NATIENS: Optimal Management and Mechanisms of SJS/TEN
NATIENS: Optimal Management and Mechanisms of SJS/TEN
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 affect 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 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
 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 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 biobanked for later analysis for other transcriptomic, proteomic whole genome studies.
 These mechanistic studies will allow us to gain important insights into the
 immunopathogenesis of SJS/TEN. Our study will be the first to examine in a blinded randomized
 controlled design both management and mechanisms of SJS/TEN. We anticipate that this will
 lead to new ways to prevent, diagnosis and treat SJS/TEN, and will create a roadmap and
 evidence-base for studies in serious immunologically mediated adverse drug reactions and
 other immunologically mediated diseases.

 Interventions Supportive care is the current 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 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
 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 site 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 size 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 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
 hospital to occur at 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 size 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 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: Study drug given as per protocol for 2 weeks. A single SC injection
 given on study day 0 of admission and study day 3.

 -  Etanercept: Study drug given as per protocol on study day 0 and 3. Receive IV
 normal saline for 2 weeks as 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 immediate 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 required 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 for
 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 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 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 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.

 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 researchmpurposes. 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
 regulation.

 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 patents 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 be 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 biospies) 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, bosentin, cholic acid, cladribine, conivaptan, crizotinb,
 dronedarone, elagolix, enalutamide, 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-maker) 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 size 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 central 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 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 as to mimic the cyclosporine schedule. A 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 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)
Inclusion:

 -  Adult age 18 or older with clinical evidence of ongoing disease and with 3 or more of
 the criteria below with criteria 1 being mandatory:

 1. erythematous to dusky macules that show evidence of coalescing and/or denuding
 skin or blistering in a predominantly truncal dsitribution. Nikolsky sign
 (sloughing with direct lateral pressure on non-blistered but involved skin)s
 should be considered a supportive feature

 2. Mucous membrane involvement

 3. prodromal symptoms including fever,myalgia and headache

 4. Increasing number of lesions

 5. History of a new medication

 -  To continue with the study a skin biopsy obtained within 24 hours of admission
 demonstrating the following pathologic criteria are required:

 1. Confirmation of interface dermatitis and/or necrotic keratinocytes 2. Negative
 DIF for features that alter the diagnosis (autoimmune blistering disease)