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NATIENS: Optimal Management and Mechanisms of SJS/TEN (NATIENS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02987257
Recruitment Status : Not yet recruiting
First Posted : December 8, 2016
Last Update Posted : April 15, 2022
University of Ottawa
University of Toronto
Information provided by (Responsible Party):
Elizabeth J Phillips, Vanderbilt University Medical Center

Brief 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).

Condition or disease Intervention/treatment Phase
Stevens-Johnson Syndrome Toxic Epidermal Necrolyses Drug: Harmonized supportive care Drug: Cyclosporine 5 mg/kg bid days 0-14 Drug: Etanercept 50 mg sc day 0 and day 3 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 267 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Estimated Study Start Date : May 23, 2022
Estimated Primary Completion Date : August 1, 2026
Estimated Study Completion Date : August 1, 2027

Arm Intervention/treatment
Placebo Comparator: Harmonized supportive care
Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3
Drug: Harmonized supportive care
Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3

Active Comparator: Cyclosporine 5mg/kg bid days 0-14
Harmonized supportive care with placebo etanercept days 0 and 3
Drug: Harmonized supportive care
Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3

Drug: Cyclosporine 5 mg/kg bid days 0-14
Harmonized supportive care with placebo etanercept days 0 and 3

Active Comparator: Etanercept 50mg sc day 0 and day 3
Harmonized supportive care with placebo cyclosporine days 0-14
Drug: Harmonized supportive care
Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3

Drug: Etanercept 50 mg sc day 0 and day 3
Harmonized supportive care with placebo cyclosporine days 0-14

Primary Outcome Measures :
  1. Time to complete re-epithelialization [ Time Frame: up to 4 weeks ]
    Patients will be assessed by two independent raters (burn surgeons, dermatologists, wound care experts) to determine the day of full re-epithelialization. For disagreements on the day of re-epithelialization the case with supporting photographs will be referred to an independent adjudication committee comprised of a minimum of three experts (a burn surgeon, dermatologist, wound care expert). In the instance of death will be the maximum period of re-epithelialization (21 days + 1)

Secondary Outcome Measures :
  1. Time to halting of progression of SJS/TEN skin disease [ Time Frame: up to 4 weeks ]
    Progression will be considered significant if there are any new blistering lesions or any new detached or detachable skin.

  2. Mortality [ Time Frame: up to 1 year ]
    Number of participants with mortality at 30 days, 3 months and 1 year

  3. Mortality [ Time Frame: up to 4 weeks ]
    Number of participants with Actual mortality versus expected mortality for each SCORTEN risk

  4. Ocular involvement [ Time Frame: up to 1 year or study outcome ]
    Time to cessation of acute ocular involvement acutely then extent of ocular incolvement at follow-up will be assessed by two independent ophthalmology experts. Will be tracked by photography

  5. Infections [ Time Frame: up to 4 weeks ]
    Incidence of nosocomial infections

  6. Hospital length of stay [ Time Frame: up to 4 weeks ]
    Duration of time in hospital

  7. Proportion of patients with Adverse events due to assigned treatment arm [ Time Frame: up to 4 weeks ]
    Adverse events due to assigned treatment arm

Other Outcome Measures:
  1. Granulysin, IL-15 and other cytokine measurements [ Time Frame: up to 1 year or study outcome ]
    Featured exploratory secondary outcome measuring difference overtime within an individual as well as differences between treatment arms at various time measurements.

  2. Cyclosporine levels [ Time Frame: up to 4 weeks ]
    C0 and C2 levels will be measure in all patients with analysis after unblinding in those randomized to cyclosporine (n=89). Relationship between levels and adverse drug events and treatment outcome will be measured.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02987257

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Contact: Elizabeth J Phillips, MD 615-310-0339
Contact: Ramya Krishna Botta, MBBS,MPH 615-936-9413

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United States, Tennessee
Vanderblt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center
University of Ottawa
University of Toronto
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Principal Investigator: Elizabeth J Phillips, MD Vanderbilt University Medical Center
  Study Documents (Full-Text)

Documents provided by Elizabeth J Phillips, Vanderbilt University Medical Center:
Informed Consent Form  [PDF] February 4, 2022

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Responsible Party: Elizabeth J Phillips, Principal Investigator, Vanderbilt University Medical Center Identifier: NCT02987257    
Other Study ID Numbers: 212370
First Posted: December 8, 2016    Key Record Dates
Last Update Posted: April 15, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There are no plans to share individual participant data available to other researchers.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Elizabeth J Phillips, Vanderbilt University Medical Center:
Supportive Care
Adverse Drug Reaction
Additional relevant MeSH terms:
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Stevens-Johnson Syndrome
Pathologic Processes
Mouth Diseases
Stomatognathic Diseases
Drug Eruptions
Skin Diseases
Erythema Multiforme
Skin Diseases, Vesiculobullous
Drug Hypersensitivity
Immune System Diseases
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents