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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis; Biomarker; JAK Inhibitor; Musculoskeletal Ultrasound; IL-6 Inhibitor
• Intervention / Treatment: Drug: filgotinib 200mg/day; Drug: subcutaneous tocilizumab 162mg/biweekly

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Nagasaki, Japan, 852-8501
    • Recruiting
    • Nagasaki University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must meet all of the following requirements to be considered for entry into the study:

  1. ≥20 years old
  2. with the diagnosis of RA based on the ACR/EULAR 2010 RA Classification Criteria
  3. with at least moderate disease activity defined as a DAS28-ESR ≥3.2 at the eligibility evaluation
  4. 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)
  5. 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:

  1. concurrent use of a corticosteroid equivalent to >5 mg/day of prednisolone
  2. applicable an item for the contraindication of filgotinib or tocilizumab
  3. a previous use of a JAK inhibitor or IL-6 inhibitor
  4. treatment with a corticosteroid and csDMARD and change of dose within 4 weeks prior to the providing consent
  5. 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
  6. treatment with a TNF inhibitor (ie, etanercept or biosimilar of etanercept) within 4 weeks prior to the providing consent
  7. use of a prohibited drug or therapy, other than the agents noted above, within 4 weeks prior to the providing consent
  8. 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)
  9. current pregnancy, breastfeeding, or noncompliant with a medically approved contraceptive regimen during and 12 months after the study period
  10. inappropriateness for inclusion in this study as determined by the investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Filgotinib monotherapy; The administration of filgotinib 200mg/day switched from MTX ± other csDMARDs throughout the study period.	Drug: filgotinib 200mg/day; 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.
Active Comparator: Tocilizumab monotherapy; The administration of subcutaneous tocilizumab 162mg/biweekly switched from MTX ± other csDMARDs throughout the study period.	Drug: subcutaneous tocilizumab 162mg/biweekly; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Atsushi Kawakami
• Collaborators: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2021
• Primary Completion (Anticipated): February 28, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: September 30, 2021
• First Submitted That Met QC Criteria: October 21, 2021
• First Posted (Actual): October 22, 2021

Study Record Updates

• Last Update Posted (Actual): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 23, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: CRB20_026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No