Trial design

FAITHFUL (Filgotinib Add-on versus swITcH to Filgotinib in patients with rheUmatoid arthritis who inadequateLy responded to methotrexate) is a multicenter, open-label, randomized, controlled, investigator-initiated non-inferiority trial conducted at 10 rheumatology centers in Japan (Fig 1 and 2). Patients with rheumatoid arthritis who have an inadequate response to MTX or bDMARDs combined with MTX will be randomly assigned, in a 1:1 ratio, to either the group adding filgotinib (Add-on group) or the group switching to filgotinib monotherapy (Switch group). MTX will be maintained at the same dose as at enrollment unless clinically significant adverse events occur. bDMARDs and csDMARDs will be discontinued at the start of filgotinib administration. The primary endpoint is the change in disease activity score 28 (DAS28)-C-reactive protein (CRP) from baseline at week 24. After week 24, patients in the Add-on group may reduce or discontinue MTX if desired and agreed upon by the attending rheumatologist, while patients in the Switch group may resume MTX administration.

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Fig 1. SPIRIT schedule.

Common laboratory tests include white blood cell count, white blood cell differential (eosinophils, basophils, neutrophils, lymphocytes, atypical lymphocytes, monocytes), red blood cell count, hemoglobin, mean corpuscular volume, platelet count, erythrocyte sedimentation rate, blood urea nitrogen, creatinine, uric acid, total bilirubin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, gamma-glutamyl transferase, alkaline phosphatase, C-reactive protein, total protein, albumin, immunoglobulin G. Baseline X-ray examinations of the hands and feet can use results obtained within 12 weeks prior. X-ray examinations of the hands and feet are not required at the time of discontinuation if the discontinuation occurs within 28 days of the previous X-ray examination. Abbreviation: VAS: Visual Analog Scale; HAQ: Health Assessment Questionnaire; WPAI: Work Productivity and Activity Impairment; MMP-3: Matrix Metalloproteinase-3; RF: Rheumatoid Factor; CRP: C-reactive Protein; ESR: Erythrocyte Sedimentation Rate; LDL: Low-Density Lipoprotein; HDL: High-Density Lipoprotein; TG: Triglycerides; SDM: Shared Decision-Making; FIL: Filgotinib; MTX: Methotrexate.

https://doi.org/10.1371/journal.pone.0322621.g001

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Fig 2. Study design.

At 24 weeks, SDM determines whether to discontinue or initiate MTX. In the FIL + MTX group, MTX may be discontinued, whereas in the FIL group, MTX may be added if deemed necessary. Abbreviation: MTX-IR, methotrexate-inadequate response; FIL, filgotinib; SDM, shared decision making; DAS28-CRP, disease activity score 28-C-reactive protein.

https://doi.org/10.1371/journal.pone.0322621.g002

Eligibility criteria

Eligible patients are those who satisfy all the inclusion criteria and do not meet any of the exclusion criteria.

Inclusion criteria

1. 1) Patients aged 18 years or older
2. 2) Patients diagnosed with rheumatoid arthritis based on the 1987 ACR classification criteria or the 2010 ACR/EULAR classification criteria
3. 3) Patients who have received stable treatment with MTX at a dose of at least 6 mg/week or combination therapy with bDMARDs and MTX for at least 8 weeks prior to enrollment but still demonstrate moderate to high disease activity, defined by a DAS28-CRP score of 3.2 or higher
4. 4) Patients with at least 2 tender joints and at least 2 swollen joints
5. 5) Patients who have not previously used JAK inhibitors
6. 6) Patients may receive glucocorticoids at a dose equivalent to 10 mg/day or less of prednisolone
7. 7) Patients who have provided written consent to participate in this study

Exclusion criteria

1. 1) Patients who plan to become pregnant or give birth between the time of consent and the completion of study treatment
2. 2) Patients with an estimated glomerular filtration rate less than or equal to 30 mL/min/1.73 m²
3. 3) Patients with aspartate aminotransferase or alanine aminotransferase levels exceeding five times the upper normal limit
4. 4) Patients with a white blood cell count below 2000/μL
5. 5) Patients with a platelet count below 100,000/μL
6. 6) Patients with a history of venous thromboembolism within 2 months prior to obtaining consent
7. 7) Patients with a history of acute interstitial pneumonia within 2 months prior to obtaining consent
8. 8) Patients with a history of herpes zoster within 2 months prior to obtaining consent
9. 9) Patients with a history of hypersensitivity to either filgotinib or MTX components
10. 10) Patients who are breastfeeding
11. 11) Patients with pleural effusion, ascites, or other similar conditions
12. 12) Patients with active tuberculosis
13. 13) Patients deemed unsuitable for participation in the study by the principal investigator or sub-investigator

Withdrawal criteria

Subjects must be withdrawn from the study if they meet any of the withdrawal criteria listed below. Upon withdrawal, subjects should undergo the specified assessments and tests for early termination. Additionally, the reason for withdrawal should be explained to the subject as appropriate, and post-withdrawal treatment should be provided in good faith to ensure the subject experiences no disadvantage. The principal investigator or sub-investigator must document the date and reason for withdrawal in the electronic data capture (EDC) system. For traceable subjects, their clinical course should be monitored and reported to the Study Secretariat. Subjects withdrawn from the study will not be replaced, regardless of the reason for withdrawal.

1. 1) Subject wishes to discontinue his/her study treatment
2. 2) Subject wishes to withdraw his/her consent
3. 3) Serious (or significant) adverse event occurs, and the study treatment is determined to be difficult to continue
4. 4) A comorbidity (complication, etc.) exacerbates, and the study treatment is determined to be difficult to continue
5. 5) If the study treatment is interrupted for more than 28 consecutive days
6. 6) Confirmed pregnancy
7. 7) If a significant protocol deviation is identified and it is determined that continuing the study would be inappropriate
8. 8) If it is discovered after enrollment that the subject does not meet the inclusion criteria or violates the exclusion criteria, and it is determined that continuing the study would be inappropriate
9. 9) If, for any other reason, the principal investigator or sub-investigator determines that continuing the study is not appropriate

The status and timeline of the study

This trial was registered at Japan Registry of Clinical Trials (jRCTs031230673) in March 2024. Currently enrollment is ongoing.

Enrollment period: Publication date of the implementation plan – September 2025 (18 months).

Intervention period: 48 weeks

Data collection, analysis, and report generation periods: 2 years

First patient first visit: April 2024

Last patient first visit: September 2025

Last patient last visit: September 2026

Data collection and Fix: March 2027

Analysis and Clinical Study Report: September 2027

Total study period: 3 years and 6 months

The details of each rheumatology center involved in this study and site-specific recruitment date

1. Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. 25/April/2024
2. Institute of Rheumatology, Miyazaki Zenjinkai Hospital, Miyazaki, Japan. 03/July/2024
3. Kaneko Internal Medicine Rheumatology Clinic, Kawaguchi, Japan. 23/July/2024
4. Department of Rheumatology, Niigata Rheumatic Center, Shibata, Japan. 28/June/2024
5. Department of Internal Medicine and Center for Arthritis and Rheumatic Disease, Kawasaki Municipal Kawasaki Hospital, Kawasaki, Japan. 08/August/2024
6. Tohoku Medical and Pharmaceutical University, Division of Hematology and Rheumatology, Sendai, Japan. 05/September/2024
7. Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. 23/July/2024
8. Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan. 10/October/2024
9. Department of Rheumatology, Dokkyo Medical University, Mibu, Japan. 24/December/2024
10. Division of Rheumatology, Department of Internal Medicine, National Hospital Organization Tokyo Medical Center, Tokyo, Japan. 23/December/2024

Allocation and blinding

A minimization method is used with history of bDMARDs use (yes/no) and anti-cyclic citrullinated peptide antibody status (positive/negative). Eligible patients will be randomly assigned electronically by a central system in a 1:1 ratio to either the combination therapy group (Add-on group) or the group switched to filgotinib monotherapy (Switch group). This is an open-label trial with no blinding implemented.

Sample size calculation

Based on the results from the DARWIN1, DARWIN2, and FINCH3 trials, this study assumes a mean difference in change from baseline in DAS28-CRP at week 24 between the two groups of 0.07, with a standard deviation of 1.1. With an equal sample size ratio of 1:1 between the groups, and assuming a mean difference of 0.07, a standard deviation of 1.1, a one-sided significance level of 0.05, and a power of 80%, the required sample size was calculated to be 108 participants (54 per group). As for the sample size calculation, a one-sided test was employed based on the clinical assumption that filgotinib monotherapy would not be inferior to the combination of filgotinib and MTX. Considering a dropout rate of approximately 10%, the total sample size was set at 120 participants (60 per group).

Trial treatments

Outcomes

Data collection

Data management, monitoring, and auditing

At enrollment (within 8 weeks prior to the start of study treatment), the following information will be collected and recorded in the EDC system. In addition to this information, the registration number, status of informed consent, and results of the eligibility assessment will also be recorded in the EDC system:

1. 1) Gender
2. 2) Age (at the time of consent)
3. 3) Race (Asian, American Indian or Alaska Native, Black or African American, Native Hawaiian or Other Pacific Islander, White)
4. 4) Height and weight
5. 5) Time of rheumatoid arthritis diagnosis
6. 6) Treatment history of rheumatoid arthritis (glucocorticoids, DMARDs, NSAIDs, etc.)
7. 7) Surgical history related to rheumatoid arthritis
8. 8) Medical history and comorbidities
9. 9) Smoking history
10. 10) 12-lead electrocardiogram (results obtained within 12 weeks prior to consent can be used)
11. 11) Infectious disease testing (results obtained within 12 weeks prior to consent can be used; for patients using bDMARDs, pre-treatment results can be used): Either skin tuberculin test or interferon-gamma release assay (IGRA), hepatitis B surface (HBs) antigen, HBs antibody, HB core antibody, and anti- hepatitis C virus antibody. For subjects who are HBs antigen-negative but HBs antibody-positive and/or HBc antibody-positive, HBV-DNA quantification testing must be performed at least once every 6 months as a minimum requirement. This does not preclude more frequent testing, such as every 1–3 months.

The case report forms for this study will be managed using the EDC system, and the registration numbers will be issued through the EDC system. The principal investigator, co-investigators, or research collaborators will promptly enter data into the EDC system after the evaluation/investigation of each participant is completed. In accordance with a separate data management plan, the data center will follow up on delayed data entries, conduct data inquiries, address queries related to the data, make necessary data corrections, manage the database, and prepare datasets for statistical analysis based on the data entered into the database. The principal investigator will ensure that data and records are properly stored for 5 years from the later of the date the study conclusion is reported or 3 years after the final publication of the study results.

Independent monitors will visit the study sites to examine the records, verify them against source documents, and engage with the investigators and site coordinator to observe and discuss the trial’s progress. They are responsible for ensuring compliance with the protocol and guidelines, as well as overseeing the completion of the electronic Case Report Form (eCRF) and other required documentation.

This study is a collaborative research project with Gilead Sciences, Inc., the manufacturer of JYSELECAⓇ (filgotinib). Gilead Sciences, Inc. will be involved in the preparation of the study protocol. However, Gilead Sciences, Inc. will not participate in data collection, data management, statistical analysis, or the evaluation of study results. Therefore, audits are not considered mandatory, and routine audits will not be conducted. The reliability of this study is ensured by the fact that it is not a clinical trial aimed at regulatory approval. Monitoring will be implemented to protect study participants, ensure ethical standards, adhere to clinical research laws and the study protocol, and maintain data reliability and appropriate research practices.

In this study, both central monitoring and on-site monitoring will be conducted. Central monitoring will be performed every six months in principle. It will include the review of progress management items (enrollment progress and status of discontinued cases), safety management items (compliance with the study protocol and the presence or absence of adverse events), and outcome-related items (the implementation status of the primary endpoint, secondary endpoints, and efficacy assessment items). On-site monitoring will be conducted twice: once within three months after the enrollment of the first patient at each site and once after treatment completion or after the enrollment of the last patient at each site. The monitoring will include confirmation of the informed consent process, eligibility of enrolled patients, and compliance with the study protocol with data accuracy.

The accuracy, consistency, and reliability of the data will be scrutinized through independent monitoring, which operates separately from the study investigators as noted above. Furthermore, a steering committee consisting of external experts, independent of the study investigators, will conduct a thorough review of the data.

Furthermore, when publishing papers or presenting at conferences, the conflict of interest (COI) and the role of Gilead Sciences, Inc. in this study will be clearly disclosed. Quality control will be conducted through monitoring, and if significant issues arise or if events with serious implications for participant safety occur, consideration will be given to conducting an ad-hoc audit as necessary.

Analysis population

Statistical methods

For the primary endpoint, the change in DAS28-CRP from baseline will be analyzed using a Mixed Effects Model for Repeated Measures (MMRM). This method considers the baseline measurement as a covariate and incorporates group, time point, and the interaction between time point and group as fixed effects. It also reflects the variance-covariance structure of repeated measurements within each patient. Using this model, the least squares mean difference between groups at week 24 and its 90% confidence interval will be calculated. Non-inferiority will be confirmed if the upper limit of this 90% confidence interval is less than 0.6.

For the secondary endpoints, the proportion of patients meeting each endpoint and the corresponding 95% confidence intervals will be calculated. For the change from baseline in each endpoint, summary statistics (number of patients, mean, standard deviation, minimum, median, and maximum) will be presented. Additionally, the change from baseline will be analyzed using the same MMRM approach as for the primary endpoint, estimating the least squares mean and its 95% confidence interval at each time point.

As a sensitivity analysis, stratification will be performed based on stratification variables (history of bDMARD use and anti-CCP antibody positivity/negativity), and summary statistics will be calculated for baseline values, measurements at each time point, and changes from baseline by treatment group and treatment period, with intergroup comparisons conducted using t-tests.

Additionally, as a supplementary analysis, in the PPS population, intergroup comparisons of changes from baseline will be conducted using MMRM, and summary statistics will be calculated with intergroup comparisons performed using t-tests. Furthermore, in the PPS population, stratification based on the aforementioned stratification variables will be conducted, and summary statistics will be calculated for baseline values, measurements at each time point, and changes from baseline by treatment group and treatment period, with intergroup comparisons conducted using t-tests.

For the cumulative values of CRP and MMP-3, the AUC for each participant will be calculated, and summary statistics (number of patients, mean, standard deviation, minimum, median, and maximum) for each group will be presented.

For the safety analysis, treatment-emergent adverse events (TEAEs) observed during the period from the start of the study treatment to the end of the observation period will be summarized. Adverse events that cannot be ruled out as being causally related to the study treatment will be classified as adverse drug reactions. For each group, the number and percentage of cases of TEAEs and adverse drug reactions will be summarized by system organ class and preferred term. Additionally, a summary by severity level will also be provided.

Missing data at each time point will not be imputed. For patients who discontinue the study, only the data obtained up to the point of discontinuation will be used for analysis. Additionally, when analyzing the proportion of patients who achieve the endpoint, cases with missing data at each time point, including those who discontinued the study, will be considered as non-responders and included in the denominator.

Ethics and dissemination

Study discontinuation criteria

The study will be discontinued if any of the following criteria are met. The principal investigator will promptly inform the principal investigators at each participating medical institution about the decision to discontinue the study. Each principal investigator will promptly notify the subjects and take appropriate medical interventions and other necessary actions.

1. 1) If the number of enrolled subjects is significantly below the target, or if frequent deviations from the study protocol occur, making it difficult to complete the study
2. 2) If a serious adverse event is reported and it is determined that there are safety concerns regarding the protocol treatment
3. 3) If new information related to the protocol treatment is obtained, such as from publications or conference presentations, and it is determined that there are safety concerns regarding the protocol treatment