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Efficacy and safety of selective JAK 1 inhibitor Filgotinib in active rheumatoid arthritis patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs: Comparative study with Filgotinib and interleukin 6 inhibitor 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

Efficacy and safety of selective JAK 1 inhibitor Filgotinib in active rheumatoid arthritis patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs: Comparative study with Filgotinib and interleukin 6 inhibitor 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

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The analysis population (FAS: Full analysis set) comprised 26 patients (13 in the filgotinib group and 13 in the IL-6 inhibitor group). Continuous variables are presented as the median (interquartile range), and categorical variables as the number (percentage) of cases. In the filgotinib group, the age of the patients was 74 years (63, 78), with 10 females (77%). The hight was 152.6 cm (150, 158.5) and the weight was 48 kg (42, 65). The duration of RA was 2 years (0, 5), with 11 patients (85%) being RF positive, and 8 (62%) being anti-CCP antibody positive. The highest historical RF level was 217 IU/mL (120, 403), and the highest anti-CCP antibody level was 102 U/mL (17, 214). The baseline RF level was 76 IU/mL (32, 191) and the baseline anti-CCP antibody level was 12 U/mL (6, 373). All patients received methotrexate and the methotrexate dose at baseline was 8 mg/week (8, 12). The number of patients with a history of treatment with biologic DMARDs was 2 for infliximab, and 1 for abatacept. No patients were previously treated with JAK inhibitors. In the IL-6 inhibitor group, the age of the patients was 65 years (60, 71), with 13 females (100%). The hight was 153.6 cm (152.1, 154.5) and the weight was 51 kg (46, 63). The duration of RA was 4 years (0, 13), with 12 patients (92%) being RF positive, and 8 (62%) being anti-CCP antibody positive. The highest historical RF level was 64 IU/mL (56, 105), and the highest anti-CCP antibody level was 102 U/mL (34, 227). The baseline RF level was 49 IU/mL (30, 83) and the baseline anti-CCP antibody level was 92 U/mL (15, 143). Twelve patients (92%) received methotrexate and the methotrexate dose at baseline was 9 mg/week (7.5, 10.5). The number of patients with a history of treatment with biologic DMARDs was 1 for infliximab, 1 for etanercept, 1 for tocilizumab and 1 for otilimab. No patients were previously treated with JAK inhibitors.

The number of patients registered at each institution was: 5 patients from Yamanashi University; 5 patients from Kitaharima medical center; 4 patients from Juntendo University; 3 patients from Aomori Prefectural Central Hospital; 1 patient from Miyazaki Zenjinkai Hospital; 1 patient from Hokkaido University; 1 patient from Kumamoto Shinto General Hospital; 1 patient from Miyakonojo Medical Center; 1 patient from Nagasaki Genbaku Hospital; 1 patient from Chiba University; 1 patient from Sasebo Chuou Hospital; and 1 patient from Nagasaki University.

[Adverse events] In the filgotinib group (13 patients), there were 9 adverse events, including 4 severe adverse events (urinary tract infection, heart failure, bacteremia and tumor-forming pancreatitis). Two adverse events led to discontinuation of the study. In the IL-6 inhibitor group (13 patients), there were 12 adverse events with no severe adverse events. [Illnesses] In the filgotinib group, there were 3 illnesses (urinary tract infection, bacteremia and tumor-forming pancreatitis). In the IL-6 inhibitor group, there were 10 illnesses (4 cases for stomatitis, 1 case each of Pseudomonas aeruginosa pneumonia, eczema on the right thigh, periodontitis, upper respiratory tract infection, infusion reaction and dyslipidemia)

[primary endpoint] The proportion of patients achieving ACR50 response at 12 weeks after the first dose, was 5 out of 13 (38.5%) in the filgotinib group and 6 out of 13 (46.2%) in the IL-6 inhibitor group, and the risk difference (filgotinib group - IL-6 inhibitor group) was -7.69 (95% CI: -42.26 to -28.8), and the risk ratio (filgotinib group/IL-6 inhibitor group) was 0.83 (95% CI: 0.36 to 1.98), resulting in no clear difference. [Secondary endpoints] The proportion of patients achieving ACR50 response at 2, 4, 8, 24, 36 and 52 weeks. 2 weeks: The filgotinib group: 2 out of 13 (15.4%) The IL-6 inhibitor group: 0 out of 13 (0%) The risk difference (filgotinib group - IL-6 inhibitor group): 15.38% (95%CI: -9.27 to 42.23) The risk ratio (filgotinib group/IL-6 inhibitor group): Inf (95%CI: 0.26 to 94.69) 4 weeks: The filgotinib group: 4 out of 13 (30.8%) The IL-6 inhibitor group: 4 out of 13 (30.8%) The risk difference (filgotinib group - IL-6 inhibitor group): 0% (95%CI: -34.26 to 34.26) The risk ratio (filgotinib group/IL-6 inhibitor group): 1.00 (95%CI: 0.34 to 2.91) 8 weeks: The filgotinib group: 3 out of 13 (23.1%) The IL-6 inhibitor group: 2 out of 13 (15.4%) The risk difference (filgotinib group - IL-6 inhibitor group): 7.69% (95%CI: -24.21 to 38.65) The risk ratio (filgotinib group/IL-6 inhibitor group): 1.5 (95%CI: 0.33 to 5.89) 24 weeks: The filgotinib group: 7 out of 13 (53.8%) The IL-6 inhibitor group: 8 out of 13 (61.5%) The risk difference (filgotinib group - IL-6 inhibitor group): -7.69% (95%CI: -42.26 to 28.8) The risk ratio (filgotinib group/IL-6 inhibitor group): 0.87 (95%CI: 0.47 to 1.65) 36 weeks: The filgotinib group: 6 out of 13 (46.2%) The IL-6 inhibitor group: 4 out of 13 (30.8%) The risk difference (filgotinib group - IL-6 inhibitor group): 15.38% (95%CI: -21.39 to 48.44) The risk ratio (filgotinib group/IL-6 inhibitor group): 1.5 (95%CI: 0.57 to 3.68) 52 weeks: The filgotinib group: 3 out of 13 (23.1%) The IL-6 inhibitor group: 5 out of 13 (38.5%) The risk difference (filgotinib group - IL-6 inhibitor group): -15.38% (95%CI: -47.59 to 20.08) The risk ratio (filgotinib group/IL-6 inhibitor group): 0.6 (95%CI: 0.21 to 1.93) The mean (SD) and median (IQR) changes from baseline to 4, 12, 24, 36 and 52 weeks in the total GS score, total PD score, composite score. The mean (SD), median (IQR) are listed in this order. The filgotinib group: Total GS score Change 4 weeks: -7.25 (12.6), -4.5 (-15.5, 0.25) Change 12 weeks: -9.36 (11), -5 (-16, -1.5) Change 24 weeks: -13.7 (12.7), -6 (-23, -4) Change 36 weeks: -5.14 (8.82), -5 (-6, -0.5) Change 52 weeks: -8.33 (12.7), -1 (-12, -1) Total PD score Change 4 weeks: -5 (9.29), -2.5 (-6.25, -1.75) Change 12 weeks: -7.64 (8.49), -4 (-11.5, -1.5) Change 24 weeks: -9.11 (9.6), -5 (-18, -3) Change 36 weeks: -3 (1.91), -3 (-4, -1.5) Change 52 weeks: -1. 33 (1.53), -1 (-2, -0.5) Composite score Change 4 weeks: -7.67 (12.8), -4.5 (-16.2, -0.5) Change 12 weeks: -9.73 (11.2), -5 (-16, -2.5) Change 24 weeks: -14.2 (12.8), -6 (-23, -5) Change 36 weeks: -5.29 (8.86), -6 (-6, -0.5) Change 52 weeks: -8.67 (12.4), -2 (-12.5, -1.5) The IL-6 inhibitor group: Total GS score Change 4 weeks: -2.83 (4.91), -1.5 (-5.5, 0.25) Change 12 weeks: -5.17 (5.41), -4.5 (-8, -0.75) Change 24 weeks: -6.9 (5.4), -7 (-10, -2.25) Change 36 weeks: -3.75 (8.03), -5.5 (-9.5, 0.25) Change 52 weeks: -4.67 (5.85), -2.5 (-6.75, -0.5) Total PD score Change 4 weeks: -2.17 (4.37), -1 (-5, 0) Change 12 weeks: -2.67 (3.65), -2 (-5.5, 0) Change 24 weeks: -3.8 (3.91), -2.5 (-8, -0.25) Change 36 weeks: -2.75 (4.95), 0 (-6, 0.25) Change 52 weeks: -1.83 (4 .36), 0 (-3.75, 0) Composite score Change 4 weeks: -2.58 (5.58), -1.5 (-4.75, 0.5) Change 12 weeks: -5.33 (5.65), -5 (-9, -0.75) Change 24 weeks: -7.1 (5.24), -7.5 (-10.8, -3) Change 36 weeks: -4 (8.25), -6 (-9.75, 0.25) Change 52 weeks: -4.67 (6.15), -2.5 (-7.5, -6.25)

The proportion of patients achieving ACR50 response at 12 weeks after the first dose was 5 out of 13 (38.5%) in the filgotinib group and 6 out of 13 (46.2%) in the IL-6 inhibitor group, and the risk difference (filgotinib group - IL-6 inhibitor group) was -7.69 (95% CI: -42.26 to -28.8), and the risk ratio (filgotinib group/IL-6 inhibitor group) was 0.83 (95% CI: 0.36 to 1.98), resulting in no clear difference.

Dec. 01, 2024

No

None.

https://jrct.mhlw.go.jp/latest-detail/jRCTs071200107

Kawakami Atsushi

Nagasaki University Hospital

1-7-1 Sakamoto, Nagasaki-city, Nagasaki

atsushik@nagasaki-u.ac.jp

Kawashiri Shinya

Nagasaki University Hospital

1-7-1 Sakamoto, Nagasaki-city, Nagasaki

+81-95-819-7200

shin-ya@nagasaki-u.ac.jp

Complete

Mar. 22, 2021

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1)Patients aged 18 years or older at the time of providing consent.
2)Patients diagnosed as having RA according to the 2010 RA classification criteria of the American College of Rheumatology/European League Against Rheumatology.
3)Patients with moderate or more disease activity (DAS28-ESR >= 3.2) at the time of the eligibility evaluation.
4) Patients who have been treated with csDMARDs (any or combination of MTX, sodium gold thiolate, auranofin, penicillamine, salazosulfapyridine, lobenzalit, busiramine, actalit, tacrolimus, mizoribine, leflunomide, and iguratimod) for at least 8 weeks at the time of consent and did not have sufficient response after 4-week or longer csDMARDs treatment without modifying the dose.
5)Patients who can personally provide written consent at their own free will after being receiving a thorough explanation of the study and fully understanding their participation in the study.

1) Patients receiving more than 5 mg per day of prednisolone equivalent of corticosteroids.
2)Patients with contraindications for filgotinib, tocilizumab and sarilumab treatment.
3)Patients with a history of using filgotinib.
4) Patients treated with corticosteroid but have modified the dose within 4 weeks prior to the time of consent.
5) Patients who have received treatment with TNF inhibitors (ie, infliximab, infliximab BS, adalimumab, adalimumab BS, golimumab, and certolizumab pegol), IL-6 inhibitors (tocilizumab and sarilumab) and abatacept within 8 weeks prior to the time of providing consent.
6)Patients who have received TNF inhibitors (ie. etanercept and etanercept BS) within 4 weeks prior to the time of consent.
7)Patients who have received anti-rheumatic molecular targeted drugs (ie. tofacitinib, baricitinib, peficitinib and upadacitinib) within 4 weeks prior to the time of consent.
8)Patients who have used non-steroidal anti-inflammatory analgesics (suppositories), intra-articular injections, investigational drugs, or medical devices under development within 4 weeks prior to the time of consent.
9) Patients with concurrent musculoskeletal disorders other than RA (i.e. ankylosing spondyloarthritis, reactive arthritis, psoriatic arthritis, crystal-induced arthritis, systemic lupus erythematosus, systemic scleroderma, inflammatory myopathy and mixed connective tissue disease).
10)Women who are breastfeeding, pregnant, or wish to fall pregnant, and those who do not consent to use contraception from the time of the eligibility evaluation until 12 months after the final dose of the investigational drug.
11)Individuals who, for other reasons, are deemed ineligible of study participation by the principal investigator.

Both

Rheumatoid arthritis

Patients with active RA who have had inadequate response after 8-week or longer csDMARDs treatment will be advised to switch to filgotinib or IL-6 inhibitor (tocilizumab or sarilumab) monotherapy. csDMARDs treatment will be interrupted at baseline. Patients meeting eligibility criteria will be randomized (in a ratio of 1:1) to receive filgotinib or IL-6 inhibitor (either tocilizumab or sarilumab) continuously until Week 52. Patients allocated to IL-6 inhibitor will receive either tocilizumab (subcutaneously or intravenously) or sarilumab (subcutaneously) at the discretion of the principal investigator or a subinvestigator. The proportion of patients achieving ACR50 12 weeks after initiation of filgotinib or IL-6 inhibitor (tocilizumab or sarilumab) monotherapy will be the primary endpoint to demonstrate non-inferiority of filgotinib monotherapy to IL-6 inhibitor (tocilizumab or sarilumab) monotherapy.

Proportion of subjects who achieve an ACR50 response at week 12

1)Each of the proportions of subjects who achieve an ACR50 response at Week 2, 4, 24, 36, and 52.
2)Each of the proportions of subjects who achieve an ACR 20/70 response at Week 2, 4, 12, 24, 36, and 52.
3)Change from Week0 at 2, 4, 12, 24, 36, and 52 weeks after initiation of first dose for the following tests per case: CDAI/SDAI, DAS28-ESR/CRP, HAQ-DI, EQ-5D-5L, FACIT-F, and morning stiffness duration/activity rating.
4)Changes from Week0 in the following clinical evaluations at Week 4, 12, 24, 36, and 52: MSUS total PD score, MSUS GS score, and MSUS total composite score.
5)Changes from Week0 in the following clinical evaluations at Week 2, 4, 12, 24, 36, and 52: blood concentration of cytokines and chemokines.
6) Changes from Week0 in mTSS at Week 24 and 52.

+81-95-819-7229

Feb. 12, 2021

none