NATIENS: Optimal Management and Mechanisms of SJS/TEN (NATIENS)
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|ClinicalTrials.gov Identifier: NCT02987257|
Recruitment Status : Not yet recruiting
First Posted : December 8, 2016
Last Update Posted : February 25, 2021
|First Submitted Date ICMJE||November 25, 2016|
|First Posted Date ICMJE||December 8, 2016|
|Last Update Posted Date||February 25, 2021|
|Estimated Study Start Date ICMJE||August 1, 2021|
|Estimated Primary Completion Date||August 1, 2026 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Time to complete re-epithelialization [ Time Frame: up to 4 weeks ]
Patients will be assessed by two independent raters (burn surgeons, dermatologists, wound care experts) to determine the day of full re-epithelialization. For disagreements on the day of re-epithelialization the case with supporting photographs will be referred to an independent adjudication committee comprised of a minimum of three experts (a burn surgeon, dermatologist, wound care expert). In the instance of death will be the maximum period of re-epithelialization (21 days + 1)
|Original Primary Outcome Measures ICMJE
||Time to complete re-epithelialization [ Time Frame: 3 weeks ]
Absence of erosion and compromised skin
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||NATIENS: Optimal Management and Mechanisms of SJS/TEN|
|Official Title ICMJE||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|
|Brief Summary||The NATIENS study is a phase III randomized study to examine the optimal treatment and mechanisms of each of two treatments (cyclosporine 5 mg/kg bid for 14 days versus etanercept 50 mg subcutaneously at day 0 and day 3) versus the current standard of care which is harmonized supportive care for the treatment of Stevens-Johnson Syndrome and toxic epidermal necrolysis (SJS/TEN). SJS/TEN is typically a drug-induced disease in adults with a mortality of up to 50% or higher in elderly adults. Although progress has been made in elucidating strong genetic risk factors that have led to pre-prescription screening and prevention the risk factors for most drugs and ethnicities represented in the United States are currently unknown. Currently there are a number of small observational studies and a non-blinded small randomized study however there is no strong or definitive evidence base to support any one treatment intervention over supportive care alone and this remains considered a standard of care for SJS/TEN. The primary objective of the study is to conduct a randomized double-blind double dummy stratified multicenter phase III study across 24 sites across the Unites States to determine whether two therapeutic interventions (etanercept versus cyclosporine) will improve short-term outcomes associated with SJS/TEN. The primary hypothesis of this study is that both etanercept and cyclosporine will show benefit over supportive care alone and that single dose etanercept 50 mg sc at days 0 and repeated 72 hours following initial dosing will show significant benefit over cyclosporine 5 mg/kg bid and supportive care alone. Our secondary outcomes are to determine the clinical outcomes at 3 and 12 months following initial presentation and to determine the molecular and cellular mechanisms of SJS/TEN through collection of timed samples to include DNA, RNA, PBMCs, blister cells and supernatant and skin. We hypothesize that patients will have significant sequelae identified at 3 and 12 months that will differ between treatment arms and that treatment interventions will significantly impact cytotoxic and cytokine signals with these biomarkers correlating with primary and secondary outcome. We also hypothesize that significant genetic associations will be found in association with drug-induced SJS/TEN. Eligible patients are >/= 18 who meet evidence for SJS/TEN clinical criteria as evidence by erythematous/dusky macules coalescing or denuded skin and blistering with positive Nikolsky sign which is mandatory criteria associated with mucous membrane involvement, prodromal symptoms including fever, myalgia and headache, increasing number of lesions and history of a medication. To continue with the study patients must meet pathological criteria. Randomization will occur by a secure central online computer-generated random number system through REDCap. Subjects will be allocated 1:1:1 to cyclosporine plus best supportive care, etanercept plus best supportive care or best supportive care alone. Patients, treating physician and outcome assessors will be blinded to the allocated treatment. The primary outcome of the study is time to complete re-epithelialization as defined by complete absence of erosion and compromised skin. Time to expected re-epithelialization of 21 days is the maximum healing time with supportive care in SJS/TEN patients which reflects the healing time of adult skin. The primary outcome will be independently assessed by the treating team to include any of a burn surgeon, dermatologist or wound specialist. Disagreement will be solved by independent adjudication by a minimum of two reviewers. Patients who have to discontinue a study medication will be analyzed by intent-to-treat analysis and followed for complications of SJS/TEN as per study protocol. Secondary outcomes of the study include: 1)time to halting of progression of SJS/TEN skin disease. Progression will be considered significant if there are any new blisters or erosions and halting of progression is defined as absence of these criteria with any new lesions; 2) all-cause mortality at 30 days, 3 months and 1 year following symptoms onset; 3) composite cause-specific mortality - outcome including death from sepsis, multi-organ failure and acute respiratory distress syndrome; 4) actual mortality versus expected mortality (as calculated by SCORTEN); 5) Time to cessation of acute ocular involvement (this will be tracked by the same serial photography evaluated by two independent Ophthalmology experts in SJS/TEN eye disease; 6) incidence of infections; 7) hospital length of stay; 8) adverse events due to therapy; 9) serial plasma granulysin, IL-15 concentrations (and other relevant biomarkers);10) Follow-up 3 months and 1 year from initial presentation for physical and mental health complications. For aims 2 and 3 a number of mechanistic studies will be performed on paired samples (DNA, RNA, PBMCs, plasma, blister fluid and skin).|
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.
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:
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:
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)
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Not yet recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||August 1, 2027|
|Estimated Primary Completion Date||August 1, 2026 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT02987257|
|Other Study ID Numbers ICMJE||200662|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Elizabeth J Phillips, Vanderbilt University Medical Center|
|Study Sponsor ICMJE||Vanderbilt University Medical Center|
|PRS Account||Vanderbilt University Medical Center|
|Verification Date||February 2021|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP