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open-label, multicenter, single-arm study to evaluate the efficacy and safety of etanercept in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis who were ineffective with systemic steroid therapy

Etanercept therapy for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) cases of refractory to systemic steroid therapy

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The study population consisted of 5 males (62.5%) and 3 females (37.5%). The mean age at the time of consent (mean +/- standard deviation, hereafter the same) was 63.4 +/- 20.74 years, with a median age of 70.0 years, ranging from 24 to 82 years. The primary diseases were SJS in 5 cases (62.5%) and TEN in 3 cases (37.5%). All 8 cases had complications, and 7 cases (87.5%) had medical histories. The suspected causative drugs were acetaminophen in 3 cases (37.5%); sulfamethoxazole/trimethoprim in 2 cases (25.0%); and allopurinol, ipilimumab, Comirnaty RTU Intramuscular Injection, salazosulfapyridine, spironolactone, nivolumab, L-cystein, doxycycline, vonoprazan, lansoprazole, Lulu over-the-counter tablets, and hainosankyuto in 1 case each (12.5%). The mean height was 160.24 +/- 13.605 cm, and the mean weight was 56.68 +/- 17.271 kg. SCORTEN was assessed in 8 cases, with total scores of 0 in 1 case (12.5%), 1 in 2 cases (25.0%), 2 in 3 cases (37.5%), and 3 in 2 cases (25.0%).

The first case was enrolled on November 11, 2021, and the ninth case, which provided consent on August 19, 2023, was the final one. A total of 9 cases provided consent, of which 8 were enrolled in the study. The number of cases that completed the drug administration as outlined in the study protocol was also 8.

During the study period, adverse events were observed in 6 cases (75%); however, none of the events were related to the study drug. The severity of the events was mild in 3 cases (37.5%) and moderate in 3 cases (37.5%), with no severe events reported. Infections were observed in 4 cases (50.0%) as new infections, but there was no worsening of pre-existing infections. There were no cases of death, and serious adverse events occurred in 2 cases (25.0%). No adverse events led to the discontinuation of the study drug.

Results in the Full Analysis Set (FAS), the Primary Population for Efficacy Analysis Primary Endpoint (Time to Complete Re-epithelialization [days]): The median time to complete re-epithelialization, calculated using the Kaplan-Meier method, was 10.0 days, with a 95% confidence interval of (6.00, 20.00). To confirm that the time to complete re-epithelialization was not inferior to the known data of 16.7 days in the steroid-treated group, cases that had not completed re-epithelialization by day 29, as well as those who discontinued, were considered as 28 days for the evaluation of the FAS time to re-epithelialization. As a result, all 8 cases in the FAS completed re-epithelialization by day 29. The mean time to CR (CR-1 day) was 12.8 +/- 5.52 days, with a median of 10.0 days. The 95% confidence interval of the mean was (8.1, 17.4) and p-value = 0.0828. Secondary Endpoints: 1. Time to Halt Progression of Skin Symptoms (days): The mean was 4.0 +/- 3.34 days, with a median of 3.0 days, and a range of 2 to 12 days. 2. Length of Hospitalization (days): The mean was 19.3 +/- 3.51 days, with a median of 19.0 days, and a range of 16 to 23 days. 3. Mortality Rate by Day 29: 0.0%. 4. Disease Evaluation Scores: Each score (mean +/- standard deviation) was as follows: Total Score: Before treatment: 15.1 +/- 6.96 points; Day 4: 11.8 +/- 6.54 points; Day 8: 7.6 +/- 4.66 points; Day 15: 1.9 +/- 1.89 points; Day 22: 0.4 +/- 0.74 points; Day 29: 0.1 +/- 0.38 points. Ocular Lesion Score: Before treatment: 1.4 +/- 1.85 points; Day 4: 1.1 +/- 1.46 points; Day 8: 0.8 +/- 1.16 points; after Day 15: 0.0 +/- 0.00 points. Skin Lesion Score: Before treatment: 10.0 +/- 5.13 points; Day 4: 7.3 +/- 4.53 points; Day 8: 4.6 +/- 3.11 points; Day 15: 1.3 +/- 1.75 points; after Day 22: 0.0 +/- 0.00 points. Systemic Findings Score: Before treatment: 2.0 +/- 1.31 points; Day 4: 1.5 +/- 1.51 points; Day 8: 1.0 +/- 1.31 points; Day 15 and Day 22: 0.4 +/- 0.74 points; Day 29: 0.1 +/- 0.38 points. Lip/Oral Mucosal Lesion Score: Before treatment: 1.8 +/- 1.49 points; Day 4: 1.9 +/- 1.55 points; Day 8: 1.3 +/- 1.04 points; Day 15: 0.3 +/- 0.46 points; after Day 22: 0.0 +/- 0.00 points. 5. Corneal Epithelial Defect Score: All cases had a score of 0 before treatment; however, on Day 4, one case (12.5%) had a score of 3, and on Days 8, 15, and 22, one case each (12.5%) had a score of 1. Meanwhile, 7 cases (87.5%) remained at a score of 0 (on Day 22, 6 cases [75.0%] were at a score of 0). On Day 29, 7 cases (87.5%) had a score of 0, with no cases having a score above 1. Worsening of the score was observed in one case (12.5%) on Days 4, 8, 15, and 22, but no worsening was observed on Day 29. 6. Re-epithelialization: Cases that completed re-epithelialization were 1 case (12.5%) between Days 1-8, 4 cases (50.0%) between Days 9-15, and 3 cases (37.5%) between Days 16-22. There were no cases (0.0%) between Days 23-29. No cases remained incomplete or discontinued.

This study assessed the efficacy and safety of weekly 50 mg ETN0 in SJS/TEN patients unresponsive to SST. Eight patients (5 males, 3 females; mean age 63.4 years) received ETN0. The mean time to complete re-epithelialization was 12.8 days, which was not inferior to the steroid-treated group's 16.7 days, though not statistically significant (95%CI: 8.1-17.4, p = 0.0828). Adverse events occurred in 6 cases, none related to ETN0. ETN0 is effective and safe up to 29 days post-administration in SJS/TEN patients.

Aug. 29, 2024

No

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https://jrct.mhlw.go.jp/latest-detail/jRCTs031210325

Abe Riichirou

Niigata University Medical and Dental Hosipotal

1-754 Asahimachi-dori, Chuo-ku Niigata 951-8510, Japan

aberi@med.niigata-u.ac.jp

Kimura Haruna

Niigata University Medical and Dental Hosipotal

1-754 Asahimachi-dori, Chuo-ku Niigata 951-8510, Japan

+81-25-227-2282

haruna-57@med.niigata-u.ac.jp

Complete

Oct. 01, 2021

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1. Patients who meet the SJS diagnostic criteria or the TEN diagnostic criteria.
2.Patients treated with systemic steroid therapy (predonisolone equivalent administrated 20 mg/day or more) for 2 days or more.
3. Patients with progressing or unchanged symptoms after steroid therapy.
4. Patients aged 20 years or older who gave written consent to participate in the study.

1. Patients whose dose of systemic steroid therapy has been changed within 2 days (excluding cases where dose reduction is necessary due to worsening complications, etc.)
2. Patients who received steroid pulse therapy within 2 days
3. Patients who received IVIg therapy within 2 days
4. Patients who received plasma exchange therapy within 2 days
5. Patients who need to use the concomitant prohibited drugs and therapies in this study
6. Patients with a total SCORTEN score of 4 points or more
7. Patients with DIHS
8. Patients with multiple organ failure
9. Patients with serious infection and sepsis
10. Patients with demyelinating disease (multiple sclerosis, etc.)
11. Patients with serious respiratory illness (active or latent tuberculosis, etc. )
12. Patients infected with hepatitis B virus or hepatitis C virus
13. Patients with severe cerebral and cardiovascular disorders
14. Patients with severe deterioration of cardiac function
15. Patients at high risk of thrombosis embolus
16. Patients with hemolytic and blood loss anemia
17. Patients with platelet count less than 75,000 /microL
18. Patients with serum creatinine of 2 mg/dL or more
19. Patients with a history of shock and hypersensitivity to ETN
20. Patients who have been treated with ETN or other TNF-alpha inhibitors within 168 days ( 24 weeks )
21. Patients treated with other unapproved drugs within 168 days ( 24 weeks )
22. Pregnant, expected pregnant, lactating patients, or patients who disagree with contraception until the end of observation
23. Patients who are judged to be inappropriate by the responsible doctor or the sharing doctor

Both

stevens-johnson syndrome, toxic epidermal necrosis

Etanercept 50 mg / day is subcutaneously administered on the first day (Day 1). If epithelialization is not complete, administer once on day 8 (Day 8) and day 15 (Day 15) as needed.

stevens-johnson syndrome, toxic epidermal necrosis

TNF-alpha inhibitor, Etanercept

Period until re-epithelialization is completed (day)
The number of days from the first administration day (Day 1) to the completion date of re-epithelialization when the skin peeling area becomes 0% is totaled and evaluated.

1. Period until the progress of skin symptoms stops (day)
The progress of the skin symptoms stop from the first day of administration (Day 1) to aggregate the number of days until the (new blisters / skin peeling, flaking and state not recognized is likely to skin) evaluation.

2. Hospitalization period (day)
The number of days from Day 1 to the discharge date is totaled and evaluated.

3. Mortality rate until Day 29
Aggregate the deaths from Day 1 to Day 29 and evaluate the mortality rate.

4. Severity-of-illness evaluation
The severity-of-illness score at each evaluation point and amount of change from baseline for each item are evaluated.

5. Corneal epithelial defect score
Evaluate the amount of change from baseline.

6. Presence or absence of re-epithelialization
The presence or absence of re-epithelialization is confirmed every week, and the re-epithelialization rate is evaluated.

+81-25-368-9343

July. 30, 2021

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