Clinical trial NCT02987257: NATIENS: Optimal Management and Mechanisms of SJS/TEN
Official title: NATIENS: A Phase III Randomized Double-Blinded Placebo Controlled Study to Determine the Optimal Management and Mechanisms of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Stevens-Johnson Syndrome
Toxic Epidermal Necrolyses
Keywords: Therapeutics
Management
Etanercept
Supportive Care
Immunopathogenesis
Genetics
Adverse Drug Reaction
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: University of Ottawa
name: University of Toronto
First posted: 2016-12-08
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: The scientific rationale for this study is the lack of evidence-based treatment for SJS/TEN. The study will aim to establish the most clinically effective therapy for SJS/TEN, as there is currently no level 1A evidence for any treatment above aggressive supportive care which still has equipoise as the standard of care. A multi-centered, two-arm allocated 1:1, double-blind randomized controlled trial with a planned enrollment of 150 patients over 4 years will be undertaken to evaluate which of supportive care or etanercept leads to the shortest time to complete reepithelialization which is the primary outcome. The controlled setting of the clinical trial provides the basis for which samples can be sequentially collected to answer important mechanistic questions. Samples collected during the study will include DNA, PBMC, RNA, plasma, serum, blister fluid cells and supernatant, sloughed epidermis and punch biopsies of skin. Samples will be bio-banked to do immediate targeted high-resolution HLA sequencing, cytokine profiling and single cell multidimensional analyses to identify biological markers that have the potential to predict risk and outcome of SJS/TEN. A population pharmacokinetic study to assess the disposition of etanercept will be done by collecting five samples over the course of the study. Samples will be biobanked for later analysis for other transcriptomic, proteomic whole genome studies. These mechanistic studies will allow us to gain important insights into the immunopathogenesis of SJS/TEN. Our study will be the first to examine in a blinded randomized controlled design both management and mechanisms of SJS/TEN. We anticipate that this will lead to new ways to prevent, diagnosis and treat SJS/TEN, and will create a roadmap and evidence-base for studies in serious immunologically mediated adverse drug reactions and other immunologically mediated diseases.

This protocol represents the only appropriately powered randomized, double-blind mechanistic clinical trial examining therapeutic interventions for SJS/TEN. It will address several significant gaps in knowledge. From a management perspective, it will provide the highest level of supportive care and prove or refute the benefits of etanercept that is a promising therapy for SJS/TEN. The NATIENS trial will also define the standard for systematically assessing the benefit of a systemic intervention for SJS/TEN in prospective studies. We also hope to identify key biomarkers as well as immunologic and genetic determinants for risk, rapid diagnosis, baseline pathophysiology, and mechanisms of response to therapy. The population pharmacokinetics of etanercept will be established for the first time in this critically ill population to improve future dosing strategies and make recommendations. Finally, the protocols and procedures related to patient care will establish a standard for harmonization of care for these patients to provide the best outcomes possible. The study is likely to result in paradigm shifting knowledge regarding SJS/TEN treatment, diagnosis, prevention, and pathogenesis that will lead to improved care for future SJS/TEN patients.

Eligibility 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 etanercept 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 bilirubin \>3 fold the upper limit of normal).
8. Any organ transplant.
9. Pre-existing Class III/IV Heart Failure (New York Heart Association Functional Classification).
10. Multiple Sclerosis or other demyelinating diseases.
11. Pregnancy or breastfeeding.
12. Current or past history of immune checkpoint inhibitor therapy for cancer.
13. Absolute need for a drug that interacts with cyclosporine without an appropriate substitution.
14. 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 inhibitors, other TNF alpha antagonists (see MOP).
15. Use of surgical debridement and/or xenograft.
16. 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 comparable assay beyond 10 days must be evaluated by the Independent Protocol Monitor.
17. Clinical or radiographic evidence of active tuberculosis or endemic mycoses.
18. 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.
19. Known hypersensitivity to Enbrel® (etanercept).
20. Receipt of a live attenuated vaccine within 30 days of enrollment.

Primary outcomes:
measure: Time to complete re-epithelialization
timeFrame: up to 4 weeks
Secondary outcomes:
measure: Time to halting of progression of SJS/TEN skin disease
timeFrame: up to 4 weeks
measure: Mortality
timeFrame: up to 1 year
measure: Mortality
timeFrame: up to 4 weeks
measure: Ocular involvement
timeFrame: up to 1 year or study outcome
measure: Infections
timeFrame: up to 4 weeks
measure: Hospital length of stay
timeFrame: up to 4 weeks
measure: Proportion of patients with Adverse events due to assigned treatment arm
timeFrame: up to 4 weeks
Other outcomes:
measure: Granulysin, IL-15 and other cytokine measurements
timeFrame: up to 1 year or study outcome
Locations:
city: Phoenix
country: United States
facility: Valleywise Health Medical Center
state: Arizona
city: Sacramento
country: United States
facility: University of California, Davis Medical Center
state: California
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Health Burn Center
state: Florida
city: Miami
country: United States
facility: University of Miami, Ryder Trauma Center
state: Florida
city: Atlanta
country: United States
facility: Emory University at Grady Memorial Hospital
state: Georgia
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Bayview Medical Center
state: Maryland
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Memphis
country: United States
facility: University of Tennessee Health Sciences Center
state: Tennessee
city: Nashville
country: United States
facility: Vanderblt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Seattle
country: United States
facility: University of Washington, Harborview Medical Center
state: Washington
Study officials:
affiliation: Vanderbilt University Medical Center
name: Elizabeth J Phillips, MD
role: PRINCIPAL_INVESTIGATOR
References: