various biomarkers, including cytokines and chemokines, to assess the treatment's impact on the inflammatory process.

One of the strengths of this study is its prospective evaluation of therapeutic efficacy using both clinical disease activity indices and MSUS, which provides an objective assessment of disease activity at the joint level. The study also aims to standardize MSUS evaluation across multiple centers, ensuring consistent and reliable results. By integrating multilateral assessments, including clinical disease activity indices, MSUS findings, and serum biomarkers, the study aims to comprehensively evaluate the effectiveness of both filgotinib and tocilizumab.

The results of this study will help determine if filgotinib monotherapy is non-inferior to tocilizumab monotherapy in RA patients who have an inadequate response to MTX. This information will contribute to the understanding of treatment options for this patient population and may guide clinical decision-making in the future.