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

(NATIENS Trial)

Recruiting at 13 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

2 Participants Needed

Trial Summary

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.

What data supports the idea that Etanercept vs Cyclosporine for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis is an effective drug?

The available research does not provide specific data on the effectiveness of Etanercept or Cyclosporine for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. The studies mentioned focus on Etanercept's use in other conditions like juvenile idiopathic arthritis, rheumatoid arthritis, and occupational dermatitis, showing it can be effective and safe for these conditions. However, there is no direct evidence from the provided information about its effectiveness for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. ^{1 2 3 4 5}

What data supports the effectiveness of the drug etanercept for treating Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

Etanercept, a drug that blocks a protein involved in inflammation, has been shown to be effective in treating various inflammatory conditions like rheumatoid arthritis and occupational dermatitis, suggesting it may help with similar inflammatory skin conditions. ^{1 2 3 4 5}

What safety data exists for Etanercept and Cyclosporine treatments?

Etanercept, a TNF receptor fusion protein, has been studied for various conditions. In juvenile idiopathic arthritis, it showed minor side effects like injection site reactions and upper respiratory infections, with some cases of urticaria-like rash. In occupational medicamentosa-like dermatitis, it was effective without adverse reactions. In rheumatoid arthritis, it was safe and effective in a phase II trial. No specific safety data for Cyclosporine in the context of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis was provided in the research. ^{1 2 4 6 7}

Is Etanercept generally safe for human use?

Etanercept has been shown to be generally safe in humans, with minor side effects like injection site reactions and upper respiratory infections reported in some cases. In studies, no serious adverse reactions were noted, indicating it is generally well-tolerated. ^{1 2 4 6 7}

Is the drug Etanercept a promising treatment for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

Yes, Etanercept is a promising drug for treating Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis. It has been shown to stabilize conditions and prevent skin damage from worsening, especially in combination with other treatments. It can quickly reduce skin detachment and speed up healing. ^{1 8 9 10 11}

How does the drug combination of Etanercept and Cyclosporine differ from other treatments for Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

The combination of Etanercept and Cyclosporine is unique because Etanercept, a TNF receptor fusion protein, can quickly reduce skin detachment and speed up healing, while Cyclosporine, a calcineurin inhibitor, blocks T-cell function, addressing the underlying immune response. This dual approach targets both the symptoms and the immune system, unlike traditional treatments that primarily focus on supportive care. ^{1 8 9 10 11}

What is the purpose of this trial?

The North American Therapeutics in Epidermal Necrolysis Syndrome (NATIENS) study is a multicenter double-blind randomized controlled assessment of two arms - one of systemic immunomodulatory therapy (etanercept) and one of supportive care deemed to be the current standard of care. We will leverage the opportunity of this controlled design to collect multiples samples with an aim to discover new genetic and biological markers for prevention and early diagnosis and define cellular and molecular mechanisms to facilitate discovery of promising treatment strategies. This study has been preceded by a planning phase to ensure testing and development of harmonized supportive care infrastructure and operating procedures across sites.

Research Team

Elizabeth J Phillips, MD

Principal Investigator

Vanderbilt University Medical Center

Eligibility Criteria

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

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

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.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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]

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, 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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Etanercept and urticaria in patients with juvenile idiopathic arthritis. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Construction and purification of the murine p75-murine IgG1 fusion protein. [2016]

4. China 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]. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Pharmacodynamic effects of the murine p75-Fc fusion protein in mice. [2016]

6. Switzerland 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. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and immunogenicity of T0001, a newly developed anti-TNFα fusion protein, in healthy volunteers. [2018]

8. United States 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. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Pediatric Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Halted by Etanercept. [2018]

10. Australia 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. [2022]

11. Poland pubmed.ncbi.nlm.nih.gov

Stevens-Johnson syndrome in a patient with rheumatoid arthritis during long-term etanercept therapy. [2020]