Etanercept vs Cyclosporine for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis

(NATIENS Trial)

Not currently recruiting at 14 trial locations

Overseen By Michelle Martin-Pozo, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Vanderbilt University Medical Center

Must not be taking: Etanercept, IVIg, Corticosteroids, others

Disqualifiers: Organ transplant, Heart failure, Pregnancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments for Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), severe skin reactions often caused by medications. One group will receive etanercept, a drug that calms the immune system, while the other group receives cyclosporine (also known as Ciclosporin, Neoral, Sandimmune, or Gengraf), an immunosuppressant. Researchers aim to find better treatments for these conditions and discover new markers for early diagnosis. The trial seeks participants who have recently developed blistering skin and mucous membrane symptoms, possibly due to a new medication used within the last two months. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatments.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you have a history of certain immunosuppressive or immunomodulatory therapies, or if you absolutely need a drug that interacts with cyclosporine without a suitable substitute.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does exclude those who have recently used certain treatments like etanercept, intravenous immune globulin, or high doses of corticosteroids. It also excludes those who need drugs that interact with cyclosporine without a suitable alternative.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that etanercept, a treatment for autoimmune conditions like arthritis and psoriasis, may help with Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), which are serious skin reactions. Some studies found that etanercept can be effective and generally safe for patients with these conditions. Notably, etanercept is already approved for other diseases, suggesting its relative safety.

Cyclosporine is another treatment under investigation. Although specific safety information for cyclosporine in SJS/TEN is limited, it has been used safely for other conditions for many years.

Researchers are studying both treatments to ensure their safety and effectiveness for these serious skin conditions. Trial participants will be closely monitored for any side effects to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, which often involves corticosteroids and other immunosuppressants like cyclosporine, etanercept takes a unique approach by acting as a tumor necrosis factor (TNF) inhibitor. This mechanism helps reduce inflammation by blocking TNF, a substance in the body that can cause inflammation and lead to tissue damage. Researchers are excited about etanercept because it has the potential to offer quicker and more targeted relief with fewer side effects compared to traditional therapies. Plus, its ability to be administered subcutaneously provides a more convenient and possibly more effective delivery method, potentially improving patient outcomes significantly.

What evidence suggests that this trial's treatments could be effective for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

Research has shown that etanercept, one of the treatments under study in this trial, might help treat Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), both serious skin conditions. Etanercept blocks a protein called tumor necrosis factor-alpha (TNF-α), which can help manage these severe skin reactions. Some studies found that patients with TEN who took etanercept improved, suggesting it could be a promising treatment. While more research is needed, these findings offer hope for people dealing with these conditions. ^{2 5 6 7 8}

Who Is on the Research Team?

Elizabeth J Phillips, MD

Principal Investigator

Vanderbilt University Medical Center

Are You a Good Fit for This Trial?

Adults over 18 with Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis, showing skin and mucous membrane symptoms, fever, muscle pain, headache, and a recent history of medication intolerance. Pregnant or breastfeeding women and those with certain medical conditions or treatments are excluded.

Inclusion Criteria

This criterion means that the participant needs to meet at least two of the following conditions.

Subject and/or legally authorized representative must be able to understand and provide informed consent.

I have had symptoms like fever, muscle pain, and headaches recently.

Exclusion Criteria

You have a severe reaction to a drug, or a skin condition that is not related to a drug reaction.

If more than 5 days have passed since you first noticed skin or mouth problems.

Subject or legally authorized representative is not willing to provide informed consent.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either etanercept or placebo with harmonized supportive care

4 weeks

Multiple visits for treatment and sample collection

Follow-up

Participants are monitored for safety, effectiveness, and secondary outcomes such as ocular involvement and mortality

up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Cyclosporine
• Etanercept
• Harmonized Supportive Care

Trial Overview The NATIENS study is testing whether cyclosporine (for 14 days) or etanercept (two doses) alongside standard care improves recovery from SJS/TEN compared to standard care alone. It's a phase III trial involving multiple U.S. centers where patients are randomly assigned to one of the three groups in a blinded manner.

How Is the Trial Designed?

Group I: Etanercept 50mg sc day 1 and day 4 Active Control 2 Interventions

Harmonized supportive care with placebo days 1 and 4

Group II: Harmonized supportive care Placebo Group 1 Intervention

Harmonized supportive care with etanercept placebo days 1 and 4

Cyclosporine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in United States as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Approved in Canada as Neoral for:

• Prevention of organ rejection in kidney, liver, heart, lung, pancreas, and bone marrow transplants
• Treatment of severe psoriasis
• Treatment of nephrotic syndrome

Approved in Japan as Neoral for:

• Prevention of organ rejection in kidney, liver, and heart transplants
• Treatment of severe rheumatoid arthritis
• Treatment of severe psoriasis

Who Is Running the Clinical Trial?

Vanderbilt University Medical Center

Lead Sponsor

Trials

922

Recruited

939,000+

University of Ottawa

Collaborator

Trials

231

Recruited

267,000+

University of Toronto

Collaborator

Trials

739

Recruited

1,125,000+

Published Research Related to This Trial

In a study involving 12 patients with occupational medicamentosa-like dermatitis, treatment with etanercept significantly reduced the severity of the condition, as indicated by a decrease in the Drug Eruption Area and Severity Index (DASI) score from 56.33 to 0.50 after 4 weeks (P<0.01).

All patients achieved at least a 50% reduction in DASI score, and there were no reported adverse reactions, suggesting that etanercept is both effective and safe for treating this specific dermatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Recombinant human tumor necrosis factor receptor type Ⅱ-IgG Fc fusion protein for treatment of occupational medicamentosa-like dermatitis induced by trichloroethylene]. Lv, LL., Yan, ZH., Shi, X., et al.[2019]

In a 24-week study involving 60 children with juvenile idiopathic arthritis (JIA), treatment with the etanercept biosimilar rhTNFR-Fc combined with methotrexate led to a significant reduction in disease activity, as measured by the cJADAS-10 score, which dropped from 14.66 to 2.4 (P < 0.01).

Approximately half of the patients achieved inactive disease status after 24 weeks, and improvements were also observed in symptoms like morning stiffness and joint effusions, indicating that rhTNFR-Fc is both effective and safe for treating JIA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of etanercept biosimilar rhTNFR-Fc in Chinese patients with juvenile idiopathic arthritis: An open-label multicenter observational study. Xu, X., Liu, X., Zheng, W., et al.[2022]

In a randomized, double-blind, placebo-controlled trial involving 234 patients with active rheumatoid arthritis, etanercept demonstrated significant improvements in disease activity over 6 months, with 59% of patients achieving a 20% improvement compared to only 11% in the placebo group.

Etanercept was well tolerated and showed a dose-dependent effect, with no dose-limiting toxic effects, confirming its safety and efficacy as a treatment for rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Moreland, LW., Schiff, MH., Baumgartner, SW., et al.[2022]

T0001, a new recombinant fusion protein, was found to be safe and well-tolerated in a first-in-human trial involving 56 healthy Chinese volunteers, with no serious adverse events reported.

The pharmacokinetics of T0001 showed a slow absorption and elimination rate, with increasing plasma concentrations of TNFα after administration, although the study could not confirm linear pharmacokinetics across the tested doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and immunogenicity of T0001, a newly developed anti-TNFα fusion protein, in healthy volunteers. Wang, Y., Liu, C., Chen, S., et al.[2018]

An 11-year-old girl with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap, likely triggered by sulfamethoxazole-trimethoprim, was treated successfully with a combination of methylprednisolone, cyclosporine, and etanercept.

The addition of etanercept stabilized her condition and prevented further progression of skin involvement, marking the first reported use of etanercept in pediatric cases of SJS/TEN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Halted by Etanercept. Gavigan, GM., Kanigsberg, ND., Ramien, ML.[2018]

In a study of patients with Toxic Epidermal Necrolysis (TEN) treated with the TNF-α inhibitor adalimumab, all patients experienced successful resolution of their condition, highlighting its efficacy as a treatment option.

Patients treated with adalimumab had a shorter average hospital stay of 22.5 days compared to 33 days for those receiving other non-TNF-α immunosuppressants, suggesting that adalimumab may lead to quicker recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highlighting adalimumab as a treatment option for systemic treatment of toxic epidermal necrolysis: A case series from a tertiary specialised burns centre. Kherlopian, A., Mewton, E., Fong, G., et al.[2022]

Etanercept has shown preliminary effectiveness in treating methotrexate-resistant polyarticular juvenile idiopathic arthritis (JIA), suggesting it could be a valuable option for patients who do not respond to standard treatments.

While most side effects of etanercept have been minor, two patients experienced a urticaria-like rash after injections, indicating that while generally safe, some individuals may have specific adverse reactions that need monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept and urticaria in patients with juvenile idiopathic arthritis. Skyttä, E., Pohjankoski, H., Savolainen, A.[2017]

In a study of 28 patients with Stevens-Johnson syndrome and toxic epidermal necrolysis, those treated with cyclosporine showed significantly faster stabilization and healing compared to those receiving only supportive therapy.

The cyclosporine group had a much lower mortality rate (0.32) compared to the supportive treatment group, suggesting that cyclosporine may reduce the risk of death in these severe skin conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness, safety and tolerability of cyclosporine versus supportive treatment in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A record-based study. Mohanty, S., Das, A., Ghosh, A., et al.[2022]

Etanercept, an anti-TNF-alpha agent, can effectively reduce skin detachment and healing time in severe drug reactions like Stevens-Johnson syndrome, as demonstrated in a case study of a 27-year-old woman.

The case suggests that continuing etanercept treatment during Stevens-Johnson syndrome is safe and justified, as the patient did not experience a recurrence of symptoms after resuming therapy post-recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stevens-Johnson syndrome in a patient with rheumatoid arthritis during long-term etanercept therapy. Owczarczyk-Saczonek, A., Zdanowska, N., Znajewska-Pander, A., et al.[2020]

Etanercept is a fusion protein that acts as a soluble receptor for tumor necrosis factor (TNF), effectively used to treat various chronic inflammatory diseases in humans, such as rheumatoid arthritis and psoriasis.

To study its effects in mouse models, researchers developed a murine version of the soluble p75-TNF receptor, allowing for better understanding of its mechanism in conditions that mimic human granulomatous infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Construction and purification of the murine p75-murine IgG1 fusion protein. Kim, HY., Renshaw-Gegg, LW., Balciunas, AM., et al.[2016]

Murine p75-Fc, a soluble TNF receptor protein, effectively inhibits TNF-induced IL-6 production in mice, with complete inhibition observed at doses of 5 and 15 mg/kg.

At a lower dose of 1.5 mg/kg, murine p75-Fc still significantly reduced IL-6 production, indicating its potential as a therapeutic agent in managing inflammatory responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic effects of the murine p75-Fc fusion protein in mice. Hu, YL., Kim, HY., Kohno, T., et al.[2016]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12311169/

The case for etanercept in the management of toxic epidermal ... Efficacy of etanercept in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis. Cutis 2021; 107:E22–8. [DOI] [PubMed] ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0190962214014017

Etanercept therapy for toxic epidermal necrolysis Conclusion. These preliminary results suggest the possibility that tumor necrosis factor–alfa may be an effective target for control of TEN, a dangerous skin ...

3. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/1346-8138.17860?af=R

Efficacy and Safety of Etanercept in Japanese Patients ... Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe and potentially fatal adverse drug reactions ...

4. journals.sagepub.com journals.sagepub.com/doi/10.1177/03000605231223059

Tumor necrosis factor-α inhibitor for successful treatment of ... Tumor necrosis factor (TNF)-α inhibitors such as adalimumab and etanercept have been shown to be safe and effective for the treatment of TEN in some cases.

5. researchgate.net researchgate.net/publication/358361707_Evaluation_of_Combination_Therapy_With_Etanercept_and_Systemic_Corticosteroids_for_Stevens-Johnson_Syndrome_and_Toxic_Epidermal_Necrolysis_A_Multicenter_Observational_Study

Evaluation of Combination Therapy With Etanercept and ... Results Among the 242 patients (187 with SJS or SJS-TEN overlapping and 55 with TEN), patients received combination therapy with etanercept and ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK545252/

Etanercept - StatPearls - NCBI Bookshelf Etanercept is a biologic TNF inhibitor commonly used to control ankylosing spondylitis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9495335/

A Review of the Systemic Treatment of Stevens–Johnson ... Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are uncommon but life-threatening diseases mostly caused by drugs.

8. sciencedirect.com sciencedirect.com/science/article/pii/S1027811712000560

Use of etanercept to treat toxic epidermal necrolysis in a ... We show here that short-term etanercept treatment for SJS/TEN in patients with HIV/AIDS can be highly successful.