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Efficacy of Etanercept Biosimilar Switching from Etanercept Reference Product, using Ultrasound and Clinical Data in Outcomes of Real World Therapy (ESCORT-NGSK Study):Study protocol for an interventional, multicenter, open-label, single-arm clinical trial

Efficacy of Etanercept Biosimilar Switching from Etanercept Reference Product, using Ultrasound and Clinical Data in Outcomes of Real World Therapy (ESCORT-NGSK Study):Study protocol for an interventional, multicenter, open-label, single-arm clinical trial

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The full analysis set (FAS) was 17 cases, and the 17 cases are summarized. Continuous variables represent median (interquartile range) and categorical variables represent number of cases (percentage). Age was 64 (46, 68) years, 2 males (12%) and 15 females (88%). They were 154 cm (149, 157) tall and 52 kg (47, 56) in weight. 15 (7, 21) had RA for 15 years, 15 (88%) were RF positive, and 11 (65%) were anti-CCP antibody positive. The highest historical RF was 183 IU/mL (61, 264) and the highest anti-CCP antibody was 82 U/mL (44, 212). Baseline RF was 59 IU/mL (38, 180) and baseline anti-CCP antibody was 47 U/mL (24, 158). The duration of Enbrel treatment was 2.1 years (1.2, 5.1) and the duration of low disease activity (LDA)/remission maintenance was 67 weeks (56, 100). Six patients (35%) had a history of smoking, 8 pack-years (5, 20). Thirteen subjects (76%) had complications, with 50 complications. The top three complications were osteoporosis in 9 cases (18%), hypertension in 4 cases (8%), and dyslipidemia and allergic rhinitis in 3 cases (6%). The number of patients with prior biologic therapy included 3 with infliximab, 1 with adalimumab, 2 with tocilizumab, and 1 with abatacept. Eleven patients (65%) were on concomitant methotrexate at baseline at a dose of 6 mg/week (6, 8) and two patients (12%) were on prednisolone (PSL) at baseline at a dose of 0.88 mg/day (0.56, 1.19).

The number of patients enrolled per facility was 10 from Nagasaki University Hospital, 3 from Japanese Red Cross Nagasaki Genbaku Hospital, 2 from Sasebo Chuo Hospital, Nagasaki Medical Hospital of Rheumatology, and 1 each from Miyazakizenjinkai Hospital, Kumamoto Shinto General Hospital, Saga University Hospital. 2 facilities did not enroll any patients. There were 20 subjects enrolled. Overall, four cases were discontinued. Of the enrolled subjects, 17 were study subjects (FAS) evaluated for DAS28-ESR and clinical flare-up at either 24 weeks or at discontinuation, and 16 completed the study.

[Adverse events] There were 10 adverse events in the safety analysis set from the start of the study to 52 weeks. Among these, one serious adverse event occurred 19 days after initiation of the study drug, a left renal abscess. The severity was Grade 3. Consequently, the study drug was discontinued, the patient was hospitalized, underwent surgery, and subsequently recovered. Regarding other non-serious adverse events, the severity was categorized as Grade 1: mild (no intervention required for the adverse event) or Grade 2: moderate (minimal/local/non-invasive treatment required for the adverse event). Notably, one subject was discontinued from the study drug due to drug eruption. [Adverse drug reactions] From the start of study to 52 weeks, there were 7 cases of adverse drug reactions: left renal abscess, acute bronchitis, nasal herpes, pneumonia, injection site reaction, drug eruption, and vomiting.

[Primary endpoints] The proportion of study participants meeting LDA/remission criteria at 24 weeks without clinical relapse throughout the observation period was 16 of 17, 94.1% (95% confidence interval: 0.713-0.999). [Secondary endpoint] 1. The proportion of study participants meeting LDA/remission criteria at 12, 36, and 52 weeks without clinical relapse throughout the observation period. The analysis included 17 participants with FAS up to 24 weeks and 11 participants after 36 weeks, except for one patient who was discontinued at 24 weeks by the physician's decision. At 12 weeks: LDA/remission achieved in 17 of 17 patients (100%), of which 14 patients (82.4%) were in remission. At 24 weeks: LDA/remission achieved in 16 of 17 patients (94.1%), of which 13 patients were in remission (76.5%) At 36 weeks: 9 of 11 patients achieved LDA/remission (81.8%), of which 8 patients achieved remission (72.7%) At 52 weeks: LDA/remission achieved in 10 of 11 patients (90.9%), of which 8 patients (72.7%) were in remission. Among patients receiving 50 mg/week, the dose was reduced from 24 weeks to 25 mg/week in 11 of 12 patients, 91.7% (95% confidence interval: 0.615-0.998). The proportion of patients who remained in LDA/remission until 52 weeks after dose reduction from 24 weeks to 25 mg/week was 9 of 11, 81.8% (95% CI: 0.482-0.977). 2. Change in total GS (gray scale) score by musculoskeletal ultrasound, total PD (power doppler) score by musculoskeletal ultrasound, composite score by musculoskeletal ultrasound, DAS28-ESR, DAS28-CRP, SDAI (Simple Disease Activity Index), CDAI (Clinical Disease Activity Index) from baseline to 12 weeks, 24 weeks, 36 weeks, 52 weeks. Mean (SD), median (IQR) are listed in this order. Total GS score: Baseline: 3.5 (3.6), 2 (1, 5) 12 weeks: 4 (3.8), 3 (2, 4) 24 weeks: 4.2 (4), 3 (2, 5) 36 weeks: 4.2 (2.6), 5 (2.5, 6) 52 weeks: 5.2 (3.3), 6 (2.5, 8) Change 12 weeks: 0.53 (1.6), 0 (0, 1) Change 24 weeks: 0.71 (2.1), 1 (0, 2) Change 36 weeks: -0.091 (2.9), 0 (-0.5, 1.5) Change 52 weeks: 0.91 (2.9), 1 (0.5, 2) Total PD score: Baseline: 0.35 (1), 0 (0, 0) 12 weeks: 0.47 (1), 0 (0, 0) 24 weeks: 0.65 (1.3), 0 (0, 0) 36 weeks: 0.55 (1), 0 (0, 0.5) 52 weeks: 0.82 (1.6), 0 (0, 1) Change 12 weeks: 0.12 (0.7), 0 (0, 0) Change 24 weeks: 0.29 (1), 0 (0, 0) Change 36 weeks: 0 (0.77), 0 (0, 0) Change 52 weeks: 0.27 (1.7), 0 (0, 0) Composite score: Baseline: 3.5 (3.6), 2 (1, 5) 12 weeks: 4.1 (3.8), 4 (2, 4) 24 weeks: 4.2 (4), 3 (2, 5) 36 weeks: 4.2 (2.6), 5 (2.5, 6) 52 weeks: 5.2 (3.3), 6 (2.5, 8) Change 12 weeks: 0.59 (1.5), 0 (0, 1) Change 24 weeks: 0.71 (2.1), 1 (0, 2) Change 36 weeks: -0.091 (2.9), 0 (-0.5, 1.5) Change 52 weeks: 0.91 (2.9), 1 (0.5, 2) DAS28-ESR: Baseline: 2.1 (0.52), 2 (1.9, 2.5) 12 weeks: 2.1 (0.56), 2 (1.9, 2.5) 24 weeks: 2.2 (0.67), 2 (1.9, 2.5) 36 weeks: 2.3 (0.66), 2.2 (1.9, 2.7) 52 weeks: 2.4 (0.72), 2.2 (1.9, 2.6) Change 12 weeks: -0.0071 (0.47), -0.06 (-0.31, 0.05) Change 24 weeks: 0.087 (0.53), 0.03 (-0.16, 0.31) Change 36 weeks: 0.31 (0.51), 0.09 (-0.02, 0.69) Change 52 weeks: 0.39 (0.65), 0.1 (-0.1, 0.69) DAS28-CRP: Baseline: 1.5 (0.29), 1.4 (1.3, 1.6) 12 weeks: 1.5 (0.33), 1.6 (1.3, 1.8) 24 weeks: 1.5 (0.36), 1.5 (1.3, 1.6) 36 weeks: 1.7 (0.56), 1.6 (1.3, 2) 52 weeks: 1.8 (0.76), 1.6 (1.3, 2.3) Change 12 weeks: 0.091 (0.31), 0.06 (-0.03, 0.32) Change 24 weeks: 0.08 (0.43), 0.04 (-0.05, 0.2) Change 36 weeks: 0.31 (0.49), 0.11 (-0.035, 0.61) Change 52 weeks: 0.47 (0.73), 0.14 (-0.085, 0.82) SDAI: Baseline: 2.8 (1.8), 2.7 (1.7, 3.9) 12 weeks: 2.5 (2), 1.8 (0.9, 3.5) 24 weeks: 2.7 (1.6), 3 (1.2, 4) 36 weeks: 3.4 (3.1), 2.7 (1.5, 4.7) 52 weeks: 3.9 (4), 2.6 (0.75, 5.5) Change 12 weeks: -0.3(1.4), -0.1(-1, 0) Change 24 weeks: -0.088(1.7), 0(-0.7, 0.3) Change 36 weeks: 1 (3), 0.1 (-0.25, 1.3) Change 52 weeks: 1.5 (3.7), 0 (-0.95, 2.8) CDAI: Baseline: 2.7 (1.8), 2.6 (1.5, 3.9) 12 weeks: 2.3 (2.1), 1.7 (0.6, 3.5) 24 weeks: 2.4 (1.7), 2.5 (1.2, 3.8) 36 weeks: 3.2 (3.1), 2.6 (0.8, 4.5) 52 weeks: 3.7 (4), 2.5 (0.55, 5.5) Change 12 weeks: -0.41 (1.3), -0.3 (-1.2, 0) Change 24 weeks: -0.31 (1.7), -0.2 (-0.7, 0.2) Change 36 weeks: 0.91 (3.1), -0.2 (-0.7, 1.3) Change 52 weeks: 1.4 (3.7), 0 (-1.1, 2.5) 3. Change in mTSS from baseline to 24 and 52 weeks. Mean (SD), median (IQR) are listed in this order. mTSS: Baseline: 69 (90), 27 (7, 120) 24 weeks: 69 (90), 27 (7, 120) 52 weeks: 76 (100), 27 (7, 94) Change 24 weeks: 0.029 (0.12), 0 (0, 0) Change 52 weeks: 0.36 (0.55), 0 (0, 0.75) 4. Change in HAQ-DI from baseline to 12, 24, 36, and 52 weeks. Mean (SD), median (IQR) are listed in this order. HAQ-DI: Baseline: 0.38 (0.66), 0 (0, 0.5) 12 weeks: 0.38 (0.68), 0 (0, 0.5) 24 weeks: 0.39 (0.73), 0 (0, 0.25) 36 weeks: 0.61 (0.77), 0.25 (0, 1.2) 52 weeks: 0.64 (0.94), 0 (0, 1.2) Change 12 weeks: 0 (0.11), 0 (0, 0) Change 24 weeks: 0.0074 (0.18), 0 (0, 0) Change 36 weeks: 0.014 (0.25), 0 (-0.12, 0) Change 52 weeks: 0.042 (0.21), 0 (0, 0.12)

At 24 weeks, the number of study subjects who remained in LDA/remission on DAS28-ESR was 16 of 17, 94.1% (95% CI: 0.713- 0.999). The group 50 mg/week was reduced to 25 mg/week at 24 weeks, and LDA/remission was sustained until 52 weeks in 9 of 11 subjects, 81.8% (95% CI: 0.482-0.977). There was no apparent worsening of scores for DAS28-ESR, DAS28-CRP, SDAI, and CDAI. While the total GS score showed a tendency to increase slightly over time, the total PD score remained 0 at the median in all groups.

June. 30, 2024

Mar. 06, 2025

https://pubmed.ncbi.nlm.nih.gov/40010737/

No

none

https://jrct.mhlw.go.jp/latest-detail/jRCTs071190046

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

April. 01, 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 have been treated Enbrel (Subcutaneous injection of 25 mg once weekly or 25 mg twice weekly or 50 mg once weekly or 50 mg once biweekly) for 24 weeks or longer and who have been in LDA/remission with no change in Enbrel dosage for at least 24 weeks prior to obtaining consent.
4.Patients who give written informed consent after receiving sufficient information.

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

Both

Rheumatoid arthritis

Rheumatoid arthritis patients who have been treated with enbrel (Subcutaneous injection of 25 mg once weekly or 25 mg twice weekly or 50 mg once weekly or 50 mg once biweekly) over 24 weeks and persisted with LDA/remission are switched to the same dose of etanercept BS "MA" from enbrel. In addition, for patients receiving etanercept BS "MA" 50 mg weekly, the dose will be reduced from 24 weeks to etanercept BS "MA" 25 mg weekly to test whether LDA/remission persists until week 52.

The proportion of study participants meeting LDA/remission criteria at 24 weeks without clinical relapse throughout the observation period.

The proportion of study participants meeting LDA/remission criteria at 12 weeks, 36 weeks, 52 weeks without clinical relapse throughout the observation period Differences of total power Doppler (PD) score by musculoskeletal ultrasound at 12, 24, 36, and 52 weeks.
Differences of total gray scale (GS) score by musculoskeletal ultrasound at 12, 24, 36, and 52 weeks.
Differences of combined score by musculoskeletal ultrasound at 12, 24, 36, and 52 weeks.
Differences of DAS28-ESR at 12, 24, 36, and 52 weeks.
Differences of DAS28-CRP at 12, 24, 36, and 52 weeks.
Differences of SDAI at 12, 24, 36, and 52 weeks.
Differences of CDAI at 12, 24, 36, and 52 weeks.

+81-95-819-7229

Jan. 31, 2020

none