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Effectiveness of Etanercept Biosimilar Initiating for Etanercept -Naive Patients, using Ultrasound, Clinical and Biomarker Assessments in Outcomes of Real World Therapy(ENPORT-NGSK Study):Study protocol for an interventional, multicenter, open-label, single-arm clinical trial

Effectiveness of Etanercept Biosimilar Initiating for Etanercept -Naive Patients, using Ultrasound, Clinical and Biomarker Assessments in Outcomes of Real World Therapy(ENPORT-NGSK Study):Study protocol for an interventional, multicenter, open-label, single-arm clinical trial

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The age of the patients was 62 years (46, 73), 7 (30%) were male and 16 (70%) were female. The height was 154 cm (149, 161) tall, and the weight was 55 kg (52, 56). The disease duration was 1-year (0, 6.5), 21 (91%) patients were RF positive, and 21 (91%) patients were anti-CCP antibody positive. 12 patients (52%) had a history of smoking, including 6 subjects who were current smokers. They smoked 15 cigarettes/day (9.8, 20.0) and 34 years (22, 40). The top 3 comorbidities were hypertension in 7 (30%), osteoporosis in 6 (26%), and osteoarthritis in 4 (17%). 13 patients (57%) had prior therapy for RA, the number of patients treated with biologics was 1 with infliximab, 1 with adalimumab, 2 with tocilizumab, and 6 with abatacept. Concomitant medications for RA included methotrexate in 17 patients (74%) at a dose of 10 mg/week (8.0, 12). Concomitant prednisolone was found in 9 patients (39%), at a dose of 5 mg /day (2.5, 5). *Continuous variables represent median (interquartile range) and categorical variables represent number of cases (percentage).

The number of patients enrolled per facility was 14 from Nagasaki University Hospital, 6 from Sasebo Chuo Hospital, and 1 each from the Japanese Red Cross Nagasaki Genbaku Hospital, Yoshitama Clinic for Rheumatic Diseases, and Saga University Hospital. 5 facilities did not enroll any patients. Twenty-three patients were enrolled; one had no examination at discontinuation, and the analysis population (FAS) was 22 patients. One patient discontinued at 12 weeks at the subject's request, leaving 21 completed cases.

[Adverse events] There were 16 adverse events in the safety analysis set from the start of study to 24 weeks. Of these, there were no serious adverse events, and the severity of all adverse events was Grade 2: moderate (requiring minimal/local/non-invasive treatment for the adverse event). [Adverse drug reactions] There were 8 cases of adverse drug reactions from the start of study to 24 weeks. 2 cases were herpes zoster (8.7%), and 1 case (4.3%) each was nasopharyngitis, leucocytepenia, abnormal liver function, cellulitis, injection site reaction, and oral herpes. No serious adverse drug reactions were observed.

[Primary endpoints] Spearman's correlation coefficient and its 95% confidence interval were calculated for the change in ultrasound GLOESS and DAS28-CRP from baseline to 12 and 24 weeks in the bilateral second to fifth MCP joints. At 12 weeks: rho = 0.405 [-0.020, 0.706], at 24weeks: rho = -0.075 [-0.491, 0.368] and no correlation was observed in either case. [Secondary endpoint] 1. Percentage of study subjects achieving low disease activity/remission at 12 and 24 weeks after study entry. Fifteen (68%) study subjects achieved low disease activity/remission at 12 weeks by DAS28-CRP criteria, of which 10 (45%) were in remission. Eighteen (86%) study subjects achieved low disease activity/remission at 24 weeks, of which 14 (67%) were in remission. 2. Total PD score, total GS score, GLOESS, GLOESS at bilateral 2-5 MCP joints, values at each evaluation time point, change from baseline to 12 and 24 weeks, SRM (standardized responsemean). Mean (SD), median (IQR), and SRM are listed in this order. Total PD score: Baseline: 6.6 (5.3), 6 (2.2, 9),12 weeks: 2.3 (2.9), 1.5 (0, 3.8), 24 weeks: 0.95(1.6), 0 (0, 1), Change 12 weeks: -4.3 (4.3), -3.5 (-6, -1.2), -0.99, Change 24 weeks: -5 (4.8),-4 (-8, -2), -1 Total GS score: Baseline: 12 (7.7), 10 (6, 17), 12weeks: 8.5 (6.1), 6.5 (3, 12), 24 weeks: 6.2 (4.7),6 (3, 8), Change 12 weeks: -3.4 (5), -1.5 (-5.8, -0.25), -0.67, Change 24 weeks: -4.7 (6.3), -2 (-6, -1), -0.75 GLOESS: Baseline: 12 (7.8), 10 (6, 18), 12weeks: 8.5 (6.1), 6.5 (3, 12), 24 weeks: 6.2 (4.7),6 (3, 8), Change 12 weeks: -3.5 (5.1), -1.5 (-5.8,-0.25), -0.68, Change 24 weeks: -4.9 (6.4), -3 (-7, -1), -0.76 Bilateral 2-5MCP joint GLOESS: Baseline: 5.1 (5.1), 4 (1, 9.8), 12 weeks: 4 (4.3), 3 (1, 6.2), 24weeks: 3.1 (3.5), 2 (0, 5), Change 12 weeks: -1.1(2.8), -0.5 (-1, 0), -0.41, Change 24 weeks: -1.7(3.6), 0 (-4, 1), -0.47 3. Values of DAS28-ESR, DAS28-CRP, SDAI,CDAI, and HAQ-DI at each evaluation time point, change from baseline to 12 and 24 weeks, and SRM. DAS28-ESR: Baseline: 4.9 (1.1), 5.1 (4.2, 5.6), 12weeks: 2.8 (1.1), 2.7 (2, 3.4), 24 weeks: 2.5(1.3), 2.5 (1.4, 3.3), Change 12 weeks: -2.1(1), -2.2 (-2.8, -1.2), -2, Change 24 weeks:-2.3 (1.2), -2.2 (-3.1, -1.2), -2 DAS28-CRP: Baseline: 4.4 (0.71), 4.3 (4, 4.6),12 weeks: 2.6 (0.71), 2.6 (2, 3.3), 24 weeks:2.4 (0.8), 2.1 (1.9, 3.1), Change 12 weeks: -1.7(0.88), -1.6 (-2.4, -1), -2, Change 24 weeks: -2 (0.96), -1.8 (-2.6, -1.2), -2.1 SDAI: Baseline: 22 (6.8), 22 (19, 24), 12 weeks:8.3 (4), 7.6 (5.1, 12), 24 weeks: 6.7 (4.6), 6.6(3.4, 8.3), Change 12 weeks: -14 (7.5), -12 (-18,-8.9), -1.9, Change 24 weeks: -15(7.3), -13(-19,-11), -2.1 CDAI: Baseline: 21 (6.7), 21 (18, 23), 12 weeks:8.1 (4.1), 7.2 (4.9, 12), 24 weeks: 6.3 (4.6), 6.5(2.4, 7.6), Change 12 weeks: -13 (7.4), -12 (-18,-7.8), -1.8, Change 24 weeks: -14 (7.2), -14 (-19, -10), -2 HAQ-DI: Baseline: 0.94 (0.8), 0.88 (0.25, 1.5),12 weeks: 0.63 (0.76), 0.25 (0, 1.2), 24 weeks:0.68 (0.75), 0.25 (0, 1.2), Change 12 weeks: -0.31 (0.4), -0.19 (-0.5, 0), -0.77, Change 24weeks: -0.29 (0.37), -0.12 (-0.5, 0), -0.77 4. mTSS values at each evaluation time point, change from baseline to 24 weeks. Baseline: 23 (31), 10 (4.2, 25), 24 weeks: 24(32), 11 (6, 26), Change 24 weeks: 0.24 (0.3), 0(0, 0.5) 5. The values of biomarkers such as cytokines at each evaluation time point and the change from baseline to 24 weeks. EGF: Baseline: 84 (52), 85 (29, 120), 24 weeks:81 (51), 79 (44, 90), Change: -2.1 (39), 4.1 (-33,23) EOTAXIN: Baseline: 160 (71), 140 (110, 200),24 weeks: 170 (75), 170 (110, 200), Change:9.4 (35), 5.7 (-16, 26) FGF-2: Baseline: 96 (110), 59 (40, 100), 24weeks: 84 (75), 55 (37, 100), Change: -14 (54), -10 (-20, 0) FLT-3L: Baseline: 32 (43), 22 (5.6, 37), 24weeks: 33 (30), 23 (13, 46), Change: -0.23 (22),1.5 (-7.1, 10) FRACTALKINE: Baseline: 220 (410), 53 (38,160), 24 weeks: 190 (320), 91 (20, 130), Change: -29 (160), 0 (-28, 13) GM-CSF: Baseline: 17 (52), 2.4 (0.94, 11), 24weeks: 11 (29), 2.1 (0.94, 7), Change: -6.7 (29),-0.74 (-3.8, 0) GRO: Baseline: 1400 (480), 1300 (1100, 1600),24 weeks: 1200 (380), 1100 (1000, 1300),Change: -240 (480), -160 (-550, 140) G-CSF: Baseline: 54 (65), 28 (16, 53), 24 weeks:48 (53), 24 (13, 66), Change: -8 (31), -2.9 (-14,3.1) IFNg: Baseline: 18 (34), 7 (4.5, 15), 24 weeks:19 (30), 8.6 (3.6, 21), Change: 0.2 (8.2), -0.64 (-2.5, 3.3) IL-10: Baseline: 23 (61), 3.7 (1.8, 9.6), 24weeks: 18 (43), 4.2 (1.8, 6.1), Change: -6.4 (21),-0.54 (-3.2, 1.1) IL-12p40: Baseline: 45 (99), 7.7 (1.9, 26), 24weeks: 35 (67), 5.3 (1.9, 18), Change: -12 (45),0 (-6.6, 0) IL-12p70: Baseline: 11 (22), 2.2 (0.05, 12), 24weeks: 8.4 (14), 4.4 (0.63, 8.9), Change: -3.3(16), -0.21 (-6.2, 0) IL-13: Baseline: 61 (140), 0.27 (0.27, 26), 24weeks: 52 (120), 3.8 (0.27, 19), Change: -11(32), 0 (-4.3, 0.6) IL-15: Baseline: 9.3 (23), 3.4 (2.8, 5.4), 24weeks: 6.9 (12), 3.2 (2.4, 5.1), Change: -2.6(12), -0.2 (-1.2, 0.39) IL-17: Baseline: 2.5 (5.6), 0.22 (0.22, 1.9), 24weeks: 3.7 (4.7), 1.1 (0.22, 6.2), Change: 1.1(4.8), 0 (0, 1.5) IL-1a: Baseline: 99 (200), 13 (0.93, 43), 24weeks: 90 (180), 11 (0.93, 65), Change: -13(56), 0 (-5.1, 2.7) IL-1b: Baseline: 5.1 (12), 0.83 (0.06, 3.2), 24weeks: 3.4 (6.9), 0.76 (0.06, 2.9), Change: -2(6.9), -0.1 (-1.3, 0) IL-1ra: Baseline: 54 (85), 24 (14, 56), 24 weeks:45 (66), 18 (12, 45), Change: -10 (38), -7.4 (-16,1.1) IL-2: Baseline: 4.3 (13), 0.08 (0.08, 1.9), 24weeks: 2.6 (7.1), 0.08 (0.08, 0.82), Change: -1.8(7.1), 0 (-0.87, 0) IL-4: Baseline: 390 (900), 23 (6.7, 120), 24weeks: 350 (790), 40 (7.7, 98), Change: -55(280), -1.1 (-9.4, 5.2) IL-5: Baseline: 11 (32), 1.5 (0.77, 2.9), 24weeks: 11 (28), 1.8 (1, 2.5), Change: -1.1 (5.5),0 (-0.38, 0.5) IL-6: Baseline: 41 (60), 10 (2.6, 38), 24 weeks:28 (51), 6.6 (2, 14), Change: -11 (25), 0 (-16,0.14) IL-6 (ELISA): Baseline: 31 (50), 9.6 (3.6, 23), 24weeks: 5.5 (6.6), 2.8 (1.2, 6.4), Change: -17(35), -5.2 (-12, -1.4) IL-7: Baseline: 31 (54), 12 (6.7, 31), 24 weeks:24 (37), 8.3 (5.2, 19), Change: -8.3 (21), -2.1 (-7.5, 0) IL-8: Baseline: 30 (39), 14 (8.2, 25), 24 weeks:27 (39), 12 (8.2, 20), Change: -3.6 (9.9), -2.2 (-4.7, 2.6) IL-9: Baseline: 4.4 (12), 0.61 (0.15, 2.2), 24weeks: 2.6 (5.7), 0.15 (0.15, 2), Change: -2.1(6.9), 0 (-0.73, 0) IFNa2: Baseline: 69 (110), 37 (29, 59), 24weeks: 60 (65), 37 (29, 57), Change: -11 (72), 0(-9.5, 6.4) IP-10: Baseline: 630 (580), 410 (310, 580), 24weeks: 390 (350), 260 (180, 500), Change: -250(520), -150 (-230, -48) MCP-1: Baseline: 710 (360), 650 (480, 840), 24weeks: 800 (590), 700 (500, 820), Change: 73(370), -6.2 (-56, 83) MCP-3: Baseline: 70 (99), 31 (14, 58), 24 weeks:66 (91), 24 (17, 62), Change: -5.4 (19), -2.6 (-11, 5.3) MDC: Baseline: 740 (400), 750 (480, 980), 24weeks: 790 (370), 830 (570, 1000), Change: 33(190), 8.1 (-78, 80) MIP-1a: Baseline: 9.1 (6.1), 7 (7, 7), 24 weeks:8.1 (2.6), 7 (7, 7), Change: -1.1 (4), 0 (0, 0) MIP-1b: Baseline: 53 (39), 47 (36, 58), 24weeks: 44 (36), 40 (27, 51), Change: -8.5 (11), -8.4 (-12, -1.9) TGFa: Baseline: 7.4 (12), 1 (0.17, 11), 24 weeks:5.4 (9), 1.9 (0.07, 7), Change: -2.3 (4), -0.2 (-2.8, 0) TNFa: Baseline: 21 (17), 16 (14, 21), 24 weeks:76 (40), 63 (56, 94), Change: 54 (34), 46 (39,70) TNFa (ELISA): Baseline: 11 (2), 11 (9.9, 12), 24weeks: 150 (62), 140 (96, 180), Change: 130(62), 130 (86, 170) TNFb: Baseline: 38 (79), 2 (0.04, 17), 24 weeks:35 (79), 1.2 (0.04, 19), Change: -4.3 (24), 0 (-4,0) VEGF: Baseline: 110 (140), 57 (40, 130), 24weeks: 94 (100), 56 (22, 130), Change: -19 (65),-6 (-44, 3.2) sCD40L: Baseline: 1500 (830), 1400 (930,1800), 24 weeks: 1600 (800), 1700 (780, 1800),Change: 120 (760), 150 (-360, 350)

The treatment response was good. 15 subjects (68%) achieved low disease activity at 12 weeks, and 18 subjects (86%) achieved low disease activity at 24 weeks. Scores on joint ultrasound measures also showed improvement at both 12 and 24 weeks compared to baseline. The patients who achieved ultrasound remission at 24 weeks tended to have shorter disease duration and lower baseline total PD score, DAS28-ESR, and mTSS than those who did not achieve ultrasound remission.

Mar. 31, 2024

No

none

https://jrct.mhlw.go.jp/latest-detail/jRCTs071200054

Kawakami Atsushi

Nagasaki University Hospital

1-7-1 Sakamoto, Nagasaki

atsushik@nagasaki-u.ac.jp

Kawashiri Shinya

Nagasaki University Hospital

1-7-1 Sakamoto, Nagasaki

+81-95-819-7200

shin-ya@nagasaki-u.ac.jp

Complete

Nov. 18, 2020

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Patients with 20 years older at the time of obtaining informed consent.
2. Patients with rheumatoid arthritis (RA) fulfilled the ACR/EULAR classification criteria for RA (2010).
3. Patients who are judged by the physician to have moderate disease activity or higher at the time of obtaining consent.
4. Patients with DAS28-CRP > 3.2 at case enrollment.
5. Patients who give written informed consent after receiving sufficient information.

1. Patients under treatment with oral prednisolone >7.5 mg/day at the time of case enrollment.
2. Patients with contraindications to etanercept BS "MA".
3. Patients who have previously used an etanercept-reference product.
4. Patients who have previously used etanercept biosimilar.
5. Patients under treatment with biological agents and JAK inhibitors for RA, except for denosumab.
6. Patients whose usage and dosage of prednisolone or anti-rheumatic drugs were changed within 4 weeks prior to case enrollment.
7. Patients who treated with prohibited drugs or prohibited therapies within 4 weeks prior to case enrollment.
8. Women who are currently pregnant or will not be compliant with a medically approved contraceptive regimen during the study period and lactating women.
9. Patients who jugged unsuitable for this study by the investigator.

Both

Rheumatoid arthritis

Rheumatoid arthritis patients with moderate or high disease activity will be introduce for etanercept BS "MA" within 14 days of case enrollment. The etanercept BS "MA" is given as a weekly subcutaneous injection of 50 mg for 24 weeks.

Changes from baseline to 24 weeks in the Global OMERACT-EULAR Synovitis Score (GLOESS) by musculoskeletal ultrasound (MSUS) for bilateral 2nd-5th metacarpophalangeal (MCP) joints.

The proportion of study participants meeting low disease activity/remission criteria at 12 and 24 weeks.
Changes in total power Doppler (PD) score by MSUS from baseline to 12 and 24 weeks.
Changes in total gray scale (GS) score by MSUS from baseline to 12 and 24 weeks.
Changes in GLOESS by MSUS from baseline to 12 weeks.
Changes in DAS28-ESR from baseline to 12 and 24 weeks.
Changes in DAS28-CRP from baseline to 12 and 24 weeks.
Changes in SDAI from baseline to 12 and 24 weeks.
Changes in CDAI from baseline to 12 and 24 weeks.
Changes in mTSS from baseline to 24 weeks.
Changes in HAQ-DI from baseline to 12 and 24 weeks.
Changes in biomarker from baseline to 12 and 24 weeks.
SRM (standardized response mean) of total PD score at 12 and 24 weeks.
SRM of total GS score at 12 and 24 weeks.
SRM of GLOESS at 12 and 24 weeks.
SRM of DAS28-ESR at 12 and 24 weeks.
SRM of DAS28-CRP at 12 and 24 weeks.

+81-95-819-7229

Oct. 28, 2020

none