NATIENS: Optimal Management and Mechanisms of SJS/TEN

• Status: Not yet recruiting
• Trial end date: 2027-08-01
• Target enrollment: 0
• Participant gender: All

Summary

The NATIENS study is a phase III randomized study to examine the optimal treatment and mechanisms of each of two treatments (cyclosporine 5 mg/kg bid for 14 days versus etanercept 50 mg subcutaneously at day 0 and day 3) versus the current standard of care which is harmonized supportive care for the treatment of Stevens-Johnson Syndrome and toxic epidermal necrolysis (SJS/TEN). SJS/TEN is typically a drug-induced disease in adults with a mortality of up to 50% or higher in elderly adults. Although progress has been made in elucidating strong genetic risk factors that have led to pre-prescription screening and prevention the risk factors for most drugs and ethnicities represented in the United States are currently unknown. Currently there are a number of small observational studies and a non-blinded small randomized study however there is no strong or definitive evidence base to support any one treatment intervention over supportive care alone and this remains considered a standard of care for SJS/TEN. The primary objective of the study is to conduct a randomized double-blind double dummy stratified multicenter phase III study across 24 sites across the Unites States to determine whether two therapeutic interventions (etanercept versus cyclosporine) will improve short-term outcomes associated with SJS/TEN. The primary hypothesis of this study is that both etanercept and cyclosporine will show benefit over supportive care alone and that single dose etanercept 50 mg sc at days 0 and repeated 72 hours following initial dosing will show significant benefit over cyclosporine 5 mg/kg bid and supportive care alone. Our secondary outcomes are to determine the clinical outcomes at 3 and 12 months following initial presentation and to determine the molecular and cellular mechanisms of SJS/TEN through collection of timed samples to include DNA, RNA, PBMCs, blister cells and supernatant and skin. We hypothesize that patients will have significant sequelae identified at 3 and 12 months that will differ between treatment arms and that treatment interventions will significantly impact cytotoxic and cytokine signals with these biomarkers correlating with primary and secondary outcome. We also hypothesize that significant genetic associations will be found in association with drug-induced SJS/TEN. Eligible patients are >/= 18 who meet evidence for SJS/TEN clinical criteria as evidence by erythematous/dusky macules coalescing or denuded skin and blistering with positive Nikolsky sign which is mandatory criteria associated with mucous membrane involvement, prodromal symptoms including fever, myalgia and headache, increasing number of lesions and history of a medication. To continue with the study patients must meet pathological criteria. Randomization will occur by a secure central online computer-generated random number system through REDCap. Subjects will be allocated 1:1:1 to cyclosporine plus best supportive care, etanercept plus best supportive care or best supportive care alone. Patients, treating physician and outcome assessors will be blinded to the allocated treatment. The primary outcome of the study is time to complete re-epithelialization as defined by complete absence of erosion and compromised skin. Time to expected re-epithelialization of 21 days is the maximum healing time with supportive care in SJS/TEN patients which reflects the healing time of adult skin. The primary outcome will be independently assessed by the treating team to include any of a burn surgeon, dermatologist or wound specialist. Disagreement will be solved by independent adjudication by a minimum of two reviewers. Patients who have to discontinue a study medication will be analyzed by intent-to-treat analysis and followed for complications of SJS/TEN as per study protocol. Secondary outcomes of the study include: 1)time to halting of progression of SJS/TEN skin disease. Progression will be considered significant if there are any new blisters or erosions and halting of progression is defined as absence of these criteria with any new lesions; 2) all-cause mortality at 30 days, 3 months and 1 year following symptoms onset; 3) composite cause-specific mortality - outcome including death from sepsis, multi-organ failure and acute respiratory distress syndrome; 4) actual mortality versus expected mortality (as calculated by SCORTEN); 5) Time to cessation of acute ocular involvement (this will be tracked by the same serial photography evaluated by two independent Ophthalmology experts in SJS/TEN eye disease; 6) incidence of infections; 7) hospital length of stay; 8) adverse events due to therapy; 9) serial plasma granulysin, IL-15 concentrations (and other relevant biomarkers);10) Follow-up 3 months and 1 year from initial presentation for physical and mental health complications. For aims 2 and 3 a number of mechanistic studies will be performed on paired samples (DNA, RNA, PBMCs, plasma, blister fluid and skin).

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Ottawa Hospital Research Institute; Vanderbilt University Medical Center
• Collaborators: Brooke Army Medical Center; Canadian Dermatology Foundation; University of Ottawa; University of Toronto; Vanderbilt University
• Treatments: Cyclosporine; Cyclosporins; Etanercept

Criteria

Inclusion Criteria:

1. Age >18 years

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

3. Erythematous to dusky macules that show evidence of coalescing and/or denuding skin or blistering in a predominantly truncal distribution (Nikolsky sign = sloughing with direct lateral pressure on non-blistered but involved skin should be considered as a supportive feature

4. At least two of the following:

1. Mucous membrane involvement

2. Prodromal symptoms including fever, myalgia, and headache

3. Evidence of disease progression with an increasing number of skin lesions

5. History of a newly used medication within the last 2 months that has not been tolerated for longer than 12 weeks in the past

6. Females of childbearing potential must have a negative pregnancy test prior to randomization.

Exclusion Criteria:

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

2. A serious drug reaction or possible alternative dermatologic diagnosis at the time of initial evaluation not in keeping with drug-induced SJS/TEN (e.g. graft versus host disease).

3. If greater than 5 days has elapsed from onset of initial cutaneous or mucosal signs of the disease as obtained by patient history or documentation.

4. Patients who have received either etanercept or cyclosporine in the last 6 months.

5. Patients who in time since onset of SJS/TEN illness have received intravenous immune globulin (IVIg) or > 2 doses of pulsed corticosteroid (defined by > 250 mg prednisone equivalent) prior to enrollment in the study.

6. End-stage liver disease (Child Pugh A, B or C or severe liver dysfunction).

7. Grade 2 or higher liver dysfunction (alanine aminotransferase >3 fold or Tbilirubin >3 fold the upper limit of normal).

8. Patients with chronic kidney disease and eGFR<30 ml/min/1.73 m2 (as calculated by the admission value at the site laboratory and support by a mean outpatient eGFR 7-365 days prior to admission if available).

9. Patients receiving renal replacement therapy for any reason

10. Any organ transplant.

11. Pre-existing Class III/IV Heart Failure (New York Heart Association Functional Classification).

12. Multiple Sclerosis or other demyelinating diseases.

13. Pregnancy or breastfeeding.

14. Current or past history of immune checkpoint inhibitor therapy for cancer.

15. Absolute need for a drug that interacts with cyclosporine without an appropriate substitution.

16. History of other immunosuppressive or immunomodulatory therapy that could significant impact treatment or interpretation of response to treatment (i.e. azathioprine, methotrexate, mycophenolate mofetil, mycophenolate sodium, rituximab, JAK inhibitors, IL-17 inhibitors, IL-23 inbibitors, other TNF alpha antagonists (see MOP).

17. Use of surgical debridement and/or xenograft.

18. Known positive SARS-CoV-2 on RT-PCR within 10 days prior to screening or within 5 days of admission or symptomatic COVID-19 infection at screening. Symptomatic patients with a positive SARS-CoV-2 on RT-PCR or comparible assay beyond 10 days must be evaluated by the Independent Protocol Monitor.

19. Clinical or radiographic evidence of active tuberculosis or endemic mycoses.

20. History or evidence of any other clinically significant medical or psychiatric disorder, condition or disease that in the opinion of the treating physician would pose a risk or interfere with evaluation or completion of the study such as known sepsis/systemic infection requiring antibiotic therapy.

21. Known hypersensitivity to Sandimmune® (cyclosporine) and/or Cremophor® EL (polyoxyethylated castor oil).

22. Known hypersensitivity to Enbrel® (etanercept).

23. Receipt of a live attenuated vaccine within 30 days of enrollment.