<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02987257</url>
  </required_header>
  <id_info>
    <org_study_id>212370</org_study_id>
    <nct_id>NCT02987257</nct_id>
  </id_info>
  <brief_title>NATIENS: Optimal Management and Mechanisms of SJS/TEN</brief_title>
  <acronym>NATIENS</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Ottawa</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The NATIENS study is a phase III randomized study to examine the optimal treatment and&#xD;
      mechanisms of each of two treatments (cyclosporine 5 mg/kg bid for 14 days versus etanercept&#xD;
      50 mg subcutaneously at day 0 and day 3) versus the current standard of care which is&#xD;
      harmonized supportive care for the treatment of Stevens-Johnson Syndrome and toxic epidermal&#xD;
      necrolysis (SJS/TEN). SJS/TEN is typically a drug-induced disease in adults with a mortality&#xD;
      of up to 50% or higher in elderly adults. Although progress has been made in elucidating&#xD;
      strong genetic risk factors that have led to pre-prescription screening and prevention the&#xD;
      risk factors for most drugs and ethnicities represented in the United States are currently&#xD;
      unknown. Currently there are a number of small observational studies and a non-blinded small&#xD;
      randomized study however there is no strong or definitive evidence base to support any one&#xD;
      treatment intervention over supportive care alone and this remains considered a standard of&#xD;
      care for SJS/TEN. The primary objective of the study is to conduct a randomized double-blind&#xD;
      double dummy stratified multicenter phase III study across 24 sites across the Unites States&#xD;
      to determine whether two therapeutic interventions (etanercept versus cyclosporine) will&#xD;
      improve short-term outcomes associated with SJS/TEN. The primary hypothesis of this study is&#xD;
      that both etanercept and cyclosporine will show benefit over supportive care alone and that&#xD;
      single dose etanercept 50 mg sc at days 0 and repeated 72 hours following initial dosing will&#xD;
      show significant benefit over cyclosporine 5 mg/kg bid and supportive care alone. Our&#xD;
      secondary outcomes are to determine the clinical outcomes at 3 and 12 months following&#xD;
      initial presentation and to determine the molecular and cellular mechanisms of SJS/TEN&#xD;
      through collection of timed samples to include DNA, RNA, PBMCs, blister cells and supernatant&#xD;
      and skin. We hypothesize that patients will have significant sequelae identified at 3 and 12&#xD;
      months that will differ between treatment arms and that treatment interventions will&#xD;
      significantly impact cytotoxic and cytokine signals with these biomarkers correlating with&#xD;
      primary and secondary outcome. We also hypothesize that significant genetic associations will&#xD;
      be found in association with drug-induced SJS/TEN. Eligible patients are &gt;/= 18 who meet&#xD;
      evidence for SJS/TEN clinical criteria as evidence by erythematous/dusky macules coalescing&#xD;
      or denuded skin and blistering with positive Nikolsky sign which is mandatory criteria&#xD;
      associated with mucous membrane involvement, prodromal symptoms including fever, myalgia and&#xD;
      headache, increasing number of lesions and history of a medication. To continue with the&#xD;
      study patients must meet pathological criteria. Randomization will occur by a secure central&#xD;
      online computer-generated random number system through REDCap. Subjects will be allocated&#xD;
      1:1:1 to cyclosporine plus best supportive care, etanercept plus best supportive care or best&#xD;
      supportive care alone. Patients, treating physician and outcome assessors will be blinded to&#xD;
      the allocated treatment. The primary outcome of the study is time to complete&#xD;
      re-epithelialization as defined by complete absence of erosion and compromised skin. Time to&#xD;
      expected re-epithelialization of 21 days is the maximum healing time with supportive care in&#xD;
      SJS/TEN patients which reflects the healing time of adult skin. The primary outcome will be&#xD;
      independently assessed by the treating team to include any of a burn surgeon, dermatologist&#xD;
      or wound specialist. Disagreement will be solved by independent adjudication by a minimum of&#xD;
      two reviewers. Patients who have to discontinue a study medication will be analyzed by&#xD;
      intent-to-treat analysis and followed for complications of SJS/TEN as per study protocol.&#xD;
      Secondary outcomes of the study include: 1)time to halting of progression of SJS/TEN skin&#xD;
      disease. Progression will be considered significant if there are any new blisters or erosions&#xD;
      and halting of progression is defined as absence of these criteria with any new lesions; 2)&#xD;
      all-cause mortality at 30 days, 3 months and 1 year following symptoms onset; 3) composite&#xD;
      cause-specific mortality - outcome including death from sepsis, multi-organ failure and acute&#xD;
      respiratory distress syndrome; 4) actual mortality versus expected mortality (as calculated&#xD;
      by SCORTEN); 5) Time to cessation of acute ocular involvement (this will be tracked by the&#xD;
      same serial photography evaluated by two independent Ophthalmology experts in SJS/TEN eye&#xD;
      disease; 6) incidence of infections; 7) hospital length of stay; 8) adverse events due to&#xD;
      therapy; 9) serial plasma granulysin, IL-15 concentrations (and other relevant&#xD;
      biomarkers);10) Follow-up 3 months and 1 year from initial presentation for physical and&#xD;
      mental health complications. For aims 2 and 3 a number of mechanistic studies will be&#xD;
      performed on paired samples (DNA, RNA, PBMCs, plasma, blister fluid and skin).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and Scientific Rationale Stevens-Johnson syndrome (SJS) and toxic epidermal&#xD;
      necrolysis (TEN), are severe, life-threatening immunologically mediated adverse drug&#xD;
      reactions representing the same disease across a spectrum of severity that affects 60,000&#xD;
      patients per year globally at an incidence of 5 cases per 1,000,000 in the United States.&#xD;
      This study has been preceded by a planning phase to ensure the testing and development of&#xD;
      standardized infrastructure and operating procedures across sites. The scientific rationale&#xD;
      for this study is the lack of evidence-based treatment for SJS/TEN. The study will aim to&#xD;
      establish the most clinically effective therapy for SJS/TEN, as there is currently no level&#xD;
      1A evidence for any treatment above aggressive supportive care which still has equipoise as&#xD;
      to the standard of care. A multi-centered, three-arm, double-blind double-dummy randomized&#xD;
      controlled trial with a planned enrollment of 267 patients over 6 years will be undertaken to&#xD;
      evaluate which of supportive care, cyclosporine or etanercept leads to the shortest time to&#xD;
      complete re-epithelialization. The controlled setting of the clinical trial provides the&#xD;
      basis for which samples can be sequentially collected to answer important mechanistic&#xD;
      questions. Samples collected in the course of the study will include DNA, RNA, plasma, serum,&#xD;
      blister fluid cells and supernatant, sloughed epidermis, and punch biopsies of skin. Samples&#xD;
      will be biobanked to do immediate targeted high-resolution HLA sequencing, cytokine&#xD;
      profiling, and single-cell multidimensional analyses to identify biological markers that have&#xD;
      the potential to predict the risk and outcome of SJS/TEN. A pharmacokinetic study to assess&#xD;
      the disposition of cyclosporine and etanercept will be done on a subset of patients. Samples&#xD;
      will be biobank for later analysis for other transcriptomic, proteomic whole-genome studies.&#xD;
      These mechanistic studies will allow us to gain important insights into the&#xD;
      immunopathogenesis of SJS/TEN. Our study will be the first to examine in a blinded randomized&#xD;
      controlled design both management and mechanisms of SJS/TEN. We anticipate that this will&#xD;
      lead to new ways to prevent, diagnose and treat SJS/TEN, and will create a roadmap and&#xD;
      evidence-based for studies in serious immunologically mediated adverse drug reactions and&#xD;
      other immunologically mediated diseases.&#xD;
&#xD;
      Interventions Supportive care is the currently accepted standard of care of SJS/TEN. Systemic&#xD;
      treatment of SJS/TEN and the preferred agents remain a matter of debate and contention.&#xD;
      Observational studies performed over the last 15 years suggest that cyclosporine and&#xD;
      etanercept may be promising treatments.&#xD;
&#xD;
        1. Study Hypotheses/Objectives 1.1. Hypotheses Our primary hypothesis is that both&#xD;
           cyclosporine and etanercept will show benefit over supportive care alone and that&#xD;
           etanercept 50 mg subcutaneously given at study day 1 and repeated at day 4. We further&#xD;
           hypothesize that we will discover a number of genetic and biological predictors of both&#xD;
           occurrence and prognosis of SJS/TEN including genetic associations (HLA and others),&#xD;
           cytokine biomarkers that predict that course, and the likelihood of re-epithelialization&#xD;
           and single-cell multidimensional studies that will identify promising targets for&#xD;
           prognosis and treatment.&#xD;
&#xD;
           1.2. Primary Objective(s) Our primary objective is to conduct a 25-site three-arm&#xD;
           randomized double-blind controlled stratified multicenter phase III study to determine&#xD;
           whether two therapeutic interventions - cyclosporine and etanercept will improve&#xD;
           short-term outcomes associated with Stevens-Johnson Syndrome and toxic epidermal&#xD;
           necrolysis (SJS/TEN) over harmonized best supportive care alone. Our hypothesis is that&#xD;
           both etanercept and cyclosporine will show benefit over supportive care alone and that&#xD;
           etanercept 50 mg subcutaneously on study day 0 and repeated 72 hours later on study day&#xD;
           3 for all subjects will show significant benefit over both cyclosporine and supportive&#xD;
           care alone. The justification for a second dose is the short half-life of the drug and&#xD;
           the usual twice a week dosing in other skin conditions such as psoriasis and a recent&#xD;
           non-blinded randomized study of etanercept in SJS/TEN that used repeat dosing of&#xD;
           etanercept.&#xD;
&#xD;
           Secondary Objective(s) Secondary objectives of this study are to determine the acute&#xD;
           secondary outcomes and secondary clinical outcomes at 3 and 12 months (see secondary&#xD;
           outcomes) and to determine the molecular and cellular mechanisms of SJS/TEN through the&#xD;
           collection of timed DNA, PBMC, RNA, blister fluid and blister fluid cells and skin. We&#xD;
           hypothesize that patients will have significant sequelae identified at 3 and 12 months&#xD;
           that will differ between treatment arms. We hypothesis that treatment interventions will&#xD;
           significantly impact cytotoxic and cytokine signals and that these biomarkers will&#xD;
           correlate with primary and secondary outcomes. We further hypothesize that significant&#xD;
           genetic associations (in particular class I HLA) will be found in association with&#xD;
           drug-induced SJS/TEN.&#xD;
&#xD;
        2. Study Design 2.1. Description of Study Design This is a three-arm, randomized,&#xD;
           double-blind double-dummy phase III multicenter placebo-controlled trial comparing&#xD;
           cyclosporine, etanercept, and best supportive care for the treatment of SJS/TEN. A total&#xD;
           enrollment of 267 subjects (89 per arm) over 24 sites is planned. The sample size is&#xD;
           based on a 90% power to determine the primary outcome and a minimum clinically important&#xD;
           difference (MCID) of one day for full re-epithelialization of the skin. The study will&#xD;
           enroll from multiple sites due to the low SJS/TEN incidence at individual sites and the&#xD;
           need to identify patients with very specific inclusion criteria including those who have&#xD;
           had no more than a 5-day window from onset of symptoms to presentation. We aim to&#xD;
           complete enrollment over a period of 6 years.&#xD;
&#xD;
           Consenting adult subjects (≥18 years of age) who meet clinical criteria for diagnosis of&#xD;
           SJS/TEN will undergo randomization stratified by baseline SJS/TEN prognosis (SCORTEN)&#xD;
           and will be allocated 1:1:1 to cyclosporine plus best supportive care, etanercept plus&#xD;
           best supportive care or best supportive care alone. Randomization will occur by a secure&#xD;
           central online, computer-generated random randomization tool in REDCap using permuted&#xD;
           blocks of sizes 3 and 6.&#xD;
&#xD;
           The active treatment period is from randomization until re-epithelialization is&#xD;
           achieved. This is expected to be at most 21 days. The primary outcome is time (days) to&#xD;
           full re-epithelialization of the skin. Subjects will be followed in the hospital during&#xD;
           their admission; patients with SJS/TEN in this study will be on active drug or placebo&#xD;
           intravenously for at least 14 days. The plan will be the earliest discharge from the&#xD;
           hospital to occur at the completion of the full 14 days of placebo versus active&#xD;
           treatment if full re-epithelialization has occurred at that time but not until complete&#xD;
           re-epithelialization. Death is a competing risk for the primary outcome (see statistical&#xD;
           plan section 4.4). Subjects will be followed for 3 months and 12 months after complete&#xD;
           re-epithelialization. Under circumstances where patients are inadvertently discharged&#xD;
           prior to complete re-epithelialization appropriate and comparable follow-up to provide&#xD;
           documentation of appropriate wound, eye, and urogynecological care and of the timing of&#xD;
           complete re-epithelialization at a clinical research center at supportive sites and/or&#xD;
           the Hawthorne effect clinical trials services (see operations manual).&#xD;
&#xD;
           2.2. Stratification, Randomization, and Blinding/Masking&#xD;
&#xD;
           Randomization will occur by a secure central online, computer-generated random number&#xD;
           system in REDCap. Randomization will be stratified by baseline SJS/TEN prognosis&#xD;
           (SCORTEN) and will occur in randomly varying blocks of sizes 3 and 6. Subjects will be&#xD;
           allocated 1:1:1 to cyclosporine plus best supportive care, etanercept plus best&#xD;
           supportive care, or best supportive care alone. Patients, treating physicians and&#xD;
           outcome assessors will be blinded to the allocated treatment. All patients will receive&#xD;
           supportive care, either with a double placebo or with their study drug (cyclosporine or&#xD;
           etanercept) plus placebo. The central randomization scheme will provide the site&#xD;
           pharmacist with a unique drug code corresponding to either study drugs and matching&#xD;
           placebos. These will be kept in identical, coded containers. Only the study central&#xD;
           pharmacy and the site pharmacy who will prepare the preparations for blinding will be&#xD;
           aware of the coding scheme. Masking will be carried out as follows:&#xD;
&#xD;
             -  Cyclosporine: The study drug is given as per protocol for 2 weeks. A single SC&#xD;
                injection is given on study day 0 of admission and study day 3.&#xD;
&#xD;
             -  Etanercept: Study drug given as per protocol on study days 0 and 3. Receive IV&#xD;
                normal saline for 2 weeks to mimic the cyclosporine schedule.&#xD;
&#xD;
             -  Supportive therapy: A single saline SC injection on study day 0 and study day 3 of&#xD;
                admission and an additional 14 days of IV normal saline placebo to mimic the&#xD;
                cyclosporine schedule 2.2.1. Procedure for Unblinding/Unmasking Unblinding must be&#xD;
                approved by the study medical monitor unless an immediately life-threatening&#xD;
                condition has developed, and the medical monitor is not available. The site&#xD;
                investigator will notify the protocol chair(s) and the study statistical and&#xD;
                clinical coordinating center of the unblinding event by the next business day. The&#xD;
                emergency unblinding will also be reported to the Data and Safety Monitoring Board&#xD;
                (DSMB). A full account of the event will be recorded, including the date, time of&#xD;
                the unblinding, the reason or the decision to unblind and the name of the&#xD;
                individual who made the decision and the names of the Medical Monitor, and others&#xD;
                who were notified. The reasons for unblinding of a participant's treatment will be&#xD;
                included in the final study report. Unblinding the study due to an approved interim&#xD;
                analysis, final analysis, or study termination will require written approval from&#xD;
                the institute sponsor (NIAID).&#xD;
&#xD;
        3. Selection of Participants and Clinical Sites/Laboratories 3.1. Rationale for Study&#xD;
           Population Subject enrollment will reflect the population at large in our participating&#xD;
           centers. All subjects who meet inclusion criteria will be screened for enrollment into&#xD;
           the study. We will not discriminate based on sex, race, or ethnicity. Females, including&#xD;
           those of childbearing potential, will be included in the trial.&#xD;
&#xD;
           Supportive care High-quality supportive care is always used in the treatment of SJS/TEN.&#xD;
           We know it can decrease the chance of serious complications and death even in the&#xD;
           absence of adjuvant medications to treat the condition.&#xD;
&#xD;
           There are no significant side effects associated with supportive care aside from&#xD;
           possible discomfort with dressing changes.&#xD;
&#xD;
           3.5. Risks of Other Protocol Specified Medications Cyclosporine&#xD;
&#xD;
           The risks of the venipuncture (bruising at the site and very low risk of infection)&#xD;
           apply as cyclosporine is an intravenous medication. There is extensive experience with&#xD;
           this medication in SJS/TEN for the treatment of other conditions. In general, few side&#xD;
           effects have been seen when used for SJS/TEN. When they have occurred, they have had no&#xD;
           long-term impact on the person receiving the medication. Risks include:&#xD;
&#xD;
           Less likely (5% to 20%):&#xD;
&#xD;
             -  Mild changes in kidney function: 1-6% had mild changes in their kidney function&#xD;
                that required a change of dose; Serious infections were not more common than those&#xD;
                treated with short-term use, as proposed in this study. Flu-like illness symptoms&#xD;
                and a predisposition for lung infections have been experienced in 8- 10% of&#xD;
                patients with long-term use (months to years).&#xD;
&#xD;
           Rare (1% to 4%):&#xD;
&#xD;
           • Hypertension: 1-3% needed to have their blood pressure lowered. Very rare but serious&#xD;
           (less than 1%): Severe liver or kidney problems may be permanent in those taking&#xD;
           cyclosporine for greater than one 1year. Patients receiving cyclosporine under the&#xD;
           NATIENS protocol will undergo treatment for a short amount of time; therefore, the&#xD;
           chance of this occurring in this study is extremely unlikely. Close monitoring for&#xD;
           hepatic or renal dysfunction is built into the NATIENS study protocol.&#xD;
&#xD;
           Discontinuing the study medication in the case of imminently organ-threatening effects,&#xD;
           type I allergy, or rare immune reactions (e.g., thrombotic thrombocytopenic purpura] in&#xD;
           the case of cyclosporine) will be documented. Cyclosporine would be the only arm where&#xD;
           this may occur as the protocol is for 2 weeks of therapy.&#xD;
&#xD;
           An investigator and research coordinator will be available 24 hours a day from both the&#xD;
           Vanderbilt Coordinating Center and Ottawa Coordinating Center. The consent form has&#xD;
           contact numbers for reaching study personnel. In the event an investigator or research&#xD;
           coordinator is on vacation or out-of-town, appropriate coverage will be provided.&#xD;
&#xD;
           The safety of the participant will remain of primary importance. All patients will&#xD;
           undergo intensive monitoring while in hospital in accordance with usual ICU and Burn&#xD;
           Unit practices.&#xD;
&#xD;
           3.6. Risks of Study Procedures Venipuncture and Blood Samples: The protocol requires&#xD;
           patients to have blood drawn for research purposes. The risks of drawing blood are&#xD;
           uncommon and may include bleeding, minor infection, and bruising. Blood draws may be&#xD;
           painful. Some people may feel faint or dizzy. The amount of blood drawn represents a&#xD;
           small percentage of the amount of the total blood volume and will not represent a&#xD;
           significant risk to the patient. Samples are planned to align with blood samples taken&#xD;
           in the course of usual clinical care to minimize the need for repeat venipuncture. Blood&#xD;
           sampling is performed by trained nurses or phlebotomists with experience performing&#xD;
           venipuncture. We have also aligned our study-related blood samples with those taken for&#xD;
           usual patient care. Multiple tests are also performed on blood from the same sample&#xD;
           tubes. This minimizes the volume of blood required to complete Aims 2 and 3 as well as&#xD;
           significantly reduces the number of needle sticks.&#xD;
&#xD;
           Tissue Samples: Tissue samples will be taken to understand the disease process of&#xD;
           SJS/TEN. A sample of healthy skin, where possible, will be taken for comparison. Where&#xD;
           samples of normal skin can be taken, this will be discussed with the patient. Some&#xD;
           patients have little healthy skin to sample. Risks primarily include minor bleeding, a&#xD;
           small chance of infection, and a small scar.&#xD;
&#xD;
           All tissue sampling will be done by an experienced physician to reduce the risk of&#xD;
           complications.&#xD;
&#xD;
           Salivary Swab: There are no significant risks associated with the saliva samples being&#xD;
           collected. In those with oral mucosal involvement due to SJS/TEN, there may be&#xD;
           irritation or a small degree of discomfort while producing a sample.&#xD;
&#xD;
           Blister Fluid Collection: This process involves aspirating fluid from an intact blister.&#xD;
           There is a very low risk of infection, but there is no discomfort with the procedure.&#xD;
&#xD;
        4. Investigational Agent /Device/Intervention (see investigators brochure, section 5) 4.1.&#xD;
           Drug Accountability Under Title 21 of the Code of Federal Regulations (21CFR §312.62),&#xD;
           the investigator will maintain adequate records of the disposition of the&#xD;
           investigational agent, including the date and quantity of the drug received, to whom the&#xD;
           drug was dispensed (participant-by-participant accounting), and a detailed accounting of&#xD;
           any drug accidentally or deliberately destroyed.&#xD;
&#xD;
           Records for receipt, storage, use, and disposition will be maintained by the study site.&#xD;
           A drug-dispensing log will be kept current for each participant. This log will contain&#xD;
           the identification of each participant and the date and quantity of drug dispensed. All&#xD;
           records regarding the disposition of the investigational product will be available for&#xD;
           inspection. Any remaining product will be destroyed in accordance with pharmacy&#xD;
           regulations.&#xD;
&#xD;
           4.2. Assessment of Participant Compliance with Investigational Agent All medications&#xD;
           will be administered by the investigator and/or study staff in the Burn Unit.&#xD;
           Administration of study medication(s) will be witnessed by the investigator and/or study&#xD;
           staff. The total volume of study medication-infused will be compared with the total&#xD;
           volume prepared to determine compliance with each dose administered.&#xD;
&#xD;
           4.3. Toxicity Prevention and Management Etanercept: No modifications are permitted.&#xD;
           Cyclosporine: The study is blinded and the adjustment and stopping rules that primarily&#xD;
           apply to cyclosporine will be carried out by an unblinded pharmacists according to&#xD;
           well-defined rules. A table will be provided for anticipated severe drug interactions&#xD;
           with cyclosporine and for patients where those drugs are necessary these patients may be&#xD;
           excluded from the study. Non-serious medication side-effects such as diastolic&#xD;
           hypertension or mild renal failure will be medically managed while still maintaining&#xD;
           blinding. For example, standard adjustments for cyclosporine will be made based on serum&#xD;
           creatinine and blood pressure monitoring. These orders will be written and carried out&#xD;
           by an unblinded pharmacist. The adjusted dose will appear on the IV bag&#xD;
           cyclosporine/placebo and the treating team will remain blinded as to the treatment arm&#xD;
           of the patient. Creatinine will be monitored daily by a non-blinded pharmacist at each&#xD;
           site for all patients. A standard dose-adjustment algorithm to maintain a target&#xD;
           creatinine of &lt;130% above baseline will be used. Down-dosing of 25-30% will be used if&#xD;
           diastolic blood pressure &gt;100 mm. If &gt;3 dose adjustments, 48-hours apart fail to control&#xD;
           rises in creatinine beyond this threshold, cyclosporine is stopped. Any study treatment&#xD;
           will also be stopped in the presence of any grade 3-4 toxicity (e.g.&#xD;
           leukoencephalopathy) or creatinine &gt;150% of initial value and diastolic blood pressure&#xD;
           &gt;110 or systolic persistently &gt; 160 mmHg which is a common indicator of cyclosporine&#xD;
           toxicity.&#xD;
&#xD;
           6.5 Premature Discontinuation of Investigational Agent Patients who discontinue any&#xD;
           study medication will be analyzed by intent-to-treat analysis and followed for&#xD;
           complications of SJS/TEN as per study protocol. Stopping for lack of efficacy will occur&#xD;
           according to pre-described stopping rules. Study therapy may be prematurely discontinued&#xD;
           for any participant for any of the following reasons:1. Grade 3 or 4 toxicity 2.&#xD;
           Toxicity that has not responded to clinical management (see cyclosporine above); 3.&#xD;
           Necessary medication that interacts with cyclosporine (as per protocol table) 4. Patient&#xD;
           request. All patients are administered the drug in the ICU and are monitored around the&#xD;
           clock for adverse signs and symptoms by the investigator and/or study staff. If adverse&#xD;
           signs are observed, patients will be evaluated by physicians from various specialties&#xD;
           including intensive care, and dermatology. Following evaluations, decisions will be&#xD;
           taken to decrease, adjust, or stop the dosage. Each site will be individually managed&#xD;
           for treating adverse reactions.&#xD;
&#xD;
           Study therapy may also be prematurely discontinued for any participant if the&#xD;
           investigator believes that the study treatment is no longer in the best interest of the&#xD;
           participant.&#xD;
&#xD;
        5. Other Medications 5.1. Concomitant Medications 5.1.1. Protocol-mandated 1% lidocaine&#xD;
           with epinephrine at a dilution of 1:100,000 as local anesthesia at the time of&#xD;
           obtainment of biopsy samples (for research biopsies) 5.1.2. Other permitted concomitant&#xD;
           medications All topical agents for wound and eye care are permitted as outlined in the&#xD;
           respective supportive care protocols.&#xD;
&#xD;
           5.2. Prophylactic Medications Any non-interacting medications (as per cyclosporine&#xD;
           protocol) may be administered at the discretion of the clinical team.&#xD;
&#xD;
           5.3. Prohibited Medications 1) Medications that interact with cyclosporine where there&#xD;
           are suitable alternatives20,21; 2) immunomodulatory agents other than those used in this&#xD;
           clinical trial&#xD;
&#xD;
           The following medications will be considered to be contraindicated during the course of&#xD;
           the study. If patients are on these medications and an alternative is available it&#xD;
           should be substituted:&#xD;
&#xD;
           Aliskiren, atorvastatin, bosentan, cholic acid, cladribine, conivaptan, crizotinib,&#xD;
           dronedarone, elagolix, enzalutamide, eplerenone, foscarnet, any new drug found to be a&#xD;
           significant CYP3A4 inhibitor or p-glycoprotein/ABCB1 inhibitor). A complete list of&#xD;
           interacting drugs, potentially interacting drugs is included in the operations manual.&#xD;
&#xD;
           5.4. Rescue Medications Cyclosporine increases blood pressure. Blood pressure will be&#xD;
           managed by administering non-interacting blood pressure-lowering drugs at the discretion&#xD;
           of the treating physician. Cyclosporine could also decrease renal function. Patients&#xD;
           will be managed as per standard of care protocols for patients with acute renal failure&#xD;
           (see operations manual for detailed procedures).&#xD;
&#xD;
        6. Study procedures (for laboratory procedures and sampling schedule, see section 5,&#xD;
           comprehensive laboratory plan) Enrollment The research study will be explained in lay&#xD;
           terms to each potential research participant. The potential participant will sign an&#xD;
           informed consent form before undergoing any study procedures. Once informed consent has&#xD;
           been signed and completed by both the participant and key study personnel, the&#xD;
           participant is considered enrolled in the study and will be assigned a unique&#xD;
           participant number. Consent will be obtained at the time of clinical encounter or&#xD;
           diagnosis. To initially identify patients for consent, medical records may be reviewed&#xD;
           for suitability or the admitting service (e.g., emergency, intensive care unit, burn&#xD;
           surgery) may identify suitable patients to the study team. Then, a health care&#xD;
           professional from the research team of key personnel will discuss the study with&#xD;
           prospective participants (or substitute decision-makers) or obtain permission for the&#xD;
           research personnel to discuss the study. In rare cases where emergency treatment is&#xD;
           required (e.g., altered level of consciousness, lack of capacity), enrollment may still&#xD;
           occur; however, confirmation of consent will be required by the research team at the&#xD;
           first opportunity after the patient is initially managed or restoration of capacity&#xD;
           occurs. Consent will be obtained from a substitute decision-maker or the patient at the&#xD;
           earliest possible moment and the subject will be reconsented when their capacity for&#xD;
           medical decision-making returns. A copy of the patient's consent will be kept in the&#xD;
           patient's chart. It is available in English and Spanish. If consent is withdrawn at any&#xD;
           time, it should be determined to what aspect of the study consent is being withdrawn&#xD;
           (e.g., consent to the use of genetic samples or the study itself). In case of full&#xD;
           withdrawal of consent, the treating team may modify any of the study procedures as per&#xD;
           their medical judgment.&#xD;
&#xD;
      8.1 Screening/Baseline Visit The purpose of the screening period is to confirm eligibility to&#xD;
      continue in the study.&#xD;
&#xD;
      The following procedures, assessments, and laboratory measures will be conducted to determine&#xD;
      participant eligibility:&#xD;
&#xD;
        1. Research staff will screen potential participants upon being notified of their admission&#xD;
           to the ICU or Burn ICU based on the study inclusion/exclusion criteria. (so as written&#xD;
           here - the subjects will be screened and consented here).&#xD;
&#xD;
        2. A diagnostic punch biopsy will be obtained from the patient on the day of admission by&#xD;
           the institution's appropriate staff. (is this a clinical biopsy or a research biopsy)&#xD;
&#xD;
        3. The results of the diagnostic biopsy will be reviewed by research staff to determine&#xD;
           eligibility to continue in the study within 2-3 days after admission.&#xD;
&#xD;
      Randomization: will occur by a secure central online, computer-generated random number&#xD;
      system. Randomization will be stratified by baseline SJS/TEN prognosis (SCORTEN) and will&#xD;
      occur in randomly varying blocks of sizes 3 and 6. Subjects will be allocated 1:1:1 to&#xD;
      cyclosporine plus best supportive care, etanercept plus best supportive care, or best&#xD;
      supportive care alone. Continuation of the patient in the study will be contingent on a&#xD;
      compatible clinical picture in combination with supportive pathology. Since pathology can&#xD;
      take 48 hours to come back however subject randomization will occur prior to the availability&#xD;
      of the biopsy results.&#xD;
&#xD;
      Patients, treating physicians, and outcome assessors will be blinded to the allocated&#xD;
      treatment. The central randomization scheme will provide the site pharmacists with a unique&#xD;
      drug code corresponding to either study drugs or matching placebo. These will be kept in&#xD;
      identical, coded containers. Only the study center and site pharmacy will be aware of the&#xD;
      coding scheme. Masking will be carried out as follows: 1) Cyclosporine: study drug given as&#xD;
      per protocol for 2 weeks. A single SC injection is given on Day 1 of admission. With a second&#xD;
      injection given on day 4 of admission.; 2) Etanercept: Study drug given as per protocol.&#xD;
      Receive IV normal saline for 2 weeks to mimic the cyclosporine schedule. Subcutaneous&#xD;
      injection of etanercept given on study day 1 and study day 4; 3) Supportive therapy: A single&#xD;
      saline SC injection on Day 1 and Day 4 to mimic etanercept and normal saline for 14 days to&#xD;
      mimic the cyclosporine schedule.&#xD;
&#xD;
      8.2 Study Visits or Study Assessments&#xD;
&#xD;
      Also as listed in the research plan, facilities, and resources, and detailed laboratory&#xD;
      plan).&#xD;
&#xD;
      8.3 Unscheduled Visits (following discharge between 3 and 12-month follow-ups) Following&#xD;
      discharge, the patient will be discharged to the care of their clinical team that will&#xD;
      generally include follow-up with dermatology and ophthalmology at a minimum and if disease&#xD;
      activity increase or other concerns arise they will be asked to liaise with the clinical team&#xD;
      however study personnel should also be contacted and the participant may be asked to return&#xD;
      for an &quot;unscheduled&quot; visit.&#xD;
&#xD;
      9. Biospecimen Storage (see comprehensive laboratory plan) 10. Criteria for Participant and&#xD;
      Study Completion and Premature Study Termination&#xD;
&#xD;
      a. Participant Stopping Rules and Withdrawal Criteria&#xD;
&#xD;
      Participants may be prematurely terminated from the study for the following reasons:&#xD;
&#xD;
        1. The participant elects to withdraw consent from all future study activities, including&#xD;
           follow-up.&#xD;
&#xD;
        2. The participant is &quot;lost to follow-up&quot; (i.e., no further follow-up is possible because&#xD;
           attempts to reestablish contact with the participant have failed). [use specific&#xD;
           criteria to define &quot;lost to follow-up&quot;]&#xD;
&#xD;
        3. The participant dies.&#xD;
&#xD;
        4. The participant is withdrawn from the study.&#xD;
&#xD;
        5. Individual safety stopping rules as defined under the study drugs section.&#xD;
&#xD;
      Study stopping rules:&#xD;
&#xD;
      We plan two interim analyses to allow early stopping for efficacy. These analyses will take&#xD;
      place when we have acquired outcome measures for one-third and for two-thirds of the total&#xD;
      target sample. We will use the Haybittle-Peto rule applied to each of the three pairwise&#xD;
      Mann-Whitney comparisons of time to re-epithelialization between arms. As with the primary&#xD;
      analysis, patients who die prior to achieving re-epithelialization will be allocated the&#xD;
      maximum observed time to re-epithelialization plus one, so as to ensure that death is treated&#xD;
      as worse than any time to successful treatment. One arm will be declared inferior to another&#xD;
      if the p-value for the difference is less than 0.001. No adjustment will be made to the final&#xD;
      analysis for interim testing. If one arm is found to be inferior to another arm, the Data&#xD;
      Safety Monitoring Board will be instructed to strongly consider stopping recruitment to that&#xD;
      arm. If one arm is found to be inferior to both other arms, the Data Safety Monitoring Board&#xD;
      will be instructed to immediately stop recruitment in the inferior arm. If the other two arms&#xD;
      also differ with a p-value less than 0.001, the recruitment will be stopped in all arms. We&#xD;
      will have no formal stopping rules for safety outcomes different from time to&#xD;
      re-epithelialization, but the Data Monitoring Committee will be explicitly mandated to&#xD;
      carefully consider any safety signals with a view towards stopping recruitment if any&#xD;
      expected or unexpected safety signal emerges.&#xD;
&#xD;
      b. Participant Replacement If a participant withdraws or is withdrawn from the study, no&#xD;
      further data or samples will be collected. The participant will not be replaced.&#xD;
&#xD;
      c. Follow-up after Early Study Withdrawal Participants who withdraw from the study will be&#xD;
      taken out of the study and no further data or samples will be collected. Study drugs and&#xD;
      interventions will no longer continue after the patient is withdrawn from the study. Data and&#xD;
      samples collected during the time of participation in the study will still be kept for study&#xD;
      analysis.&#xD;
&#xD;
      11. Safety Monitoring and Reporting (see data safety monitoring plan section 3.3)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 21, 2023</start_date>
  <completion_date type="Anticipated">August 1, 2028</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2027</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to complete re-epithelialization</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>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)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to halting of progression of SJS/TEN skin disease</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>Progression will be considered significant if there are any new blistering lesions or any new detached or detachable skin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>up to 1 year</time_frame>
    <description>Number of participants with mortality at 30 days, 3 months and 1 year</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>Number of participants with Actual mortality versus expected mortality for each SCORTEN risk</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ocular involvement</measure>
    <time_frame>up to 1 year or study outcome</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infections</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>Incidence of nosocomial infections</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital length of stay</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>Duration of time in hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with Adverse events due to assigned treatment arm</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>Adverse events due to assigned treatment arm</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Granulysin, IL-15 and other cytokine measurements</measure>
    <time_frame>up to 1 year or study outcome</time_frame>
    <description>Featured exploratory secondary outcome measuring difference overtime within an individual as well as differences between treatment arms at various time measurements.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cyclosporine levels</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>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.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">267</enrollment>
  <condition>Stevens-Johnson Syndrome</condition>
  <condition>Toxic Epidermal Necrolyses</condition>
  <arm_group>
    <arm_group_label>Harmonized supportive care</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cyclosporine 5mg/kg bid days 0-14</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Harmonized supportive care with placebo etanercept days 0 and 3</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Etanercept 50mg sc day 0 and day 3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Harmonized supportive care with placebo cyclosporine days 0-14</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Harmonized supportive care</intervention_name>
    <description>Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3</description>
    <arm_group_label>Cyclosporine 5mg/kg bid days 0-14</arm_group_label>
    <arm_group_label>Etanercept 50mg sc day 0 and day 3</arm_group_label>
    <arm_group_label>Harmonized supportive care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclosporine 5 mg/kg bid days 0-14</intervention_name>
    <description>Harmonized supportive care with placebo etanercept days 0 and 3</description>
    <arm_group_label>Cyclosporine 5mg/kg bid days 0-14</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etanercept 50 mg sc day 0 and day 3</intervention_name>
    <description>Harmonized supportive care with placebo cyclosporine days 0-14</description>
    <arm_group_label>Etanercept 50mg sc day 0 and day 3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt;18 years&#xD;
&#xD;
          2. Subject and/or legally authorized representative must be able to understand and&#xD;
             provide informed consent.&#xD;
&#xD;
          3. Erythematous to dusky macules that show evidence of coalescing and/or denuding skin or&#xD;
             blistering in a predominantly truncal distribution (Nikolsky sign = sloughing with&#xD;
             direct lateral pressure on non-blistered but involved skin should be considered as a&#xD;
             supportive feature&#xD;
&#xD;
          4. At least two of the following:&#xD;
&#xD;
               1. Mucous membrane involvement&#xD;
&#xD;
               2. Prodromal symptoms including fever, myalgia, and headache&#xD;
&#xD;
               3. Evidence of disease progression with an increasing number of skin lesions&#xD;
&#xD;
          5. History of a newly used medication within the last 2 months that has not been&#xD;
             tolerated for longer than 12 weeks in the past&#xD;
&#xD;
          6. Females of childbearing potential must have a negative pregnancy test prior to&#xD;
             randomization.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Subject or legally authorized representative is not willing to provide informed&#xD;
             consent.&#xD;
&#xD;
          2. A serious drug reaction or possible alternative dermatologic diagnosis at the time of&#xD;
             initial evaluation not in keeping with drug-induced SJS/TEN (e.g. graft versus host&#xD;
             disease).&#xD;
&#xD;
          3. If greater than 5 days has elapsed from onset of initial cutaneous or mucosal signs of&#xD;
             the disease as obtained by patient history or documentation.&#xD;
&#xD;
          4. Patients who have received either etanercept or cyclosporine in the last 6 months.&#xD;
&#xD;
          5. Patients who in time since onset of SJS/TEN illness have received intravenous immune&#xD;
             globulin (IVIg) or &gt; 2 doses of pulsed corticosteroid (defined by &gt; 250 mg prednisone&#xD;
             equivalent) prior to enrollment in the study.&#xD;
&#xD;
          6. End-stage liver disease (Child Pugh A, B or C or severe liver dysfunction).&#xD;
&#xD;
          7. Grade 2 or higher liver dysfunction (alanine aminotransferase &gt;3 fold or Tbilirubin &gt;3&#xD;
             fold the upper limit of normal).&#xD;
&#xD;
          8. Patients with chronic kidney disease and eGFR&lt;30 ml/min/1.73 m2 (as calculated by the&#xD;
             admission value at the site laboratory and support by a mean outpatient eGFR 7-365&#xD;
             days prior to admission if available).&#xD;
&#xD;
          9. Patients receiving renal replacement therapy for any reason&#xD;
&#xD;
         10. Any organ transplant.&#xD;
&#xD;
         11. Pre-existing Class III/IV Heart Failure (New York Heart Association Functional&#xD;
             Classification).&#xD;
&#xD;
         12. Multiple Sclerosis or other demyelinating diseases.&#xD;
&#xD;
         13. Pregnancy or breastfeeding.&#xD;
&#xD;
         14. Current or past history of immune checkpoint inhibitor therapy for cancer.&#xD;
&#xD;
         15. Absolute need for a drug that interacts with cyclosporine without an appropriate&#xD;
             substitution.&#xD;
&#xD;
         16. History of other immunosuppressive or immunomodulatory therapy that could significant&#xD;
             impact treatment or interpretation of response to treatment (i.e. azathioprine,&#xD;
             methotrexate, mycophenolate mofetil, mycophenolate sodium, rituximab, JAK inhibitors,&#xD;
             IL-17 inhibitors, IL-23 inbibitors, other TNF alpha antagonists (see MOP).&#xD;
&#xD;
         17. Use of surgical debridement and/or xenograft.&#xD;
&#xD;
         18. Known positive SARS-CoV-2 on RT-PCR within 10 days prior to screening or within 5 days&#xD;
             of admission or symptomatic COVID-19 infection at screening. Symptomatic patients with&#xD;
             a positive SARS-CoV-2 on RT-PCR or comparible assay beyond 10 days must be evaluated&#xD;
             by the Independent Protocol Monitor.&#xD;
&#xD;
         19. Clinical or radiographic evidence of active tuberculosis or endemic mycoses.&#xD;
&#xD;
         20. History or evidence of any other clinically significant medical or psychiatric&#xD;
             disorder, condition or disease that in the opinion of the treating physician would&#xD;
             pose a risk or interfere with evaluation or completion of the study such as known&#xD;
             sepsis/systemic infection requiring antibiotic therapy.&#xD;
&#xD;
         21. Known hypersensitivity to Sandimmune® (cyclosporine) and/or Cremophor® EL&#xD;
             (polyoxyethylated castor oil).&#xD;
&#xD;
         22. Known hypersensitivity to Enbrel® (etanercept).&#xD;
&#xD;
         23. Receipt of a live attenuated vaccine within 30 days of enrollment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elizabeth J Phillips, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Elizabeth J Phillips, MD</last_name>
    <phone>615-310-0339</phone>
    <email>elizabeth.j.phillips@vumc.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Michelle Martin-Pozo, PhD</last_name>
    <phone>6153439672</phone>
    <email>michelle.martinpozo@vumc.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Vanderblt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>November 25, 2016</study_first_submitted>
  <study_first_submitted_qc>December 6, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 8, 2016</study_first_posted>
  <last_update_submitted>March 27, 2023</last_update_submitted>
  <last_update_submitted_qc>March 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 28, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Elizabeth J Phillips</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Therapeutics</keyword>
  <keyword>Management</keyword>
  <keyword>Cyclosporine</keyword>
  <keyword>Etanercept</keyword>
  <keyword>Supportive Care</keyword>
  <keyword>Immunopathogenesis</keyword>
  <keyword>Genetics</keyword>
  <keyword>Adverse Drug Reaction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stevens-Johnson Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Etanercept</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There are no plans to share individual participant data available to other researchers.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 4, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/57/NCT02987257/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02987257
org study id: 212370
nct id: NCT02987257
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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).
Background and Scientific Rationale Stevens-Johnson syndrome (SJS) and toxic epidermal
      necrolysis (TEN), are severe, life-threatening immunologically mediated adverse drug
      reactions representing the same disease across a spectrum of severity that affects 60,000
      patients per year globally at an incidence of 5 cases per 1,000,000 in the United States.
      This study has been preceded by a planning phase to ensure the testing and development of
      standardized infrastructure and operating procedures across sites. 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
      to the standard of care. A multi-centered, three-arm, double-blind double-dummy randomized
      controlled trial with a planned enrollment of 267 patients over 6 years will be undertaken to
      evaluate which of supportive care, cyclosporine or etanercept leads to the shortest time to
      complete re-epithelialization. The controlled setting of the clinical trial provides the
      basis for which samples can be sequentially collected to answer important mechanistic
      questions. Samples collected in the course of the study will include DNA, RNA, plasma, serum,
      blister fluid cells and supernatant, sloughed epidermis, and punch biopsies of skin. Samples
      will be biobanked 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 the risk and outcome of SJS/TEN. A pharmacokinetic study to assess
      the disposition of cyclosporine and etanercept will be done on a subset of patients. Samples
      will be biobank 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, diagnose and treat SJS/TEN, and will create a roadmap and
      evidence-based for studies in serious immunologically mediated adverse drug reactions and
      other immunologically mediated diseases.

      Interventions Supportive care is the currently accepted standard of care of SJS/TEN. Systemic
      treatment of SJS/TEN and the preferred agents remain a matter of debate and contention.
      Observational studies performed over the last 15 years suggest that cyclosporine and
      etanercept may be promising treatments.

        1. Study Hypotheses/Objectives 1.1. Hypotheses Our primary hypothesis is that both
           cyclosporine and etanercept will show benefit over supportive care alone and that
           etanercept 50 mg subcutaneously given at study day 1 and repeated at day 4. We further
           hypothesize that we will discover a number of genetic and biological predictors of both
           occurrence and prognosis of SJS/TEN including genetic associations (HLA and others),
           cytokine biomarkers that predict that course, and the likelihood of re-epithelialization
           and single-cell multidimensional studies that will identify promising targets for
           prognosis and treatment.

           1.2. Primary Objective(s) Our primary objective is to conduct a 25-site three-arm
           randomized double-blind controlled stratified multicenter phase III study to determine
           whether two therapeutic interventions - cyclosporine and etanercept will improve
           short-term outcomes associated with Stevens-Johnson Syndrome and toxic epidermal
           necrolysis (SJS/TEN) over harmonized best supportive care alone. Our hypothesis is that
           both etanercept and cyclosporine will show benefit over supportive care alone and that
           etanercept 50 mg subcutaneously on study day 0 and repeated 72 hours later on study day
           3 for all subjects will show significant benefit over both cyclosporine and supportive
           care alone. The justification for a second dose is the short half-life of the drug and
           the usual twice a week dosing in other skin conditions such as psoriasis and a recent
           non-blinded randomized study of etanercept in SJS/TEN that used repeat dosing of
           etanercept.

           Secondary Objective(s) Secondary objectives of this study are to determine the acute
           secondary outcomes and secondary clinical outcomes at 3 and 12 months (see secondary
           outcomes) and to determine the molecular and cellular mechanisms of SJS/TEN through the
           collection of timed DNA, PBMC, RNA, blister fluid and blister fluid cells and skin. We
           hypothesize that patients will have significant sequelae identified at 3 and 12 months
           that will differ between treatment arms. We hypothesis that treatment interventions will
           significantly impact cytotoxic and cytokine signals and that these biomarkers will
           correlate with primary and secondary outcomes. We further hypothesize that significant
           genetic associations (in particular class I HLA) will be found in association with
           drug-induced SJS/TEN.

        2. Study Design 2.1. Description of Study Design This is a three-arm, randomized,
           double-blind double-dummy phase III multicenter placebo-controlled trial comparing
           cyclosporine, etanercept, and best supportive care for the treatment of SJS/TEN. A total
           enrollment of 267 subjects (89 per arm) over 24 sites is planned. The sample size is
           based on a 90% power to determine the primary outcome and a minimum clinically important
           difference (MCID) of one day for full re-epithelialization of the skin. The study will
           enroll from multiple sites due to the low SJS/TEN incidence at individual sites and the
           need to identify patients with very specific inclusion criteria including those who have
           had no more than a 5-day window from onset of symptoms to presentation. We aim to
           complete enrollment over a period of 6 years.

           Consenting adult subjects (≥18 years of age) who meet clinical criteria for diagnosis of
           SJS/TEN will undergo randomization stratified by baseline SJS/TEN prognosis (SCORTEN)
           and will be allocated 1:1:1 to cyclosporine plus best supportive care, etanercept plus
           best supportive care or best supportive care alone. Randomization will occur by a secure
           central online, computer-generated random randomization tool in REDCap using permuted
           blocks of sizes 3 and 6.

           The active treatment period is from randomization until re-epithelialization is
           achieved. This is expected to be at most 21 days. The primary outcome is time (days) to
           full re-epithelialization of the skin. Subjects will be followed in the hospital during
           their admission; patients with SJS/TEN in this study will be on active drug or placebo
           intravenously for at least 14 days. The plan will be the earliest discharge from the
           hospital to occur at the completion of the full 14 days of placebo versus active
           treatment if full re-epithelialization has occurred at that time but not until complete
           re-epithelialization. Death is a competing risk for the primary outcome (see statistical
           plan section 4.4). Subjects will be followed for 3 months and 12 months after complete
           re-epithelialization. Under circumstances where patients are inadvertently discharged
           prior to complete re-epithelialization appropriate and comparable follow-up to provide
           documentation of appropriate wound, eye, and urogynecological care and of the timing of
           complete re-epithelialization at a clinical research center at supportive sites and/or
           the Hawthorne effect clinical trials services (see operations manual).

           2.2. Stratification, Randomization, and Blinding/Masking

           Randomization will occur by a secure central online, computer-generated random number
           system in REDCap. Randomization will be stratified by baseline SJS/TEN prognosis
           (SCORTEN) and will occur in randomly varying blocks of sizes 3 and 6. 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 physicians and
           outcome assessors will be blinded to the allocated treatment. All patients will receive
           supportive care, either with a double placebo or with their study drug (cyclosporine or
           etanercept) plus placebo. The central randomization scheme will provide the site
           pharmacist with a unique drug code corresponding to either study drugs and matching
           placebos. These will be kept in identical, coded containers. Only the study central
           pharmacy and the site pharmacy who will prepare the preparations for blinding will be
           aware of the coding scheme. Masking will be carried out as follows:

             -  Cyclosporine: The study drug is given as per protocol for 2 weeks. A single SC
                injection is given on study day 0 of admission and study day 3.

             -  Etanercept: Study drug given as per protocol on study days 0 and 3. Receive IV
                normal saline for 2 weeks to mimic the cyclosporine schedule.

             -  Supportive therapy: A single saline SC injection on study day 0 and study day 3 of
                admission and an additional 14 days of IV normal saline placebo to mimic the
                cyclosporine schedule 2.2.1. Procedure for Unblinding/Unmasking Unblinding must be
                approved by the study medical monitor unless an immediately life-threatening
                condition has developed, and the medical monitor is not available. The site
                investigator will notify the protocol chair(s) and the study statistical and
                clinical coordinating center of the unblinding event by the next business day. The
                emergency unblinding will also be reported to the Data and Safety Monitoring Board
                (DSMB). A full account of the event will be recorded, including the date, time of
                the unblinding, the reason or the decision to unblind and the name of the
                individual who made the decision and the names of the Medical Monitor, and others
                who were notified. The reasons for unblinding of a participant's treatment will be
                included in the final study report. Unblinding the study due to an approved interim
                analysis, final analysis, or study termination will require written approval from
                the institute sponsor (NIAID).

        3. Selection of Participants and Clinical Sites/Laboratories 3.1. Rationale for Study
           Population Subject enrollment will reflect the population at large in our participating
           centers. All subjects who meet inclusion criteria will be screened for enrollment into
           the study. We will not discriminate based on sex, race, or ethnicity. Females, including
           those of childbearing potential, will be included in the trial.

           Supportive care High-quality supportive care is always used in the treatment of SJS/TEN.
           We know it can decrease the chance of serious complications and death even in the
           absence of adjuvant medications to treat the condition.

           There are no significant side effects associated with supportive care aside from
           possible discomfort with dressing changes.

           3.5. Risks of Other Protocol Specified Medications Cyclosporine

           The risks of the venipuncture (bruising at the site and very low risk of infection)
           apply as cyclosporine is an intravenous medication. There is extensive experience with
           this medication in SJS/TEN for the treatment of other conditions. In general, few side
           effects have been seen when used for SJS/TEN. When they have occurred, they have had no
           long-term impact on the person receiving the medication. Risks include:

           Less likely (5% to 20%):

             -  Mild changes in kidney function: 1-6% had mild changes in their kidney function
                that required a change of dose; Serious infections were not more common than those
                treated with short-term use, as proposed in this study. Flu-like illness symptoms
                and a predisposition for lung infections have been experienced in 8- 10% of
                patients with long-term use (months to years).

           Rare (1% to 4%):

           • Hypertension: 1-3% needed to have their blood pressure lowered. Very rare but serious
           (less than 1%): Severe liver or kidney problems may be permanent in those taking
           cyclosporine for greater than one 1year. Patients receiving cyclosporine under the
           NATIENS protocol will undergo treatment for a short amount of time; therefore, the
           chance of this occurring in this study is extremely unlikely. Close monitoring for
           hepatic or renal dysfunction is built into the NATIENS study protocol.

           Discontinuing the study medication in the case of imminently organ-threatening effects,
           type I allergy, or rare immune reactions (e.g., thrombotic thrombocytopenic purpura] in
           the case of cyclosporine) will be documented. Cyclosporine would be the only arm where
           this may occur as the protocol is for 2 weeks of therapy.

           An investigator and research coordinator will be available 24 hours a day from both the
           Vanderbilt Coordinating Center and Ottawa Coordinating Center. The consent form has
           contact numbers for reaching study personnel. In the event an investigator or research
           coordinator is on vacation or out-of-town, appropriate coverage will be provided.

           The safety of the participant will remain of primary importance. All patients will
           undergo intensive monitoring while in hospital in accordance with usual ICU and Burn
           Unit practices.

           3.6. Risks of Study Procedures Venipuncture and Blood Samples: The protocol requires
           patients to have blood drawn for research purposes. The risks of drawing blood are
           uncommon and may include bleeding, minor infection, and bruising. Blood draws may be
           painful. Some people may feel faint or dizzy. The amount of blood drawn represents a
           small percentage of the amount of the total blood volume and will not represent a
           significant risk to the patient. Samples are planned to align with blood samples taken
           in the course of usual clinical care to minimize the need for repeat venipuncture. Blood
           sampling is performed by trained nurses or phlebotomists with experience performing
           venipuncture. We have also aligned our study-related blood samples with those taken for
           usual patient care. Multiple tests are also performed on blood from the same sample
           tubes. This minimizes the volume of blood required to complete Aims 2 and 3 as well as
           significantly reduces the number of needle sticks.

           Tissue Samples: Tissue samples will be taken to understand the disease process of
           SJS/TEN. A sample of healthy skin, where possible, will be taken for comparison. Where
           samples of normal skin can be taken, this will be discussed with the patient. Some
           patients have little healthy skin to sample. Risks primarily include minor bleeding, a
           small chance of infection, and a small scar.

           All tissue sampling will be done by an experienced physician to reduce the risk of
           complications.

           Salivary Swab: There are no significant risks associated with the saliva samples being
           collected. In those with oral mucosal involvement due to SJS/TEN, there may be
           irritation or a small degree of discomfort while producing a sample.

           Blister Fluid Collection: This process involves aspirating fluid from an intact blister.
           There is a very low risk of infection, but there is no discomfort with the procedure.

        4. Investigational Agent /Device/Intervention (see investigators brochure, section 5) 4.1.
           Drug Accountability Under Title 21 of the Code of Federal Regulations (21CFR §312.62),
           the investigator will maintain adequate records of the disposition of the
           investigational agent, including the date and quantity of the drug received, to whom the
           drug was dispensed (participant-by-participant accounting), and a detailed accounting of
           any drug accidentally or deliberately destroyed.

           Records for receipt, storage, use, and disposition will be maintained by the study site.
           A drug-dispensing log will be kept current for each participant. This log will contain
           the identification of each participant and the date and quantity of drug dispensed. All
           records regarding the disposition of the investigational product will be available for
           inspection. Any remaining product will be destroyed in accordance with pharmacy
           regulations.

           4.2. Assessment of Participant Compliance with Investigational Agent All medications
           will be administered by the investigator and/or study staff in the Burn Unit.
           Administration of study medication(s) will be witnessed by the investigator and/or study
           staff. The total volume of study medication-infused will be compared with the total
           volume prepared to determine compliance with each dose administered.

           4.3. Toxicity Prevention and Management Etanercept: No modifications are permitted.
           Cyclosporine: The study is blinded and the adjustment and stopping rules that primarily
           apply to cyclosporine will be carried out by an unblinded pharmacists according to
           well-defined rules. A table will be provided for anticipated severe drug interactions
           with cyclosporine and for patients where those drugs are necessary these patients may be
           excluded from the study. Non-serious medication side-effects such as diastolic
           hypertension or mild renal failure will be medically managed while still maintaining
           blinding. For example, standard adjustments for cyclosporine will be made based on serum
           creatinine and blood pressure monitoring. These orders will be written and carried out
           by an unblinded pharmacist. The adjusted dose will appear on the IV bag
           cyclosporine/placebo and the treating team will remain blinded as to the treatment arm
           of the patient. Creatinine will be monitored daily by a non-blinded pharmacist at each
           site for all patients. A standard dose-adjustment algorithm to maintain a target
           creatinine of <130% above baseline will be used. Down-dosing of 25-30% will be used if
           diastolic blood pressure >100 mm. If >3 dose adjustments, 48-hours apart fail to control
           rises in creatinine beyond this threshold, cyclosporine is stopped. Any study treatment
           will also be stopped in the presence of any grade 3-4 toxicity (e.g.
           leukoencephalopathy) or creatinine >150% of initial value and diastolic blood pressure
           >110 or systolic persistently > 160 mmHg which is a common indicator of cyclosporine
           toxicity.

           6.5 Premature Discontinuation of Investigational Agent Patients who discontinue any
           study medication will be analyzed by intent-to-treat analysis and followed for
           complications of SJS/TEN as per study protocol. Stopping for lack of efficacy will occur
           according to pre-described stopping rules. Study therapy may be prematurely discontinued
           for any participant for any of the following reasons:1. Grade 3 or 4 toxicity 2.
           Toxicity that has not responded to clinical management (see cyclosporine above); 3.
           Necessary medication that interacts with cyclosporine (as per protocol table) 4. Patient
           request. All patients are administered the drug in the ICU and are monitored around the
           clock for adverse signs and symptoms by the investigator and/or study staff. If adverse
           signs are observed, patients will be evaluated by physicians from various specialties
           including intensive care, and dermatology. Following evaluations, decisions will be
           taken to decrease, adjust, or stop the dosage. Each site will be individually managed
           for treating adverse reactions.

           Study therapy may also be prematurely discontinued for any participant if the
           investigator believes that the study treatment is no longer in the best interest of the
           participant.

        5. Other Medications 5.1. Concomitant Medications 5.1.1. Protocol-mandated 1% lidocaine
           with epinephrine at a dilution of 1:100,000 as local anesthesia at the time of
           obtainment of biopsy samples (for research biopsies) 5.1.2. Other permitted concomitant
           medications All topical agents for wound and eye care are permitted as outlined in the
           respective supportive care protocols.

           5.2. Prophylactic Medications Any non-interacting medications (as per cyclosporine
           protocol) may be administered at the discretion of the clinical team.

           5.3. Prohibited Medications 1) Medications that interact with cyclosporine where there
           are suitable alternatives20,21; 2) immunomodulatory agents other than those used in this
           clinical trial

           The following medications will be considered to be contraindicated during the course of
           the study. If patients are on these medications and an alternative is available it
           should be substituted:

           Aliskiren, atorvastatin, bosentan, cholic acid, cladribine, conivaptan, crizotinib,
           dronedarone, elagolix, enzalutamide, eplerenone, foscarnet, any new drug found to be a
           significant CYP3A4 inhibitor or p-glycoprotein/ABCB1 inhibitor). A complete list of
           interacting drugs, potentially interacting drugs is included in the operations manual.

           5.4. Rescue Medications Cyclosporine increases blood pressure. Blood pressure will be
           managed by administering non-interacting blood pressure-lowering drugs at the discretion
           of the treating physician. Cyclosporine could also decrease renal function. Patients
           will be managed as per standard of care protocols for patients with acute renal failure
           (see operations manual for detailed procedures).

        6. Study procedures (for laboratory procedures and sampling schedule, see section 5,
           comprehensive laboratory plan) Enrollment The research study will be explained in lay
           terms to each potential research participant. The potential participant will sign an
           informed consent form before undergoing any study procedures. Once informed consent has
           been signed and completed by both the participant and key study personnel, the
           participant is considered enrolled in the study and will be assigned a unique
           participant number. Consent will be obtained at the time of clinical encounter or
           diagnosis. To initially identify patients for consent, medical records may be reviewed
           for suitability or the admitting service (e.g., emergency, intensive care unit, burn
           surgery) may identify suitable patients to the study team. Then, a health care
           professional from the research team of key personnel will discuss the study with
           prospective participants (or substitute decision-makers) or obtain permission for the
           research personnel to discuss the study. In rare cases where emergency treatment is
           required (e.g., altered level of consciousness, lack of capacity), enrollment may still
           occur; however, confirmation of consent will be required by the research team at the
           first opportunity after the patient is initially managed or restoration of capacity
           occurs. Consent will be obtained from a substitute decision-maker or the patient at the
           earliest possible moment and the subject will be reconsented when their capacity for
           medical decision-making returns. A copy of the patient's consent will be kept in the
           patient's chart. It is available in English and Spanish. If consent is withdrawn at any
           time, it should be determined to what aspect of the study consent is being withdrawn
           (e.g., consent to the use of genetic samples or the study itself). In case of full
           withdrawal of consent, the treating team may modify any of the study procedures as per
           their medical judgment.

      8.1 Screening/Baseline Visit The purpose of the screening period is to confirm eligibility to
      continue in the study.

      The following procedures, assessments, and laboratory measures will be conducted to determine
      participant eligibility:

        1. Research staff will screen potential participants upon being notified of their admission
           to the ICU or Burn ICU based on the study inclusion/exclusion criteria. (so as written
           here - the subjects will be screened and consented here).

        2. A diagnostic punch biopsy will be obtained from the patient on the day of admission by
           the institution's appropriate staff. (is this a clinical biopsy or a research biopsy)

        3. The results of the diagnostic biopsy will be reviewed by research staff to determine
           eligibility to continue in the study within 2-3 days after admission.

      Randomization: will occur by a secure central online, computer-generated random number
      system. Randomization will be stratified by baseline SJS/TEN prognosis (SCORTEN) and will
      occur in randomly varying blocks of sizes 3 and 6. Subjects will be allocated 1:1:1 to
      cyclosporine plus best supportive care, etanercept plus best supportive care, or best
      supportive care alone. Continuation of the patient in the study will be contingent on a
      compatible clinical picture in combination with supportive pathology. Since pathology can
      take 48 hours to come back however subject randomization will occur prior to the availability
      of the biopsy results.

      Patients, treating physicians, and outcome assessors will be blinded to the allocated
      treatment. The central randomization scheme will provide the site pharmacists with a unique
      drug code corresponding to either study drugs or matching placebo. These will be kept in
      identical, coded containers. Only the study center and site pharmacy will be aware of the
      coding scheme. Masking will be carried out as follows: 1) Cyclosporine: study drug given as
      per protocol for 2 weeks. A single SC injection is given on Day 1 of admission. With a second
      injection given on day 4 of admission.; 2) Etanercept: Study drug given as per protocol.
      Receive IV normal saline for 2 weeks to mimic the cyclosporine schedule. Subcutaneous
      injection of etanercept given on study day 1 and study day 4; 3) Supportive therapy: A single
      saline SC injection on Day 1 and Day 4 to mimic etanercept and normal saline for 14 days to
      mimic the cyclosporine schedule.

      8.2 Study Visits or Study Assessments

      Also as listed in the research plan, facilities, and resources, and detailed laboratory
      plan).

      8.3 Unscheduled Visits (following discharge between 3 and 12-month follow-ups) Following
      discharge, the patient will be discharged to the care of their clinical team that will
      generally include follow-up with dermatology and ophthalmology at a minimum and if disease
      activity increase or other concerns arise they will be asked to liaise with the clinical team
      however study personnel should also be contacted and the participant may be asked to return
      for an "unscheduled" visit.

      9. Biospecimen Storage (see comprehensive laboratory plan) 10. Criteria for Participant and
      Study Completion and Premature Study Termination

      a. Participant Stopping Rules and Withdrawal Criteria

      Participants may be prematurely terminated from the study for the following reasons:

        1. The participant elects to withdraw consent from all future study activities, including
           follow-up.

        2. The participant is "lost to follow-up" (i.e., no further follow-up is possible because
           attempts to reestablish contact with the participant have failed). [use specific
           criteria to define "lost to follow-up"]

        3. The participant dies.

        4. The participant is withdrawn from the study.

        5. Individual safety stopping rules as defined under the study drugs section.

      Study stopping rules:

      We plan two interim analyses to allow early stopping for efficacy. These analyses will take
      place when we have acquired outcome measures for one-third and for two-thirds of the total
      target sample. We will use the Haybittle-Peto rule applied to each of the three pairwise
      Mann-Whitney comparisons of time to re-epithelialization between arms. As with the primary
      analysis, patients who die prior to achieving re-epithelialization will be allocated the
      maximum observed time to re-epithelialization plus one, so as to ensure that death is treated
      as worse than any time to successful treatment. One arm will be declared inferior to another
      if the p-value for the difference is less than 0.001. No adjustment will be made to the final
      analysis for interim testing. If one arm is found to be inferior to another arm, the Data
      Safety Monitoring Board will be instructed to strongly consider stopping recruitment to that
      arm. If one arm is found to be inferior to both other arms, the Data Safety Monitoring Board
      will be instructed to immediately stop recruitment in the inferior arm. If the other two arms
      also differ with a p-value less than 0.001, the recruitment will be stopped in all arms. We
      will have no formal stopping rules for safety outcomes different from time to
      re-epithelialization, but the Data Monitoring Committee will be explicitly mandated to
      carefully consider any safety signals with a view towards stopping recruitment if any
      expected or unexpected safety signal emerges.

      b. Participant Replacement If a participant withdraws or is withdrawn from the study, no
      further data or samples will be collected. The participant will not be replaced.

      c. Follow-up after Early Study Withdrawal Participants who withdraw from the study will be
      taken out of the study and no further data or samples will be collected. Study drugs and
      interventions will no longer continue after the patient is withdrawn from the study. Data and
      samples collected during the time of participation in the study will still be kept for study
      analysis.

      11. Safety Monitoring and Reporting (see data safety monitoring plan section 3.3)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Time to complete re-epithelialization
time frame: up to 4 weeks
description: 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)
measure: Time to halting of progression of SJS/TEN skin disease
time frame: up to 4 weeks
description: Progression will be considered significant if there are any new blistering lesions or any new detached or detachable skin.
measure: Mortality
time frame: up to 1 year
description: Number of participants with mortality at 30 days, 3 months and 1 year
measure: Mortality
time frame: up to 4 weeks
description: Number of participants with Actual mortality versus expected mortality for each SCORTEN risk
measure: Ocular involvement
time frame: up to 1 year or study outcome
description: 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
measure: Infections
time frame: up to 4 weeks
description: Incidence of nosocomial infections
measure: Hospital length of stay
time frame: up to 4 weeks
description: Duration of time in hospital
measure: Proportion of patients with Adverse events due to assigned treatment arm
time frame: up to 4 weeks
description: Adverse events due to assigned treatment arm
measure: Granulysin, IL-15 and other cytokine measurements
time frame: up to 1 year or study outcome
description: Featured exploratory secondary outcome measuring difference overtime within an individual as well as differences between treatment arms at various time measurements.
measure: Cyclosporine levels
time frame: up to 4 weeks
description: 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.
arm group label: Harmonized supportive care
arm group type: Placebo Comparator
description: Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3
arm group label: Cyclosporine 5mg/kg bid days 0-14
arm group type: Active Comparator
description: Harmonized supportive care with placebo etanercept days 0 and 3
arm group label: Etanercept 50mg sc day 0 and day 3
arm group type: Active Comparator
description: Harmonized supportive care with placebo cyclosporine days 0-14
intervention type: Drug
intervention name: Harmonized supportive care
description: Harmonized supportive care with placebo cyclosporine days 0-14 and etanercept placebo days 0 and 3
arm group label: Cyclosporine 5mg/kg bid days 0-14
arm group label: Etanercept 50mg sc day 0 and day 3
arm group label: Harmonized supportive care
intervention type: Drug
intervention name: Cyclosporine 5 mg/kg bid days 0-14
description: Harmonized supportive care with placebo etanercept days 0 and 3
arm group label: Cyclosporine 5mg/kg bid days 0-14
intervention type: Drug
intervention name: Etanercept 50 mg sc day 0 and day 3
description: Harmonized supportive care with placebo cyclosporine days 0-14
arm group label: Etanercept 50mg sc day 0 and day 3
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Elizabeth J Phillips, MD
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
last name: Elizabeth J Phillips, MD
phone: 615-310-0339
email: elizabeth.j.phillips@vumc.org
last name: Michelle Martin-Pozo, PhD
phone: 6153439672
email: michelle.martinpozo@vumc.org
facility: 
status: Recruiting
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Elizabeth J Phillips
investigator title: Principal Investigator
mesh term: Stevens-Johnson Syndrome
mesh term: Syndrome
mesh term: Cyclosporine
mesh term: Etanercept
mesh term: Cyclosporins
sharing ipd: No
ipd description: There are no plans to share individual participant data available to other researchers.
provided document: 